Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:25]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[O:28])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](OCC2C=CC=CC=2)=[O:12])[C@H:7]([CH3:21])[CH2:6]1.CCN(CC)CC.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[NH:57]1[CH2:60][CH2:59][CH2:58]1>CO.C1COCC1.[Pd]>[N:57]1([C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]3[C:2]([F:1])=[C:25]([NH:26][C:27]([NH:29][C:30]4[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[O:28])[CH:24]=[CH:23][CH:22]=3)[CH2:6][C@H:7]2[CH3:21])=[O:12])[CH2:60][CH2:59][CH2:58]1
Reactant: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(C(=O)OCc4ccccc4)[C@H](C)C3)c2F)cn1
Reactant: C1CNC1
Agent: [Pd]
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(C(=O)N4CCC4)[C@H](C)C3)c2F)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
To a solution of (R)-benzyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate (7.0 g, 14.3 mmol, 1.0 equiv) in MeOH (50 mL) was added 10% Pd/C (approx. 5 g). The resulting suspension was stirred and sparged with hydrogen gas using a balloon and needle. After 1 h, reaction was complete, as determined by LCMS. The mixture was filtered through a pad of Celite, and the celite pad was washed with additional methanol. The mixture was concentrated in vacuo, and 2.55 g (7.14 mmol) of the resulting residue was dissolved in dry THF (35 mL). To this room temperature solution was added Et3N (4.0 mL, 28.6 mmol, 4.0 equiv), followed by 4-nitrophenyl chloroformate (1.58 g, 7.85 mmol, 1.1 equiv). After 15 min, the reaction was complete, as judged by LCMS. Azetidine (530 μL, 7.85 mmol, 1.1 equiv) was added by syringe. After 1 h, additional azetidine (265 μL, 3.9 mmol, 0.5 equiv) and Et3N (500 μL, 3.6 mmol, 0.5 equiv) were added by syringe, and the reaction mixture was heated to 60° C. overnight. The reaction was the allowed to cool to room temperature, and the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed three times with 1 N NaOH, and once with brine. The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel (20% MeOH/DCM) provided (R)-1-(3-((4-(azetidine-1-carbonyl)-3-methylpiperazin-1-yl)methyl)-2-fluorophenyl)-3-(6-methylpyridin-3-yl)urea as a white foam (885 mg, 28%). LCMS m/z (APCI)=441.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.O=[C:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10](OC)=[O:11]>C1(C)C=CC=CC=1>[CH2:14]([C:8]1[CH:9]=[C:10]([OH:11])[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Nc1cc[nH]n1
Reactant: CCCCC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: CCCCc1cc(O)n2nccc2n1
Temperature: 100 °C
Yield: 80.1 %

Procedure:
A suspension of 100 g of 3-aminopyrazole and 190 g of methyl 3-oxoheptanoate in 120 ml of toluene was heated under reflux at 100° C. for 3 hours and cooled. Toluene was distilled off under reduced pressure, and diethyl ether was added to the residue. The crystals precipitated were collected and sequentially washed with diethyl ether and acetonitrile to provide 184 g of 5-n-butyl-7-hydroxypyrazolo[1,5-a]pyrimidine as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1 below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(COC)OC>[C:26]1([S:32]([N:11]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Fc1ccc(-c2nc[nH]c2-c2ccc(F)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)n1cnc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a stirred mixture of 10.0 g (0.04 mole) of 4,5-bis(4-fluorophenyl)imidazole and 4.8 g (0.043 mole) of potassium t-butoxide in 150 ml glyme at 0° was added dropwise a solution of 7.6 g (0.043 mole) of benzenesulfonyl chloride in 25 ml glyme. The mixture was stirred at 0° one hour, then at room temperature overnight. The mixture was poured into ice water and the solid was collected and air dried to give 15.2 g, mp 172°-5°. Recrystallization from toluene/methylcyclohexane gave 12.3 g of 1-benzenesulfonyl-4,5-bis(4-fluorophenyl)imidazole as a white solid, mp 181°-2°.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C([N:14](CC)CC)C.S(Cl)(Cl)=O>O1CCCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:14])=[O:6]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cccc(Br)c1F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cccc(Br)c1F
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a solution of 3-bromo-2-fluorobenzoic acid (3.77 g, 17.2 mmol) in dry tetrahydrofuran (200 ml) was added triethylamine (4.77 ml, 34.4 mmol) and thionyl chloride (1.69 ml, 21.5 mmol). The reaction mixture was stirred for 1 h and then quenched with ammonia in methanol (10 ml, saturated). After an additional hour of stirring the mixture was evaporated and the crude product was purified by flash column chromatography (ethyl acetate/isooctane 1:1) to give the title compound (1.76 g). MS m/z (rel. intensity, 70 eV) 219 (M+, 26), 217 (M+, 26), 203 (62), 201 (70), 94 (bp).
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]=12.[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C=O)C>[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23][N:2]1[CH:3]=[C:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2=[N:1]1
Reactant: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2cn(COCC[Si](C)(C)C)nc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (20 g, 96 mmol) in DMF (200 mL) at 0° C. was added sodium hydride (4.21 g, 105 mmol). After stirring for 1 h at RT, 2-trimethylsilylethoxymethyl chloride (SEM-Cl) (4.65 mL, 26.3 mmol) was added. The resulting mixture was stirred at RT overnight. The mixture was quenched with saturated NH4OH, and the solvents were removed. The residue was diluted with ethyl acetate (500 mL), washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on a silica gel Biotage 65i® column, eluting with 0 to 20% ethyl acetate in hexanes to give the title compound as a colorless gum. LC-MS: 340.1 (M+H)
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[CH2:10]([N:17]1[CH2:24][CH:23]2[O:25][CH:19]([CH2:20][NH:21][CH2:22]2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:26]([NH2:30])(=[O:29])[CH:27]=[CH2:28]>C(O)C>[CH2:10]([N:17]1[CH2:24][CH:23]2[O:25][CH:19]([CH2:20][N:21]([CH2:28][CH2:27][C:26]([NH2:30])=[O:29])[CH2:22]2)[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=CC(N)=O
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)CCN1CC2CN(Cc3ccccc3)CC(C1)O2
Yield: 77.2 %

Procedure:
Triethylamine (3.60 g, 35.7 mmol) was added slowly to a solution of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (see Preparation B(iv) above; 5 g, 17 mmol) in ethanol (50 mL). Acrylamide (1.34 g, 18 mmol) was added to this mixture, which was then heated at reflux for 7 hours. The reaction mixture was then concentrated under reduced pressure. Water (50 mL) and sodium hydroxide (1 M, 150 mL) were added to the residue and the mixture extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a colourless solid. This was recrystallised from ethyl acetate (50 mL) to give the sub-title compound (3.80 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7]1.CN1CCOCC1.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>C(Cl)Cl>[Cl:30][C:22]1[CH:21]=[C:20]([C@@H:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([NH:11][C:8]2[CH:9]=[CH:10][N:6]([CH2:5][C:4]3[CH:32]=[CH:33][CH:34]=[C:2]([NH:1][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])[CH:3]=3)[N:7]=2)=[O:31])[CH:25]=[CH:24][C:23]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CCS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(N)c3)n2)cc1Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCS(=O)(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.7 %

Procedure:
N-[1-(3-Amino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared in example 58, 110 mg, 0.22 mmol) was dissolved in methylene chloride (2 mL) and N-methyl-morpholine (26 μL, 0.24 mmol) was added. Ethanesulfonyl chloride (21 μL, 0.22 mmol) was added and the reaction stirred at 25° C. for 30 min. The reaction was warmed to 80° C. for 4 h. The reaction was concentrated in vacuo to give a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 60% ethyl acetate/methylene chloride) followed by preparative thin layer chromatography (Merck Silica gel 60 F254, 500 μm, 20×20 cm; 50% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-ethanesulfonylamino-benzyl)-1H-pyrazol-3-yl]-propionamide (14 mg, 11%) as a white powder: ESI-LRMS m/e calcd for C27H33ClN4O5S2 [M+] 592.2, found 593.7 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.16 (m, 2H, CH2), 1.14 (t, J=7.3 Hz, 3H, CH3), 1.37-1.83 (m, 8H, 4×CH2), 2.01-2.16 (m, 1H, CH), 3.03 (q, J=7.3 Hz, 2H, SO2CH2), 3.32 (s, 3H, SO2CH3), 3.84-3.92 (m, 1H, CH), 5.15 (s, 2H, NCH2), 6.46 (d, J=2.2 Hz, 1H, Ar), 6.88 (d, Jo=7.7 Hz, 1H, Ar), 7.01 (t, Jm=1.6 Hz, 1H, Ar), 7.06-7.14 (m, 1H, Ar), 7.24 (t, Jo=7.7 Hz, 1H, Ar), 7.56 (dd, Jo=8.2, Jm=1.6 Hz, 1H, Ar), 7.66 (d, Jm=1.6 Hz, 1H, Ar), 7.69 (d, J=2.2 Hz, 1H, Ar), 7.98 (d, Jo=8.2 Hz, 1H, Ar), 9.75 (s, 1H, NH), 10.78 (s, 1H, NH).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)#[N:2].C[Si](C#N)(C)C.[OH:19]C1C=CC=C2C=1C=CC=[N+]2[O-].C(N(CC)CC)C>CC#N>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:19])[N:4]=1)#[N:2]
Reactant: [O-][n+]1cccc2c(O)cccc21
Reactant: N#Cc1ccc2ccccc2n1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(O)cccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Typical procedure to prepare 2-cyanoquinoline from N-oxide: Preparation of 2-cyano-5-hydroxyl-2-quinoline: Trimethylsilyl cyanide (12.4 ml) was added into a solution of 5-hydroxyl-quinoline N-oxide (5 g) with triethylamine (13 ml) in MeCN. After the reaction was stirred at room temperature for 12 hours, solvents were removed under vaccum to provide a residue which was then partitioned between saturated NaHCO3 solution (100 ml) and EtOAc (100 ml). The aqueous solution was then extracted with EtOAc (2×100 ml). And the combined organic layer was dried over anhydrous MgSO4, filtered and concentrated to afford a crude product which purified by silica gel column chromatography to provide 5.3 g of 2-cyano-5-hydroxylquinoline. MS m/z: (M+H)+ calcd for C10H7N2O 171.06, found 171.03. HPLC retention time: 1.22 minutes (column I).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1Cl

Procedure:
A solution of 2-chlorophenylacetic acid (10.0 g) in methanol (100 ml) containing 1 drop of concentrated sulphuric acid was heated at reflux for 2 hours. The reaction mixture was evaporated to half volume and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was dried over magnesium sulphate and evaporated to give the title compound (10.0 g) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[N:6]=[CH:5]2.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:16])[N:6]=[CH:5]2
Reactant: Oc1ncc2c(F)c(Br)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1c(Br)ccc2nc(Cl)ncc12

Procedure:
A solution of 6-bromo-5-fluoroquinazolin-2-ol (3.0 g, 12.34 mmol) in phosphoryl trichloride (10 mL) was refluxed at 135° C. for 5 hours. Most of phosphoryl trichloride was removed under reduced pressure, and the residue was dropwise added to ice water (200 mL). The resulting precipitate was collected via filtration as a yellow solid (3.1 g, 96%). MS (ES+) C8H3BrClFN2 requires: 260, found: 261, 263 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:23])[NH:7][C:8](=[N:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])[CH3:3].Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:45][S:46]([N:49]1[CH2:54][CH2:53][N:52]([C@@H:55]2[CH2:59][NH:58][C@H:57]([C:60]([NH:62][C:63]3[CH:75]=[CH:74][C:66]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[CH:65][CH:64]=3)=[O:61])[CH2:56]2)[CH2:51][CH2:50]1)(=[O:48])=[O:47]>C1COCC1>[CH3:19][C:18]([O:17][C:16]([NH:15][C:8]([N:9]1[CH2:10][CH2:11][N:12]([C:25]([N:58]2[CH2:59][C@@H:55]([N:52]3[CH2:53][CH2:54][N:49]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:50][CH2:51]3)[CH2:56][C@H:57]2[C:60]([NH:62][C:63]2[CH:75]=[CH:74][C:66]([C:67]([O:69][C:70]([CH3:72])([CH3:71])[CH3:73])=[O:68])=[CH:65][CH:64]=2)=[O:61])=[O:27])[CH2:13][CH2:14]1)=[N:7][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:23])=[O:22])([CH3:21])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCN(C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a solution of the compound prepared in Example 28 (0.05 g, 0.15 mmol) in THF (10 mL), triphosgene (0.054 g, 0.182 mmol) and N,N-diisopropylethylamine (0.08 mL, 0.456 mmol) were added at 0° C. and the reaction mixture warmed to room temperature. After stirring for 1 h, the reaction mixture was concentrated to dryness and the crude residue was dissolved in THF. To this mixture, the compound prepared in Example 6 (0.065 g, 0.152 mmol) and N,N-diisopropylethylamine (0.08 mL, 0.456 mmol) were added at 0° C., and the reaction warmed to room temperature. After stirring for 4 h, the mixture was diluted with ice cold water and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine, dried and concentrated. Purification by flash chromatography (silica gel, 40 g, 20-60% ethyl acetate/hexanes) provided the title compound (0.045 g, 39%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH2:17][C:18]#[CH:19])=[N:4][C:5]2[CH:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][C:10]=2[N:11]=1.OS(O)(=O)=O.[OH-].[Na+]>>[Cl:1][C:2]1[C:3]2[N:4]([C:18]([CH3:19])=[CH:17][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[CH:6]=2
Reactant: C#CCNc1nc2cc3ccccc3cc2nc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc2c(Cl)nc3cc4ccccc4cc3n12
Temperature: 80 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
2-Chloro-3-(propargylamino)benzo[g]quinoxaline (0.420 g, 1.57 mmol) was treated with 4 mL of concentrated H2SO4 and the mixture was stirred at 80° C. for 1 hour, cooled to RT and poured into ice water. The mixture was cautiously neutralized with aqueous NaOH, and the resulting precipitate was filtered, washed with water, and dried in vacuo to give the title compound as a beige solid (0.124 g, 30%); mp 221-223° C.; IR (KBr, cm−1)1538, 1479, 1456, 1398, 1101, 919; 1H NMR (DMSO) δ 8.79 (s, 1H), 8.53 (s, 1H), 8.23 (d, J=8.1, 1H), 8.13 (d, J=8.5, 1H), 7.69-7.59 (m, 3H), 3.04 (s, 3H); LC/MS 100% (220 nm), m/z (M+H+) 268.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[CH2:14](Cl)[CH2:15]Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:28][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66](C)(C)[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH2:60])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>CN(C=O)C>[CH3:30][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][CH2:66][CH2:67][CH2:14][CH3:15])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH:60][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: ClCCCl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCOC(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)[C@@H](C)CC
Reaction time: 0.25 h

Procedure:
With the exclusion of air, 270 mg (1.43 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 513 mg (2.67 mmol) to EDC and 241 mg (1.78 mmol) of HOBT are dissolved in 7.8 ml of DMF. After stirring for 15 min, 0.75 ml (5.4 mmol) of TEA and 510 mg (0.89 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 25f) in 3.7 ml of DMF are added. After 20 hours, the mixture is worked up analogously to Example 25g to yield the title compound: HPLC20-100: tRet=18.5; FAB MS (M+H)+=743.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C:7]1[CH:16]=[CH:15][C:10]2[C:11](=[O:14])[O:12][CH2:13][C:9]=2[C:8]=1[Cl:17])[CH:5]=C.CSC>CO>[Cl:17][C:8]1[C:9]2[CH2:13][O:12][C:11](=[O:14])[C:10]=2[CH:15]=[CH:16][C:7]=1[CH2:4][CH:5]=[O:1]
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(c1Cl)COC2=O
Solvent: CSC
Solvent: CO
Product: O=CCc1ccc2c(c1Cl)COC2=O
Temperature: 25 °C

Procedure:
Ozone was bubbled through a solution of 5-allyl-4-chloro-2-benzofuran-1(3H)-one (80 mg, 0.38 mmol) in MeOH at −78° C. until it turned light blue. After excess ozone was removed by bubbling nitrogen through the solution, dimethyl sulfide (0.57 mL, 7.7 mmol) was added into the reaction. The solution was allowed to warm to RT. The crude material was purified by MPLC to provide (4-chloro-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. LC-MS (IE, m/z): 211 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[C:22]([F:29])[CH:21]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:26][C:24]1[CH:25]=[C:20]([C:18]#[C:17][CH:16]=[C:13]2[CH2:14][CH2:15][N:10]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:11][CH2:12]2)[CH:21]=[C:22]([F:29])[C:23]=1[O:27][CH3:28]
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: COc1c(F)cc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1c(F)cc(C#CC=C2CCN(c3ncccc3[N+](=O)[O-])CC2)cc1F
Temperature: 80 °C
Yield: 27.7 %

Procedure:
A mixture of Compound 1c (50 mg, 0.206 mmol), 4-bromo-2,6-difluoroanisole (45.9 mL, 0.206 mmol), bis(triphenylphosphine)palladium(II)dichloride (7.23 mg, 0.012 mmol), CuI (3.92 mg, 0.206 mmol) in anhydrous and degassed triethylamine (3 mL) was heated at 80° C. under a nitrogen atmosphere for 2 h in a sealed vessel. The reaction mixture was cooled, filtered on Celite, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 10:90) affording the title product (22 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2O.O=P(Cl)(Cl)[Cl:20]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2[Cl:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(Br)cccc2c1O
Product: CCOC(=O)c1cnc2c(Br)cccc2c1Cl

Procedure:
A solution of ethyl 8-bromo-4-hydroxyquinoline-3-carboxylate (2.0 g, 6.75 mmol) in POCl3 (10 mL) was heated at 80° C. for 3 h. Then the volatiles were removed and ice-water was added to the residue. The precipitated solid was filtered and dried to afford 1.8 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 9.26 (s, 1H), 8.44-8.37 (m, 2H), 7.79-7.64 (t, J=7.8 Hz, 1H), 4.48-4.43 (q, J=7.2, 14.1 Hz, 2H), 1.41-1.36 (t, J=6.9 Hz, 3H); MS (m/z): 314.01 (M+H)+.
Reaction SMILES: [ClH:1].O1[CH2:7][CH2:6]OCC1.[NH2:8][C:9]1[CH:13]=[C:12]([CH3:14])[NH:11][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(#N)CCCC>[ClH:1].[CH3:14][C:12]1[NH:11][C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([NH:8][C:9](=[NH:8])[CH2:10][CH2:15][CH2:6][CH3:7])[CH:13]=1
Reactant: CCOC(=O)c1[nH]c(C)cc1N
Reactant: C1COCCO1
Agent: Cl
Solvent: CCCCC#N
Product: CCCCC(=N)Nc1cc(C)[nH]c1C(=O)OCC
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Hydrogen chloride in dioxane (4M, 308 mL, 1.2 mol) was added dropwise to ethyl 3-amino-5-methyl-1H-pyrrole-2-carboxylate (38.3 g, 228 mmol) (J. Med. Chem. 2008, 51, 68) in valeronitrile (383 mL). The resultant mixture was heated at 50° C. overnight. An additional portion of acid (160 mL, 0.64 mol) was added and the mixture heated at 55° C. overnight. The reaction mixture was cooled to room temperature, filtered and the filtrate evaporated. The residue was slurried in TBME (1200 mL) for 30 minutes then the solid filtered and washed with TMBE and dried. The title compound was obtained as a brown solid (58.9 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:23][CH2:24][C:25](=[O:27])[CH3:26]>>[ClH:23].[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([CH2:24][C:25](=[O:27])[CH3:26])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)CCl
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Product: CC(=O)CN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 55, starting from 4-(5-(4-trifluoromethylphenyl)pyridin-2-yl)piperazine and chloroacetone.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[CH:38]([NH2:41])([CH3:40])[CH3:39]>>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24][NH:41][CH:38]([CH3:40])[CH3:39])[C:12]2=[O:26])[CH2:27][CH2:28]1)=[O:7]
Reactant: CC(C)N
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCCO)CN2c1ccccc1
Product: CC(C)NCCCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=571.1 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-hydroxy-propyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and isopropylamine.