Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:11][C:12](=[O:34])[CH:13]([C:23](=[O:33])[N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(#N)C>FC(F)(F)C(O)=O.ClCCl>[CH2:26]([N:24]([CH3:25])[C:23]([CH:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=1)[C:12]([NH:11][C@@H:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:3]([OH:35])=[O:2])=[O:34])=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C#N)cc1)C(=O)N(C)Cc1ccccc1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 240 h
Yield: 63 %

Procedure:
1.5 g (3.15 mmol) of the above [2-(R,S)-(Benzyl-methyl-carbamoyl)-3-(4-cyano-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid methyl ester was suspended in water/concentrated hydrochloric acid (1/1, 40 ml) and acetonitrile (40 ml) was added to give a solution. The reaction mixture was stirred at room temperature for 10 days. The reaction mixture was concentrated in vacuo and the residue lyophilized to give the desired product in 63% yield.
Reaction SMILES: [NH3:1].[CH2:2]1[CH:8]([S:9](Cl)(=[O:11])=[O:10])[CH2:7][S:4](=[O:6])(=[O:5])[CH2:3]1>O1CCOCC1.CO>[S:4]1(=[O:6])(=[O:5])[CH2:3][CH2:2][CH:8]([S:9]([NH2:1])(=[O:11])=[O:10])[CH2:7]1
Reactant: N
Reactant: O=S1(=O)CCC(S(=O)(=O)Cl)C1
Solvent: C1COCCO1
Solvent: CO
Product: NS(=O)(=O)C1CCS(=O)(=O)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Dioxane (30 mL) is saturated with ammonia and cooled down to 0° C. A solution of tetrahydrothiophene-3-sulfonyl chloride 1,1-dioxide (0.5 g; 2.3 mmol; 1 eq) in dioxane (5 mL) is then added dropwise over 10 min. The reaction mixture is allowed to return to room temperature and stirred for 3 h while keeping ammonia bubbling. The suspension is filtered through a short plug of silica using dioxane as eluent, and the resulting solution is concentrated in vacuo to give a slightly yellow oil. The oil is taken up in MeOH and the solvent is evaporated to dryness to afford 0.37 g (81%) of the title compound as a beige solid. 1H NMR (DMSO-d6) δ 7.25 (s, 2H), 3.98 (quint., J=8.3 Hz, 1H), 3.49 (dd, J=14.0, 9.1 Hz, 1H), 3.38-3.14 (m, 3H), 2.50-2.24 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](OCC)(=[O:26])[CH3:25].O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH2:25][CH2:24][OH:26])[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CC=C(c2c[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.0 g, 0.00462 mol) and triethylamine (0.77 ml, 0.00555 mol) in DMF (60 ml), was added dropwise under nitrogen 2-bromoethanol (0.42 ml, 0.00555 mol) then allowed to stir at room temperature overnight. Workup involved addition of ethyl acetate (80 ml) and water (50 ml), the organic layer was washed with water (4×50 ml). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 2-(4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethanol as a yellow solid 1.02 g.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=1)[CH2:6]Br)[CH3:2].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].O>CN(C)C=O>[Cl:14][C:13]1[C:8]([C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][N:20]2[C:19](=[O:21])[C:18]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]3[C:16]2=[O:26])=[N:9][CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCON=C(CBr)c1ncc(Cl)cc1Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
To 3.00 g of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone-O-ethyloxime in 20 ml of N,N-dimethylformamide, 2.32 g of potassium phthalimide was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was mixed with 50 ml of water and extracted with ethyl acetate (100 ml×1), the resulting organic layer was washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was washed with 10 ml of diisopropyl ether to obtain 3.08 g of the desired product as white crystals. m.p.: 99.0 to 101.0° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH:1]1([N:6]2[C:7]3[C:12](=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=3)[CH:13]=[CH:33][S:34]2(=[O:36])=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(C1CCCC1)S(=O)(=O)C=C2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
A solution of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (prepared as described in WO 98/33798 (incorporated herein by reference)) (30 g, 126 mmol) was suspended in dry THF (700 mL) under argon, and the mixture was cooled to −70° C. A solution of lithium bis(trimethylsilyl) amide, 1.0M in hexane (316 mL, 316 mmol) was added dropwise with stirring over 30 minutes. A solution of methanesulfonylchloride (10.5 ml, 136 mmol) in dry THF (25 mL) was added over 5 minutes, and then the reaction mixture was left to stir at −55° C. for at least 1 hour. An additional portion of methanesulfonylchloride (9 ml, 78 mmol) was added over 2 hours as the temperature was allowed to reach 0° C. The reaction was then cooled to −70° C. and left undisturbed overnight. The reaction mixture was then evaporated in vacuo to an oil and poured into a mixture of diethyl ether (1 L) and 1N citric acid solution (375 ml). The pH of the mixture was adjusted to 8 by addition of 4N NaOH, agitated, and the ether phase was decanted. The aqueous phase was extracted with diethylether, the organic phases were combined, washed with water, brine, and dried over anhydrous magnesium sulfate. After removal of the drying agent and evaporation of the solvent, the crude product was purified by chromatography on 300 g silica gel (10%–20% ethyl acetate in hexanes) to yield 7.01 g (18.7% yield) 1-Cyclopentyl-7-methylsulfanyl-1H-2-thia-1,6,8-triaza-naphthalene 2,2-dioxide as a colorless solid. MS: APCI: M+1: 298.1 (M: 297.4).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14](I)=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C(=O)([O-])[O-].[Na+].[Na+].O1CCO[CH2:33][CH2:32]1>O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH:32]=[CH2:33])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: C1COCCO1
Reactant: COc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=Cc1nn(C(C)c2cc(Cl)c(C)c(Br)c2OC)c2ncnc(N)c12
Temperature: 95 °C
Reaction time: 4 h

Procedure:
Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (12 mg, 0.017 mmol) was added to a mixture of vinyl boronic acid MIDA (110 mg, 0.6 mmol, from Aldrich, item #704415), 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.30 g, 0.57 mmol) and sodium carbonate (0.14 g, 1.1 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) and then the reaction was degassed with N2 3 times. The reaction was stirred at 95° C. for 4 h. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product was purified by chromatography eluting with CH2Cl2/EtOAc (max. EtOAc 60%). LCMS calculated for C17H18BrClN5O (M+H)+: m/z=422.0; Found: 422.2.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25]>O1CCCC1>[CH3:22][O:21][C:19](=[C:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)[O:20][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: COC(=O)C1CCOCC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(O[Si](C)(C)C)=C1CCOCC1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of diisopropylamine (1.6 g, 0.016 mol) in tetrahydrofuran (4 mL) was added dropwise n-butyllithium (1.59 M in hexane, 9.2 mL, 0.014 mol) at 0° C. under nitrogen, and stirred for 20 min. Then, the reaction mixture was cooled to −40° C., methyl tetrahydro-2H-pyran-4-carboxylate (1.9 g, 0.013 mol) and trimethylsilyl chloride (2.0 mL, 0.015 mol) in tetrahydrofuran (1 mL) was added, and the resulting mixture was gradually warmed to room temperature over 3 h. The volatile components were removed by evaporation and the residue was filtered through a pad of celite washing with hexane. The filtrate was dried in vacuo to give 2.9 g (quant.) of the title compound as a clear yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[OH:13].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccc(OC)c1O
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(OC)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of methyl 3-methoxysalicylate (1.0 g, 5.49 mmol) in 5 ml tetrahydrofuran and 5 ml dimethylformamide was added sequentially at room temperature, benzyl alcohol (0.71 ml, 6.86 mmol), triphenylphosphine (2.16 g, 8.23 mmol) and diethyl azodicarboxylate (1.3 ml, 8.23 mmol). The reaction solution was stirred at room temperature overnight, then ethyl acetate was added and the resulting solution was washed sequentially with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was triturated with diethyl ether and filtered to remove triphenylphosphine oxide. The ether solution was concentrated to dryness in vacuo and the residue was purified by column chromatography on silica gel, eluting with 95:5 hexane/ethyl acetate, yielding the title compound as an oil (870 mg 58% yield). MS (M+1)+273.1
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[O:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16](O)[CH2:15][CH2:14]1.[SH:24][C:25]1[N:29]=[CH:28][NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.N1C=CC=CC=1.ClCCl>[O:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]([S:24][C:25]2[N:29]=[CH:28][NH:27][N:26]=2)[CH2:15][CH2:14]1
Reactant: Sc1nc[nH]n1
Reactant: OC1CCOc2ccccc21
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: c1ccc2c(c1)OCCC2Sc1nc[nH]n1
Yield: 47.2 %

Procedure:
To a mixture of triphosgene (95 mg) and dichloromethane (4 ml), with stirring, were added pyridine (82 μl) and 4-chromanol (150 mg) in this order with cooling it on an ice bath. Additional pyridine (82 μl) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was added to a mixture of 3-mercapto-1H-1,2,4-triazole (110 mg), anhydrous potassium carbonate (200 mg) and N,N-dimethylformamide (2 ml), and stirred overnight. The reaction solution was washed with water, followed by saturated aqueous sodium chloride solution, and concentrated. The residue was subjected to a silica-gel column chromatography with 50% ethyl acetate/hexane to yield the title compound (110 mg).
Reaction SMILES: [N:1]([O-])=O.[Na+].S(=O)(=O)(O)O.[CH3:10][S:11]([C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH2:16])(=[O:13])=[O:12].C(O)(=O)CC.[C:29]([NH:33][S:34]([C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][C:43]=2[NH:47][S:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([S:57]([F:60])(=[O:59])=[O:58])[CH:52]=2)(=[O:50])=[O:49])[C:38]=1[OH:61])(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>N1C=CC=CC=1.C(O)(=O)C>[C:29]([NH:33][S:34]([C:37]1[CH:46]=[C:45]([N:1]=[N:16][C:15]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=2[S:11]([CH3:10])(=[O:13])=[O:12])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][C:43]=2[NH:47][S:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([S:57]([F:60])(=[O:59])=[O:58])[CH:52]=2)(=[O:49])=[O:50])[C:38]=1[OH:61])(=[O:36])=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: O=N[O-]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(NS(=O)(=O)c3cccc(S(=O)(=O)F)c3)cccc2c1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCC(=O)O
Solvent: CC(=O)O
Product: CC(C)(C)NS(=O)(=O)c1cc(N=Nc2ccc([N+](=O)[O-])cc2S(C)(=O)=O)c2c(NS(=O)(=O)c3cccc(S(=O)(=O)F)c3)cccc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 2-t-butylsulfamoyl-5-(3-fluorosulfonylbenzenesulfonamido)-4-(2-methylsulfonyl-4-nitrophenylazo)-1-naphthol was prepared by diazo coupling. 7.6 G. (0.11 mol) of sodium nitrite was added to 66 ml. of sulfuric acid at 5° C. and warmed to 70° C. to effect solution. After cooling to 25° C., 23.8 g. (0.11 mol) of 2-methanesulfonyl-4-nitroaniline was added, and the mixture stirred for 2 hours. The diazonium salt mixture was poured into 250 ml. of 1:5 acid (1 part propionic acid to 5 parts acetic acid) at 5° C. A solution of the coupler was prepared by dissolving 51.6 g. (0.1 mol) of 2-t-butylsulfamoyl-5-(3-fluorosulfonylbenzenesulfonamido)-1-naphthol in 66 ml. of pyridine, cooling to 10° C., and adding 520 ml. of the 1:5 acid at 30° C. The diazonium mixture was added to the coupler solution and stirred for one hour at 7° C., the solid collected on a filter funnel and then slurried twice in 500 ml. of 1% hydrochloric acid. The slurry was filtered and the solid dried in a desiccator at 60° C. to yield 25.8 g. of dye. The filtrates from the reaction mixture were diluted to 8000 ml. with water to precipitate additional dye, which was collected on a filter funnel and dried in a desiccator to yield an additional 40 g. (88% total).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[C:11]([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)([OH:12])[C:10]([CH2:20][O:21]COC)([CH3:19])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.CO>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:11]([CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)([OH:12])[C:10]([CH2:20][OH:21])([CH3:19])[CH2:9][CH2:8]2)=[CH:25][CH:26]=1
Reactant: COCOCC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)Cn1cncn1
Agent: Cl
Solvent: CO
Product: CC1(CO)CCC(Cc2ccc(Cl)cc2)C1(O)Cn1cncn1
Reaction time: 48 h

Procedure:
5-(4-Chlorobenzyl)-2-methoxymethoxymethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound (VII), R1=CH3, Ym=4-Cl, G=CH2OCH3, A=N) (629 mg, 1.66 mmol) was dissolved in methanol (6.3 ml), 10% hydrogen chloride-methanol (6.3 ml, 1.73 mmol) was added and stirring was conducted at room temperature for 48 hours. After completion of the reaction, the solvent was distilled away, and water was added. After ethyl acetate (80 ml) was added, an aqueous solution of sodium hydroxide was added until the pH became 10. The organic layer was separated, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled away to obtain the title compound (VI-1 (Compound (VI), (Ra2)Xa2na2(OH)pa1=CH3, (Rb2)Xb2nb2(OH)pb1=CH2OH, Ym=4-Cl, A=N, isomer type: C): VI-2 (Compound (VI), (Ra2)Xa2na2(OH)pa1=CH2OH, (Rb2)Xb2nb2(OH)pb1=CH3, Ym=4-Cl, A=N, isomer type: C): other isomers (isomer type: T)=6:3:1).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31]([OH:33])=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:68])[C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[C:64]([F:67])([F:66])[F:65])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[F:63][C:61]1[CH:60]=[CH:59][C:58]([C:64]([F:66])([F:65])[F:67])=[C:57]([CH:62]=1)[C:56]([N:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:31]([C:28]2[CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:30][N:29]=2)=[O:33])[CH2:51][CH2:52]1)=[O:68]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)on1
Temperature: 10 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
HOBt (38 mg, 0.28 mmol) and DIPEA (145 mg, 1.12 mmol) were added to a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid (43 mg, 0.22 mmol) in DMF (1.0 mL). Then reaction mass was cooled to 10° C. and EDCI.HCl (54 mg, 0.28 mmol) and 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (as TFA salt) (100 mg, 0.22 mmol) were added. Then resulting mixture was stirred at the room temperature overnight. The mixture was then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, evaporated and purified by column chromatography using silica gel (60-120 mesh) and 50% ethyl acetate in hexane as the eluant to afford 5-phenyl-isoxazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid in 49.1% yield. LC-MS purity: 95.66%, 1H NMR (DMSO-D6): δ 8.7 (t, 1H), 7.94 (m, 3H), 7.56 (m, 5H), 7.4 (s, 1H), 4.15 (m, 2H), 3.75 (m, 1H), 3.6 (m, 3H), 3.45 (m, 2H), 3.2 (m, 2H), 3.1 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:36])[CH2:15][NH:16][CH2:17][CH:18]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:36])[CH2:15][N:16]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:17][CH:18]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)CNCC(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)CN(CC(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Benzylchloroformate (1.4 mL, 9.81 mmol) is added dropwise to a solution of N,N-dimethylaminopyridine (1.09 g, 8.93 mmol) and [2-tert-butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propylamino]-acetic acid methyl ester (3.06 g, 8.12 mmol) in CH2Cl2 at RT. The resulting mixture is stirred overnight then concentrated to dryness. The crude product is purifed by flash chromatography eluting with 1% MeOH/CH2Cl2 to yield the title compound (3.52 g, 6.89 mmol) as a colorless oil. Ion spray MS, [M+H]+=511.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][C:2]2=O.Cl.[CH3:11][C:12]1[C:24]2[N:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[CH:17][C:16]=2[C:15]([NH:25][CH2:26][CH2:27][NH2:28])=[N:14][N:13]=1>CO.CO.CS(C)=O>[CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[NH:28][CH2:27][CH2:26][NH:25][C:15]1[C:16]2[CH:17]=[C:18]3[N:23]([C:24]=2[C:12]([CH3:11])=[N:13][N:14]=1)[CH:22]=[CH:21][CH:20]=[CH:19]3
Reactant: O=C1CCC2CCC1C2
Reactant: Cc1nnc(NCCN)c2cc3ccccn3c12
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Product: Cc1nnc(NCCNC2CCC3CCC2C3)c2cc3ccccn3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the procedure of Example 12, bicyclo[3.2.1]octan-2-one in methanol (3 to 4 mL) was added to a solution of N-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediamine hydrochloride in methanol/DMSO (90 mL:30 mL) which had been heated to boiling and then allowed to cool. After stirring at room temperature overnight, the title compound was obtained as the free base after column chromatography (silica gel, 4:1 methylene chloride:methanol to 100% methanol containing ammonium hydroxide) and recrystallized from isopropyl ether. The compound was converted to the dihydrochloride salt by ethanolic HCl, mp 339°-344° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:39]([O:43][C:44]([N-:46][S:47](N1C=CC(=[N+](C)C)C=C1)(=[O:49])=[O:48])=[O:45])([CH3:42])([CH3:41])[CH3:40].[CH2:59]1COCC1>CCOC(C)=O>[C:39]([O:43][C:44]([N:46]([CH3:59])[S:47]([N:32]1[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][CH2:26][CH:16]2[CH2:15][N:14]3[C:13]4[CH:12]=[C:11]([C:35]([O:37][CH3:38])=[O:36])[CH:10]=[CH:9][C:8]=4[C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:21]3[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[O:18][CH2:17]2)[CH2:30][CH2:31]1)(=[O:49])=[O:48])=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCCN1CCNCC1)COc1ccccc1-3
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCCN1CCN(S(=O)(=O)N(C)C(=O)OC(C)(C)C)CC1)COc1ccccc1-3
Temperature: 40 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of methyl 14-cyclohexyl-7-(3-piperazin-1-ylpropyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.11 M) in dry THF was added (tert-butoxycarbonyl){[4-(dimethyliminio)pyridin-1(4H)-yl]sulfonyl}azanide (1 eq) (prepared following literature procedure: Winum, J.-Y. et al Org. Lett. 2001, 3, 2241-2243) and the mixture stirred at 40° C. for 2 h. The reaction was allowed to cool to RT before diluting with EtOAc. The combined organics were washed with 1N HCl (aq), sat. aq. NaHCO3 then brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product as a yellow foam (58%) that was used without further purification. (ES+) m/z 695 (M+H)+.