Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:51])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]4[N:48]=[CH:49][N:50]=[C:24]34)[CH:21]=[CH:22][C:16]=2[O:15]1>C(OCC)(=O)C>[CH3:51][C:14]1([CH3:13])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]4[N:48]=[CH:49][N:50]=[C:24]34)[CH:21]=[CH:22][C:16]=2[O:15]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc3c(c2)CC(C)(C)O3)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc3c(c2)CC(C)(C)O3)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.7 g), sodium hydrogen carbonate (2.8 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.86 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.44 g, 46%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][C:24]([F:27])([F:26])[F:25])=[C:19]([CH:22]=1)[CH:20]=O>COCCOC.CCOCC>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][C:24]([F:25])([F:26])[F:27])=[C:19]([CH:20]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:22]=1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: O=Cc1cc(Br)ccc1OC(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2OC(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (2.84 g, 20.00 mmol) in anhydrous 1,2-dimethoxyethane (6 ml) is added sodium methoxide (1.19 g, 22.04 mmol) in one portion. After stirring at this temperature for 5 minutes a solution of 5-bromo-2-trifluoromethoxybenzaldehyde (4.84 g, 18.00 mmol) in 1,2-dimethoxyethane (6 ml) is added dropwise over 10 mins, followed by stirring at 0° C. for a further 1 hour. After warming to room temperature the reaction mixture is diluted with ether and washed with 2M hydrochloric acid (×2). Organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo to afford 4-[1-(5-bromo-2-trifluoromethoxyphenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (7.06 g) as an orange liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:33]=[CH:32][C:19]3[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=3[CH:17]=2)[C:4](=[O:34])[C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>[Pd].C(O)C.C(OCC)(=O)C>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]2[CH:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:2][CH:3]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:4]3=[O:34])[CH:33]=[CH:32][C:19]1=2)[CH3:31]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(-c4ccccc4)c(Cl)c4ccccc43)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3C(=O)C(c4ccccc4)Cc4ccccc43)ccc21
Reaction time: 6 h
Yield: 55.9 %

Procedure:
10% Palladium on carbon (20 mg) was added to an ethanol/ethyl acetate solution (1:1, 4 ml) of 7-[3-(4-chloro-2-oxo-3-phenyl-2H-quinoline-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.19 g). The mixture was subjected to catalytic reduction at 50° C. under normal pressure for 6 hours. The reaction mixture was subjected to celite filtration to remove the catalyst. The filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether/hexane, thereby obtaining the title compound (0.1 g) as a white powder.
Reaction SMILES: [ClH:1].CO[C:4](=O)[C@H:5]([CH2:7][CH2:8][CH2:9][NH2:10])[NH2:6].Cl.[S-:13][C:14]#[N:15].[K+].C(O)C>O>[ClH:1].[NH2:10][CH2:9][CH2:8][CH2:7][C:5]1[NH:6][C:14](=[S:13])[NH:15][CH:4]=1
Reactant: COC(=O)[C@@H](N)CCCN
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NCCCc1c[nH]c(=S)[nH]1
Temperature: 5 °C

Procedure:
To an Erlenmeyer flask was prepared a solution of L-ornithine methyl ester hydrochloride (10.50 g, 47.9 mmol) in water (125 mL). The solution was cooled to 5° C. and pH adjusted to a value of 1.5 with concentrated HCl. While being careful to maintain the above stated temperature and pH, 5% Na(Hg) (250 g) was added slowly to the solution over a time period of 35 min. After the addition was complete and bubbling had calmed the Hg was decanted from the solution. The remaining aqueous portion was drained into a separate flask where potassium thiocyanate (14.0 g, 144 mmol) and water (75 mL) was added. The pH of solution was adjusted to a value of 4.30 and the flask was then heated at 95° C. while open to the atmosphere for 1.5 h. After cooling to room temperature, ethanol (75 mL) was added and the reaction was evaporated to dryness. The residue was taken up in methanol and filtered to remove NaCl. After all of the NaCl had been removed the crude residue was purified by column chromatography (CH2Cl2/MeOH sat. with NH3 80:20) to afford the desired compound in its free base form. Addition of concentrated hydrochloric acid to a methanol solution (50 mL) of the free base followed by evaporation to dryness gave 4.51 g (48%) of the title compound 42 as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 11.69 (s, 1H), 7.77 (s, 2H), 6.58 (s, 1H), 2.73 (m, 2H), 2.42 (t, 2H, J=6.6 Hz), 1.76 (tt, 2H, J=7.5, 13.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 160.23, 128.03, 111.69, 38.08, 25.75, 21.27; HRMS (FAB) calcd for C6H12N3S (MH+) 158.0752. found 158.0743.
Reaction SMILES: [FH:1].C(N(C(C)C)CC)(C)C.O.[F:12][C:13]([F:23])([F:22])[CH:14]([O:19][CH2:20]Cl)[C:15]([F:18])([F:17])[F:16]>>[CH2:20]([F:1])[O:19][CH:14]([C:15]([F:18])([F:17])[F:16])[C:13]([F:23])([F:22])[F:12]
Reactant: F
Reactant: FC(F)(F)C(OCCl)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: FCOC(C(F)(F)F)C(F)(F)F
Temperature: 10 °C
Yield: 95 %

Procedure:
In an efficient fume hood, liquid hydrogen fluoride (85.1 g, 4.25 mol) was transferred into a 1 liter Teflon® reaction vessel chilled in a dry ice/acetone cold bath. The vessel was fitted with a dry ice condenser, thermocouple, and addition funnel and a portion of chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (80.1 g) was added. A solution of diisopropylethylamine (249.0 g, 1.93 mol) in chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (271.0 g) was slowly added while maintaining the internal temperature in the range of -5°to 10° C. After completing the addition, the mixture was transferred to a 2 liter glass boiling flask and the Teflon® vessel was rinsed out with a solution of diisopropylethylamine (307.0 g, 2.38 mol) in chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (180.0 g) which was also transferred to the glass flask. An additional 850 g of chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether was added to the reaction flask to bring the total to 1381.1 g (6.38 mol). This mixture was heated at reflux for 16 hours. After cooling to ambient temperature, water (700 mL) was added to the reaction mixture and, after vigorous shaking, the resultant layers were separated. The lower organic layer was further washed with 700 mL of dilute hydrochloric acid (35 mL of 12 N HCl in 665 mL of water). The organic layer (1259.7 g) was analyzed by NMR and gas chromatography and was shown to consist of 63.6% fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (sevoflurane) and 35.4% recovered chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, giving a 95% yield of sevoflurane based on starting material consumed.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[ClH:30]>C(OCC)(=O)C>[Cl-:30].[CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH2+:20][CH2:19][CH2:18]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cl
Reactant: CC(C)COc1cccc2onc(OCC3CCN(C(=O)OC(C)(C)C)CC3)c12
Solvent: CCOC(C)=O
Product: CC(C)COc1cccc2onc(OCC3CC[NH2+]CC3)c12
Product: [Cl-]
Reaction time: 2 h
Yield: 75 %

Procedure:
To a flask containing tert-butyl 4-{[(4-isobutyoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (98.2 mg, 0.24 mmol, EXAMPLE 1, step 3) was added 4N solution of hydrogen chloride in ethyl acetate (1 mL) at room temperature. After being stirred for 2 h, solvent was evaporated and the residual solid was washed with ethyl acetate to give the title compound (62.4 mg, 75%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([OH:41])=O)([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2].[CH3:47][C:48]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49]1.ClC1C(OC)=CC=C2C=1N=C(C1SC=C(C(C)C)N=1)C=C2OC1CC2C(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:54][S:51]([C:48]6([CH3:47])[CH2:50][CH2:49]6)(=[O:53])=[O:52])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:2])[CH3:3]
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C

Procedure:
The title compound was prepared from 17-[2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (65) and 1-methylcyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[8-chloro-2-(4-isopropylthiazole-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carbonyl](cyclopropyl) sulfonamide (56): m/z=747 (M+H)+. 1H NMR (CDCl3): 0.79-0.92 (m, 2H), 1.20-2.03 (m, 19H), 2.20-2.32 (m, 1H), 2.35-2.48 (m, 2H), 2.52-2.64 (m, 5H), 2.85-2.93 (m, 1H), 3.04 (s, 3H), 3.05-3.14 (m, 1H), 3.35-3.46 (m, 2H), 3.97 (s, 3H), 4.60 (td, J=13.2 Hz, J=2.2 Hz, 1H), 5.04 (t, J=10.5 Hz, 1H), 5.30-5.47 (m, 1H), 5.61-5.69 (m, 1H), 6.30 (s, 1H), 6.32 (d, J=2.4 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H), 7.30 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), 10.9 (br s, 1H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].Cl>C1(C)C=CC=CC=1.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: Sc1ccc(Br)cc1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CSc1ccc(Br)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To water (600 mL) solution of 88.9 g of sodium hydroxide was added 200 g of 4-bromothiophenol and dropwise added water (300 mL) solution of 105 g of chloroacetic acid, which was then stirred at 60 to 70° C. for 1 hour. After cooling the reaction mixture to 40° C., thereto were added 140 mL of hydrochloric acid and 600 mL of toluene, which was then heated to 80° C. The organic layer was separated and slowly cooled to 5° C. After stirring at the same temperature for 1 hour, the crystals precipitate was collected by filtration to provide 243 g of (4-bromophenylthio)acetic acid as white solid form.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.Cl.[CH3:11][NH:12][O:13][CH3:14].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl.O>[CH3:14][O:13][N:12]([CH3:11])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: CNOC
Reactant: Cn1cc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1cnn(C)c1
Temperature: 13 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
A mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (5.0 g, 39.6 mmol), N,O-dimethylhydroxylamine hydrochloride (4.8 g, 48.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.2 g, 48.0 mmol), hydroxybenzotriazole (6.5 g, 48.0 mmol) and triethylamine (12.1 g, 120 mmol) in dichloromethane (100 mL) was stirred at 9-17° C. overnight. The reaction mixture was diluted with water (50 mL) and the resulting mixture was extracted with EtOAc (30 mL×3), the combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo (an example of a standard aqueous/EtOAc procedure), then purified by silica gel column chromatography (PE:EtOAc=5:1) to give product (4.6 g, yield 69%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.[CH3:37][NH:38][CH3:39]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:20]=[C:19]([N:38]([CH3:39])[CH3:37])[N:18]=1
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(S(C)(=O)=O)n2)cc1
Reactant: CNC
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(N(C)C)n2)cc1
Temperature: 90 °C

Procedure:
A glass microwave reaction vessel was charged with 5-bromo-3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (204 mg, 0.356 mmol) and dimethylamine solution in water (0.4 mL, 3.02 mmol) in NMP (1 ml). The reaction was stirred and heated in a oil bath at 90° C. for 10 min. The mixture was diluted with water. The resulting white ppt was collected by filtration, washed with water, then MeOH, and dried to give the crude product. MS (ESI, pos. ion) m/z: 538/540 (1:1) (M+1).
Reaction SMILES: S([O-])(=O)(=O)C.CS(O[CH2:11][C:12]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH3:13])(=O)=O.[Na].[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>CO.CS(C)=O.O>[N:27]1([CH2:11][C:12]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:13])[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: c1nc[nH]n1
Reactant: CCCCOC(C)(COS(C)(=O)=O)c1ccc(F)cc1
Agent: CS(=O)(=O)[O-]
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: CCCCOC(C)(Cn1cncn1)c1ccc(F)cc1
Temperature: 130 °C

Procedure:
The mesylate prepared in accordance with (a) is reacted with the sodium salt of 1,2,4-triazole. This is effected by dissolving 0.52 g (23 mmoles) of sodium in 20 ml of absolute methanol, and adding 1.55 g (23 mmoles) of 1,2,4-triazole to this solution. The methanol is then removed in vacuo, and the mesylate prepared in (a) is added, dissolved in 20 ml of dimethyl sulfoxide, to the crystalline residue. The mixture is heated for 6.5 hours at a bath temperature of 130° C. and is allowed to cool to room temperature, water is added and the mixture is extracted with chloroform. The combined extracts are washed with half-saturated sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is concentrated in vacuo. The 3.74 g of crude product obtained are purified by column chromatography (silica gel; 1:1 ethyl acetate/petroleum ether) and afford 1.57 g of the pure end product in the form of an oil. 60 MHz-1H-NMR (CDCl3): δ=8.10 and 7.85 ppm (2s, 2H of triazole); 6.9-7.4 ppm (m, 4H, aromatic); 4.3 ppm (s, 2H, --CH2N); 2.9-3.4 ppm (m, 2H, OCH2); 1.2-1.7 ppm ##STR47## and OCH2CH2CH2CH3); 0.7-1.1 ppm (m, 3H, OCH2CH2CH2CH3).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]>[OH-].[Na+].O1CCOCC1>[C:6]([NH:4][CH2:3][CH2:1][OH:2])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NCCO)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
The procedure is generally as depicted in FIG. 16. Dissolve 6.1 g (10 mmol) of ethanolamine in 10 mL of 1N NaOH. Cool the solution with an ice bath and add to it a solution of 1.7 g (10 mmol) of benzyl chloroformate dissolved in 10 mL of 1,4-dioxane, dropwise, over a period of 30 minutes. When the addition is complete, remove the ice bath and stir for 30 minutes. Add 100 mL of ethyl acetate and wash with 3×50 mL of 1.0N HCl. Wash the ethyl acetate layer with 50 mL of brine. Dry the ethyl acetate layer over anhydrous sodium sulfate. Filter and concentrate the filtrate to a residue. Final purification is achieved by flash chromatography on silica gel with ethyl acetate/hexane as the eluent. N-Cbz-ethanolamine, compound 52, is isolated as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([CH2:32]O)[N:29]([CH3:31])[N:30]=2)=[CH:22][CH:21]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:32][C:28]3[N:29]([CH3:31])[N:30]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=4)[CH:27]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cn1nc(-c2ccc(Cl)cc2)cc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 1 d]) was reacted with [5-(4-chloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[5-(4-chloro-phenyl)-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:24][N:25]=1)[NH:6]2.C[N:31](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([NH2:31])=[O:29])[CH2:24][N:25]=1)[NH:6]2
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc12
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(N)=O)S3)cc12
Temperature: 25 °C
Yield: 92 %

Procedure:
To a mixture of (2-{4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (0.25 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (0.11 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.14 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=9:1-10:0), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (228 mg, yield: 92%) as colorless crystals. MS: 449 (MH+). melting point 120-121° C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][NH2:4].OC1C=CC=CN=1.[C:14]([O:18][C:19](=[O:49])[NH:20][C@H:21]([C@@H:40]1[CH2:44][C@@H:43]([CH:45]([CH3:47])[CH3:46])[C:42](=[O:48])[O:41]1)[CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH3:37])[CH2:25][C:24]1([CH3:39])[CH3:38])([CH3:17])([CH3:16])[CH3:15]>O>[C:14]([O:18][C:19](=[O:49])[NH:20][C@@H:21]([CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH3:37])[CH2:25][C:24]1([CH3:38])[CH3:39])[C@@H:40]([OH:41])[CH2:44][C@H:43]([C:42](=[O:48])[NH:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])[CH:45]([CH3:47])[CH3:46])([CH3:15])([CH3:16])[CH3:17]
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Reactant: CC(C)(C)CN
Agent: Oc1ccccn1
Solvent: O
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCC(C)(C)C)C(C)C)CC1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 74.6 %

Procedure:
0.94 ml of (2,2-dimethylpropyl)amine (8.0 mmol) and 7.6 mg of 2-hydroxypyridine (0.08 mmol) were added to 202 mg of {(S)-2-[2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (70f) (0.4 mmol), and the mixture was stirred at 70° C. for four hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 177 mg of the title compound (yield: 75%).