Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[C:12]([O:14][CH2:15][CH3:16])=O.C>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:15]([O:14][C:12]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1)[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1nc2ccccc2c(=O)o1
Reaction time: 2 h

Procedure:
To a solution of anthranilic acid (0.1 mol., 13.71 gm) in dry pyridine (100 ml) at room temperature under anhydrous conditions was added ethyl chloroformate (4 equiv., 38.25 ml) in a dropwise manner over 15 minutes. After stirring for 2 hours, excess pyridine was removed under reduced pressure at 40° C. (bath temperature) and the residue was stirred vigorously in ice cold water (250 ml) for 15 minutes. The pale yellow powder was collected by filtration, washed with water (100 ml), and air-dried to give 18.6 gm of crude product. The crude product was treated with active charcoal (2 gm) in ethyl acetate (150 ml) to afford a white solid after removal of solvent. Recrystallization from EtOAc-ether gave 17.02 (89%) of the title compound, 2-ethoxy-4H-3,1-benzoxazin-4-one, as colorless crystals; m.p. 88°-90.5° C.; IR (KBr): νmax 1760 cm-1 (C=O), 1630 cm-1 (C= N); H"NMR (CDCl3); δ 1.46 ppm (t, J=7.1 Hz, 3H,)CH2CH3), 4.53 ppm (q, J=7.1 Hz, 2H, OCH2CH3), 7.30-8.20 ppm (m, 4H, aromatic protons).
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1(C)C=CC=CC=1>[CH3:17][S:18]([O:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)C(C)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C(C)OS(C)(=O)=O
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
32.00 g (246 mmol) of 2-propenyl 2-hydroxypropionate and 31.3 g (310 mmol) of triethylamine were dissolved in 150 g of toluene (solvent), and 35.6 g (310 mmol) of methanesulfonyl chloride was dropwise added thereto at 10° C., taking 20 minutes. These were reacted at room temperature for 1 hour, the reaction liquid was washed twice with water, then the organic layer was separated and concentrated. The concentrate was purified through silica gel column chromatography, and from the fraction taken with hexane/ethyl acetate=5/1, 27 g (yield 53%) of 2-propenyl 2-(methanesulfonyloxy)propionate was obtained.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]([O:24][CH2:25]Cl)=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I-:27].[Na+]>C(#N)C>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]([O:24][CH2:25][I:27])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOC(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOC(=O)OCI
Temperature: 25 °C

Procedure:
2-(N-CBz-L-valyloxy)ethoxycarbonyloxymethyl chloride (1.16 g, 3 mmole) was dissolved in acetonitrile (10 ml). Sodium iodide (630 g, 4.2 mmole) was added to the solution. After reaction at 65° C. for 2.5 hr, the reaction mixture was cooled down to room temperature and filtered and the residue was dissolved in methylene chloride (5 ml) and refiltered. The solution was dried and gave the titled product. 1.2 g.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:11]3[N:17]=[C:16]([CH3:18])[C:15]([Cl:19])=[C:12]3[NH:13][N:14]=2)=[CH:4][CH:3]=1.[C:22]([OH:26])(=[O:25])[CH:23]=[CH2:24]>CC(N(C)C)=O>[C:22]([CH2:23][CH2:24][NH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:11]3[N:17]=[C:16]([CH3:18])[C:15]([Cl:19])=[C:12]3[NH:13][N:14]=2)=[CH:4][CH:3]=1)([OH:26])=[O:25]
Reactant: Cc1nn2c(CCCOc3ccc(N)cc3)n[nH]c2c1Cl
Reactant: C=CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1nn2c(CCCOc3ccc(NCCC(=O)O)cc3)n[nH]c2c1Cl
Temperature: 85 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
23 g 3-[3-(4-aminophenoxy)-propyl]-6-methyl-7-chloro-1H-pyrazolo[5,1-c]-1,2,4-triazole and 10.8 g acrylic acid are dissolved in dimethyl acetamide heated to 85° C. and are stirred at that temperature for 1 hour. The reaction mixture is then poured onto 300 g of an ice/water mixture, the deposit precipitated is filtered off under suction and recrystallized from ethyl acetate. 3-[3-(4-carboxyethylaminophenoxy)-propyl]-6-methyl-7-chloro-1H-pyrazolo-[5,1-c]-1,2,4-triazole melting at 151° to 153° C. is obtained in a yield of 61%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-(3-bromophenyl)ethanol (7 g) in N,N-dimethylformamide (100 ml) were added tert-butyldimethylsilyl chloride (5.77 g) and imidazole (2.84 g) at 25° C. The mixture was stirred at 25° C. for 12 h. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (100 ml×2). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography with mixed solvent of n-hexane and ethyl acetate to give [2-(3-bromophenyl)ethoxy](tert-butyl)dimethylsilane as colorless oil.
Reaction SMILES: NC1N=CN=C2N(CC3CN(C(OC(C)(C)C)=O)C3)N=[C:10]([C:11]3[CH:16]=CC(OC4C=CC=CC=4)=C[C:12]=3F)C=12.[C:37]([OH:43])([C:39](F)(F)F)=[O:38].[NH:44]1CC(CN2C3=NC=NC(N)=C3C(C3C=CC(OC4C=CC=CC=4)=CC=3F)=N2)[CH2:45]1>C(Cl)Cl>[C:45]([C:39](=[CH:10][CH:11]([CH3:16])[CH3:12])[C:37]([OH:43])=[O:38])#[N:44]
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2CC1CNC1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Solvent: ClCCl
Product: CC(C)C=C(C#N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carboxylate (780 mg) in DCM (2 mL) was cooled in an ice bath. To this was added TFA (4 mL, 1.59 mmol), the ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour, checking reaction by TLC and LC-MS. After two hours the solvent was removed, and to the residue was added water. The water layer was extracted with by EtOAc and the combined organic layer washed with 2N HCl. The combined aqueous layer was adjusted with NaOH to pH 9-10, extracted with EtOAc, and the combined organic layer washed with brine, dried over Na2SO4 and filtered. The solvent was removed to obtain 2-cyano-4-methyl-pent-2-enoic acid (48.12 mg, 0.350 mmol), 1-(azetidin-3-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>Cl(O)(=O)(=O)=O>[C:19]([O:1][CH:2]1[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)OC1C(N2CCCC2=O)c2sccc2OC1(C)C
Temperature: 0 °C

Procedure:
A solution of 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (2.0 g, 7.48 mmol) and perchloric acid (70%, 10 drops) in acetic anhydride (20 mL) were stirred for 1 h at 0°-5° C. The solution was poured into ice water (100 mL). The product was extracted into dichloromethane, washed with water (4x), and evaporated in vacuo. The resultant oil was purified by flash chromatography, using 1% methanol in dichloromethane as the eluant, then crystallized from hexanes to give the product, 2.12 g (92%), as a colorless solid: mp 92°-93° C.; IR(KBr): 1745 and 1684 cm-1 ; MS: 310 (MH+); 1 1H NMR (CDCl3): w 1.37 (s, 3H), 1.38 (s, 3H), 1.98 (m, 2H), 2.10 (s, 3H), 2.37 (m, 2H), 3.24 (m, 1H), 3.40 (m, 1H), 5.15 (d, J=9.1 Hz, 1H), 5.44 (d, J=9.1 Hz, 1H), 6.58 (d, J=5.4 Hz, 1H) and 7.13 (d, J=5.4 Hz, 1H).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19](O)=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.[Cl:23]CCl>CN(C)C=O>[C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([Cl:23])=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1
Reactant: Cc1ccc(NS(=O)(=O)c2cccc(C=CC(=O)O)c2)cc1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NS(=O)(=O)c2cccc(C=CC(=O)Cl)c2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a suspension of 3-(3-p-tolylsulfamoyl-phenyl)-acrylic acid (5d) (0.75 g, 2.36 mmol) in dichloromethane (10.0 ml) oxalyl chloride (0.62 ml, 7.08 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.79 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][F:23]>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[CH2:20][CH2:21][CH2:22][F:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: FCCCBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCF)Cc1ccc(Br)cc1
Reaction time: 24 h
Yield: 45.6 %

Procedure:
To a solution of compound 138 (286 mg, 1.0 mmol) in anhydrous DMF (3.0 mL) was added sodium hydride (NaH, 60% oil dispersion, 48.0 mg, 1.2 mmol, 1.2 equiv) at 0° C. The resulting mixture was stirred at 0° C. for 30 min before 1-bromo-3-fluoropropane 139 (170 mg, 1.2 mmol, 1.2 equiv) was added. The reaction mixture was subsequently warmed to 50–60° C. and stirred for 24 hours. The reaction mixture was then quenched with H2O (10 mL), and the resulting aqueous solution was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with H2O (10 mL) and saturated aqueous NaCl (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (10–15% EtOAc/hexane gradient elution) to afford bromide 136 (158 mg, 46% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1.CCN(CC)CC.Cl[C:27]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:27](=[O:28])[O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(Cl)nc2c1
Reactant: CC(C)(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)(C)C)C3)nc(Cl)nc2c1
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
A solution of (R)-1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-amine (100 mg, 0.38 mmol) in 2 mL of THF was cooled to −30° C. To it was added Et3N followed by the addition of neopentyl chloroformate (53 μL, 0.38 mmol) dropwise. The reaction was complete after 5 minutes. The reaction was quenched with water, the layers separated, and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography using 0%-10% EtOAc in DCM gave (R)-neopentyl 1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (100 mg, 70% yield). LC/MS: m/z 377.5 (M+H)+ at 2.90 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[Na].F[C:8]1[C:13]2[C:14](=[O:23])[C:15]3[CH:16]=[CH:17][N:18]=[CH:19][C:20]=3[C:21](=[O:22])[C:12]=2[C:11]([F:24])=[CH:10][CH:9]=1>C1COCC1.C(Cl)Cl>[F:24][C:11]1[C:12]2[C:21](=[O:22])[C:20]3[CH:19]=[N:18][CH:17]=[CH:16][C:15]=3[C:14](=[O:23])[C:13]=2[C:8]([O:2][CH3:1])=[CH:9][CH:10]=1
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(F)c21
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c2c1C(=O)c1ccncc1C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium methoxide, freshly prepared under nitrogen atmosphere from anhydrous methanol (97.6 ml) and sodium (2.024 g), is dropped in a time of 2 hours and 35 minutes into a solution of 6,9-difluorobenzo[g]isoquinolin-5,10-dione (19.615 g, preparation 3) in anhydrous THF (883 ml), under stirring and at room temperature. At the end of the addition, the reaction mixture is concentrated to half the starting volume, then is kept at 18° C. for 30 minutes. The separated solid is filtered and washed with 100 ml of THF, then it is suspended in water (80 ml), left overnight under stirring and filtered again to give 9.3 g of crude product, which is suspended in methylene chloride (45 ml) and refluxed for 30 minutes. After cooling at room temperature, the product is filtered and the separated solid is washed with methylene chloride (5×3 ml), then dried under vacuum at 40° C., to obtain 8.65 g of pure product, m.p. 248-250° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([Cl:9])=[O:8])[O:4][N:3]=1.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:12]=1>O1CCOCC1>[ClH:9].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][N:28]([C:7]([C:5]3[O:4][N:3]=[C:2]([CH3:1])[CH:6]=3)=[O:8])[CH2:27][CH2:26]2)[N:12]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Cc1cc(C(=O)Cl)on1
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=O)c4cc(C)no4)CC3)nc(N)c2cc1OC
Product: Cl
Temperature: 20 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-methylisoxazole-5-carbonyl chloride (0.73 g., 5.02 mmole) in dioxane was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.45 g., 5.02 mmole) in dioxane. The mixture was heated briefly, then was stirred at 20° C. for 2.5 hours. Workup as in Example 1 gave the title compound having a m.p. of 263°-264° C. with decomposition.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13](=[O:33])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[C:25]([C:27]3[O:28][CH:29]=[CH:30][N:31]=3)[CH:24]=[CH:23][C:22]=2[CH3:32])=[CH:17][CH:16]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl.CO>C(Cl)Cl>[CH3:32][C:22]1[CH:23]=[CH:24][C:25]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:13](=[O:33])[CH:8]([NH2:7])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:20][CH:19]=1
Reactant: Cc1ccc(-c2ncco2)cc1-c1ccc(NC(=O)C(CC(C)C)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-c2ncco2)cc1-c1ccc(NC(=O)C(N)CC(C)C)cc1
Yield: 10.3 %

Procedure:
Into a 50 ml round bottom flask, was placed [3-Methyl-1-(2′-methyl-5′-oxazol-2-yl-biphenyl-4-ylcarbamoyl)-butyl]-carbamic acid tert-butyl ester (370 mg, 0.80 mmol) followed by the slow addition of a solution of 2,2,2-trifluoroacetic acid (3 ml) in DCM (7 ml) with stirring. The resulting solution was allowed to stir at rt for 4 hours. The reaction progress was monitored by TLC (CH2Cl2/MeOH=10:1). The mixture was then concentrated by evaporation under vacuum using a rotary evaporator. Adjustment of the pH to 7-8 was accomplished by the addition of aq NaHCO3 (sat.). The resulting solution was extracted three times with 10 ml of EtOAc and the organic layers combined and dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. The residue was triturated with 10 ml of n-Hexane to provide 30 mg (21%) of 2-Amino-4-methyl-pentanoic acid (2′-methyl-5′-oxazol-2-yl-biphenyl-4-yl)-amide as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[OH:25][C@@H]1CCNC1>>[OH:25][C@@H:3]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:2]1
Reactant: O=C1NCCn2c1cc1cc(OCCCN3CCCCC3)ccc12
Reactant: O[C@@H]1CCNC1
Product: O=C1NCCn2c1cc1cc(OCCCN3CC[C@@H](O)C3)ccc12
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 2, from 8-(3-chloro-propoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 2, intermediate) and (R)-3-hydroxypyrrolidine (commercially available), to give the desired product as colorless solid (22%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[OH:19][C:20]1([C:30]#[C:31][C:32]([C:34]2[CH:35]=[N:36][C:37]([CH3:40])=[CH:38][CH:39]=2)=O)[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:32]([C:34]3[CH:35]=[N:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[CH:31][C:30]([C:20]3([OH:19])[CH2:21][CH2:22][C:23]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:28][CH2:29]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cn1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nc(C3(O)CCC4(CC3)OCCO4)cc2-c2ccc(C)nc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (359 mg, 2.06 mmol) in ethanol (4 mL), triethylamine (286 μL, 2.06 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(6-methylpyridin-3-yl)-2-propyn-1-one (Reference Example 16) (563.7 mg, 1.87 mmol) in ethanol (5.4 mL) was added dropwise, and the obtained solution was stirred at room temperature for 22 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (177 mg, 0.42 mmol, 22%) as an amorphous product.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2.NC[C:18]1([O:36][CH3:37])[CH:23]=[CH:22][C:21](N2CCCCC2)([S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[C:19]1[O:34][CH3:35]>>[CH3:35][O:34][C:19]1[CH:20]=[C:21]([S:24]([N:27]2[CH2:9][CH2:8][CH:7]([CH2:11][NH:10][CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:7]=3[CH2:8][C:9](=[O:15])[NH:10]4)[CH2:6][CH2:14]2)(=[O:25])=[O:26])[CH:22]=[CH:23][C:18]=1[O:36][CH3:37]
Reactant: COC1=CC(N2CCCCC2)(S(N)(=O)=O)C=CC1(CN)OC
Reactant: O=C1Cc2c(cccc2OC[C@@H]2CO2)N1
Product: COc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3cccc4c3CC(=O)N4)CC2)cc1OC
Yield: 55.8 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-2-oxindole (0.205 g, 1.0 mmol) and 4-aminomethyl-1-piperidinyl-3,4-dimethoxybenzenesulfonamide (0.628 g, 2.0 mmol) according to procedure used for Example 2 to give 0.145 g of the title compound as a rose colored solid. Dissolved in CH2Cl2 and treated with 0.5 mL of 1N HCl in Et2O. Resulting solids filtered and dried to give 0.140 g of title compound as the HCl salt.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.O>C(O)(=O)C>[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([F:20])([F:16])([F:17])([F:18])[F:19])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Acetic anhydride was added during 5 minutes to a stirred solution of 4-aminophenylsulphur pentafluoride (30.2 g) in acetic acid at 40° C. and then heated at 65° C. for 0.5 hour. The cooled mixture was added to water, stirred for 1 hour and filtered. The solid was washed with water, sodium bicarbonate solution and water, dried and purified by stirring with hexane to give 4-acetamidophenylsulphur pentafluoride (27.0 g), m.p.131-132° C.
Reaction SMILES: [NH:1]([CH2:3][CH2:4][OH:5])[NH2:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:17]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=3)[C:16](=[O:27])[C:15](=O)[CH:14]2[C:29](=O)[CH2:30][CH3:31])=[CH:9][CH:8]=1.CC(O)=O.S(=O)(=O)(O)N>CO>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:14]3[C:29]([CH2:30][CH3:31])=[N:2][N:1]([CH2:3][CH2:4][OH:5])[C:15]=3[C:16](=[O:27])[N:17]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:9][CH:8]=1
Reactant: NNCCO
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Agent: NS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CO
Product: CCc1nn(CCO)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 90 °C
Yield: 45 %

Procedure:
To a solution of 2-hydrazinylethanol (76 mg, 1.0 mmol) in MeOH (2 mL) was added 5-(4-chlorophenyl)-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-propionylpyrrolidine-2,3-dione (Step 60.1) (204 mg, 0.5 mmol) and the reaction mixture was heated for 1 hr at 70° C. and for 0.5 hr at 90° C. in the MW. The volume of MeOH was reduced to 1 mL and AcOH (2 mL) and sulfamic acid (97 mg, 1.0 mmol) were added. The reaction mixture was heated for 1 h at 110° C. in the MW. The reaction mixture was concentrated under reduced pressure. The residue was basified with 20% K2CO3 solution and extracted with EtOAc. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was first purified by silica gel column chromatography (hexane/EtOAc/MeOH 80:20:2 to 0:10:1) then further purified by preparative achiral SFC (column Propyl-pyridyl-urea, gradient 15-20% in 6 min_total 11 min) to afford the title product (97 mg, 0.225 mmol, 45% yield) as colorless foam. tR: 0.84 min (LC-MS 2); ESI-MS: 427 [M+H]+ (LC-MS 2); Rf=0.21 (EtOAc/MeOH 9:1); 1H NMR (400 MHz, CDCl3) δ ppm 0.91 (t, J=7.6 Hz, 3H) 2.01 (s, 3H) 2.25-2.48 (m, 2H) 3.37 (s, 3H) 3.44 (t, J=6.3 Hz, 1H) 3.95-4.05 (m, 2H) 4.43 (dd, J=5.6, 3.7 Hz, 2H) 5.50 (s, 1H) 6.91-7.03 (m, 4H) 7.25 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][N:6]=1)=[O:4].C(Cl)Cl.[H-].[Na+].Cl[C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7]([C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Suspension of 5-nitro-1H-indazole-3-carboxylic acid methyl ester 18AP (7 g, 31.67 mmol) in THF (130 ml) and DCM (15 ml) was added to a NaH (60% in Mineral Oil, 1.61 g, 41.17 mmol) at 0° C. H2 gas was evolved. Chlorotriphenyl methane (8.83 g, 31.67 mmol) was added after stirring for 20 min at 0° C. Reaction mixture was subjected to heat at 60° C. for overnight. It was then cooled to room temperature and concentrated under reduced pressure. Solid was redissolved in DCM and filtered. Filtrate was concentrated under reduced pressure to give desired 5-nitro-1-trityl-1H-indazole-3-carboxylic acid methyl ester 19AP (12.95 g, 88%).