Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:20]=3[N:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.C[O:39][C:40](=[O:43])[CH2:41][NH2:42]>CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26]([NH:42][CH2:41][C:40]([OH:39])=[O:43])=[O:27])=[CH:22][C:20]=3[N:21]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:8][C:7]=1[CH3:29]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)O)ccc2o1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)NCC(=O)O)ccc2o1
Yield: 76.6 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzooxazole-5-carboxylic acid (150 mg, 0.343 mmol), DMAP (125 mg, 1.03 mmol), EDC (99 mg, 0.514 mmol), and glycine methyl ester hydrochloride (64 mg, 0.514 mmol) are reacted and hydrolyzed analogous to Example 4 to give the title product (130 mg, 76%). MS (ES) m/e: 495.3 (M+1), 493.3 (M−1).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:24])[C:4]([N:6]1[CH2:10][CH:9]2[CH2:11][C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([N:14]=C=O)[CH2:13][CH:8]2[CH2:7]1)=[O:5].[OH-].[Na+]>>[CH3:24][N:3]([CH3:2])[C:4]([N:6]1[CH2:10][CH:9]2[CH2:11][C:12]([NH2:14])([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH:8]2[CH2:7]1)=[O:5]
Reactant: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(N=C=O)CC2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)C(=O)N1CC2CC(N)(Cc3ccccc3)CC2C1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 12 mL hydrochloric acid (8 N) was added dropwise 5-benzyl-5-isocyanato-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14e obtained from the above step at room temperature. The reaction mixture was stirred for 30 minutes and adjusted to pH 9 with a 4 N sodium hydroxide aqueous solution. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-amino-5-benzyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14f (0.55 g, yield 70%) as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[H][H].C(N1C[C@H]2[C@H](CCCC2)C1)(=O)C>[C].[Ru].CO>[C:1]([N:4]1[CH2:12][C@H:11]2[C@@H:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1Cc2ccccc2C1
Reactant: [H][H]
Agent: [Ru]
Agent: CC(=O)N1C[C@H]2CCCC[C@H]2C1
Solvent: CO
Product: CC(=O)N1C[C@@H]2CCCC[C@H]2C1
Yield: 0.2 %

Procedure:
In a 3-liter GL autoclave fitted with a electromagnetic stirrer are added 175 g of N-acetylisoindoline, 825 g of methylalcohol and 17 g of 5% ruthenium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 20 kg/cm2 and a temperature of 110° C. After a 8 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydro-N-acetylisoindoline is 93.7%. In addition, 0.2% of trans-hexahydro-N-acetylisoindoline is formed.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[OH:28].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:28][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2cc(Br)ccc2c1Br
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc4cc(Br)ccc4c3Br)c2cc1OC
Temperature: 150 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (223 mg), 1,6-dibromo-2-naphthol (910 mg), and 4-dimethylaminopyridine (366 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 150° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 4-[(1,6-dibromo-2-naphthyl)oxy]-6,7-dimethoxyquinoline (326 mg, yield 67%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].FC(F)(F)[C@](C1C=CC(N2CCN(S(C3C=CC=CC=3)(=O)=O)C[C@H]2CC2CCOCC2)=CC=1)(O)C.FC(F)(F)[C@](C1C=CC(N2CCN(S(C3C=CC=CC=3)(=O)=O)C[C@@H]2CC2CCOCC2)=CC=1)(O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:35][C:2]([F:1])([F:34])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH2:14][C@H:13]2[CH2:27][CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3ccccc3)C[C@@H]2CC2CCOCC2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3ccccc3)C[C@@H]2CC2CCOCC2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3ccccc3)C[C@H]2CC2CCOCC2)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3ccccc3)C[C@H]2CC2CCOCC2)cc1)C(F)(F)F

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-4-(phenylsulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-4-(phenylsulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-4-(phenylsulfonyl)-2-(tetrahydro-2H-pyran-4-ylmethyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.83 (s, 2H), 7.65 (s, 3H), 7.44 (d, J=8.8 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 4.06 (m, 1H), 3.92-3.82 (m, 2H), 3.80-3.72 (m, 1H), 3.67 (d, J=11.5 Hz, 1H), 3.47-3.37 (m, 1H), 3.31-3.19 (m, 1H), 2.65 (dd, J=3.1, 11.5 Hz, 1H), 2.51 (dt, J=3.6, 11.4 Hz, 1H), 1.83-1.73 (m, 1H), 1.68 (s, 4H), 1.60-1.49 (m, 2H), 1.40-1.03 (m, 5H). m/z (ESI, +ve ion) 513.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.785 μM; GK-GKRP EC50 (LC MS/MS)=0.572 μM.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:32]=[C:31]5[C:26]([CH2:27][CH2:28][C:29](=[O:33])[NH:30]5)=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[CH:9][CH:10]=[CH:11][C:4]1=2.[C:34]([O:42][CH2:43]Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>O1CCCC1>[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:32]=[C:31]5[C:26]([CH2:27][CH2:28][C:29](=[O:33])[N:30]5[CH2:43][O:42][C:34](=[O:41])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:25][CH:24]=4)[CH2:16][CH2:17]3)=[CH:9][CH:10]=[CH:11][C:4]1=2
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1
Reactant: O=C(OCCl)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)c1ccccc1
Temperature: 0 °C
Yield: 86.4 %

Procedure:
Sodium hydride (55% oil) (0.15 g, 2.52 mmol) was suspended in tetrahydrofuran (THF) (20 ml) and, under a nitrogen atmosphere, 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one (1.0 g, 2.30 mmol) synthesized in the same manner as in WO2006/112464 (Example 11) was added, and the mixture was stirred with heating under reflux for 25 min. The mixture was cooled to 0° C., chloromethyl benzoate (0.627 g, 3.67 mmol) was added, and the mixture was stirred at room temperature for 2.5 hr. Under ice-cooling, aqueous ammonium chloride was added to the reaction mixture to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 2:3) and concentrated under reduced pressure to give the title compound (yield 1.132 g, 86.55%) as a colorless amorphous solid.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:13][CH2:14][C@H:15]1[O:21][CH:19](O)[C@H:18]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[C@@H:17]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:16]1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:12])[CH3:11]>ClCCCl.C(OCC)(=O)C>[C:10]([O:13][CH2:14][C@H:15]1[O:21][C@@H:19]([F:7])[C@H:18]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[C@@H:17]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:16]1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)OC[C@H]1O[C@@H](F)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Under nitrogen gas atmosphere, diethylaminosulfur trifluoride (5.8 ml, 43.9 mmol) was added to a solution of Compound 23 (5.95 g, 11.2 mmol) in 1,2-dichloroethane (50 ml) under ice cooling, and the mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=4:1) to obtain Compound 24 (5.9 g, 99%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=O)[CH2:10][S:11][CH2:12][CH2:13][SH:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.NC(C1SCCSC=1)C([O-])=O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[OH:1][N:2]=[C:3]([C:9]1[S:14][CH2:13][CH2:12][S:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(=O)CSCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(C(=O)[O-])C1=CSCCS1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NO)C1=CSCCS1
Temperature: 60 °C
Yield: 28.5 %

Procedure:
Ethyl 2-hydroxyimino-4-(2-mercapto-ethylthio)-3-oxo-butyrate (655 g.) is suspended in toluene (3,500 cc.) in the presence of p-toluenesulphonic acid monohydrate (22 g.). The mixture is heated under reflux (the water being removed at the rate of which it is formed, in a Dean and Stark apparatus) for 40 minutes, then cooled to 60° C., and concentrated to dryness under reduced pressure (20 mm.Hg). The residue is dissolved in ethyl acetate (200 cc.) and the solution is washed twice with a saturated sodium bicarbonate solution (700 cc.), and with water (twice 700 cc.) and is then dried over magnesium sulphate and finally treated with decolourising charcoal. The solution is filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm.Hg). The residue obtained is dissolved hot in chloroform (450 cc.) and carbon tetrachloride (800 cc.). The mixture is cooled to 0° C., for 16 hours and the crystals obtained are filtered off. Ethyl α-hydroxyimino-(5,6-dihydro-1,4-dithiin-2-yl)-acetate (173 g.) is thus obtained in the form of white crystals melting at 142° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1O)#[N:17]>N1C=CC=CC=1>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])#[N:17]
Reactant: COc1ccc(C#N)c(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COc1ccc(C#N)c(OS(=O)(=O)C(F)(F)F)c1
Yield: 81.1 %

Procedure:
Trifluoromethanesulphonic anhydride (2.06 g) was added dropwise to a solution of 2-cyano-5-methoxyphenol (1.0 g) in dry pyridine (20 ml) at 0° C. under an atmosphere of argon. Volatile material was removed by evaporation and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with water (60 ml) and saturated sodium chloride solution (30 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue purified by flash chromatography, eluting with ethyl acetate/hexane (1:3 v/v), to give (2-cyano-5-methoxyphenyl)trifluoromethanesulphonate (1.53 g) as an oil; NMR (CDCl3): 3.9(s,3H), 6.95(d,1H), 7.0(d,1H), 7.7(d,1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][CH2:11][OH:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.O>C(Cl)Cl>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:11][CH2:10][C:3]2[C:4]([F:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCCc1c(F)ccc(F)c1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2c(F)ccc(F)c2F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(2,3,6-trifluorophenyl)ethyl alcohol (1. g) in methylene chloride (10 ml) are added with stirring p-toluenesulfonyl chloride (2.2 g) and triethylamine (2.0 ml), and the mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into water and is extracted with diethyl ether. The ether layer is washed with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent, methylene chloride) and recrystallized from diethyl ether - n-hexane to give 1-[2-(p-toluenesulfonyloxy)ethyl]-2,3,6-trifluorobenzene (3.4 g), as colorless prisms, m.p. 73°-74° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].O>FC(F)(F)C(O)=O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(=O)CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)C(=Cc1ccccc1C(F)(F)F)C(C)=O

Procedure:
To a solution of 2-trifluoromethylbenzaldehyde (8,7 g) and 2,4-pentanedione (5,01 g) in trifluoroacetic acid (10 ml) thionylchloride (4 ml) and catalytic amount of water (0,05 ml) were added at room temperature. The solution was stirred over night at 20°? C. The solvent was evaporated and the residue was distilled in vacuo, bp 110° C./1.5 mbar. Yield 5.3 g (41 %).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([C:18]([CH3:20])=[CH2:19])=[CH:4][N:3]=1.[OH:21]O>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:18]([CH3:20])[CH2:19][OH:21])=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[CH:7]=1
Reactant: C=C(C)c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Reactant: OO
Solvent: O
Product: CC(CO)c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a degassed solution of 2-(2-chloro-5-(prop-1-en-2-yl)pyridin-4-yl)-4-fluoro-1H-indole (50 mg, 0.17 mmol) was added BH3-DMS (0.5 mL) under N2 protection at 0° C., and the mixture was stirred for 1 hour. Then NaBO3.4H2O (60 mg, 0.34 mmol) and H2O2 (0.2 mL) was added under N2 protection at 0° C. for 0.5 hours, and the reaction mixture was stirred at RT for 2 hours. After diluted with H2O and extracted with EtOAc, the combined organic layer was washed with H2O, brine, dried over Na2SO4, and the residue was purified by prep-HPLC to give 2-(6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)propan-1-ol (20 mg, yield: 36%). 1H-NMR (CDCl3, 400 MHz) δ 10.86 (s, 1H), 8.17 (s, 1H), 7.33 (s, 1H), 7.18 (s, 1H), 7.06˜7.10 (m, 1H), 6.71˜7.76 (m, 2H), 4.10 (s, 1H), 3.95 (s, 1H), 3.75 (t, J=12.0 Hz 1H), 3.42˜3.51 (m, 1H), 1.14 (d, J=8.0 Hz, 3H). MS (M+H)+: 305/307.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:9])([CH3:8])[CH3:7])[N:3]=[CH:2]1.[CH2:10]([NH:12][C:13]([NH:15][C:16]1[S:17][C:18]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][C:22](C3C=NC(C(O)(C)C)=NC=3)=[CH:21][C:19]=2[N:20]=1)=[O:14])[CH3:11]>N1C=CC=CC=1>[CH2:10]([NH:12][C:13]([NH:15][C:16]1[S:17][C:18]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][C:22]([N:1]3[CH:5]=[C:4]([C:6]([OH:9])([CH3:8])[CH3:7])[N:3]=[CH:2]3)=[CH:21][C:19]=2[N:20]=1)=[O:14])[CH3:11]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(-c3ccccn3)c2s1
Reactant: CC(C)(O)c1c[nH]cn1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1nc2cc(-n3cnc(C(C)(C)O)c3)cc(-c3ccccn3)c2s1
Temperature: 80 °C
Reaction time: 4.67 h

Procedure:
Compound i (74 mg) and Intermediate 1 (100 mg) were suspended in pyridine with 4 Å mol. sieves. The mixture was degassed and flushed with oxygen and Cu(OAc)2.H2O added. The mixture was again degassed and flushed with oxygen then left stirring at 80° C. for 280 min. The reaction was quenched by adding NH4Cl sat. and diluted with EtOAc and H2O. The mixture was extracted with EtOAc and the organics combined, dried (Na2SO4) and evaporated to dryness. Purification by chromatography on silica, eluting with DCM/MeOH (0-10%) followed by reverse phase chromatography on a C18 column eluting with ACN/H2O afforded Compound 11 (7.5 mg).
Reaction SMILES: CO[C@H]1[C@H](O)[C@H](OC)COC1OC.C[O:15][C@@H:16]1[C@@H:23]([O:24][CH3:25])[C@@H:22]([O:26][CH3:27])[C@@H:21]([CH2:28][O:29]C)[O:20][CH:17]1[O:18][CH3:19].CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)OC1OC>>[CH3:25][O:24][C@H:23]1[C@H:22]([O:26][CH3:27])[C@@H:21]([CH2:28][OH:29])[O:20][CH:17]([O:18][CH3:19])[C@@H:16]1[OH:15]
Reactant: COC[C@H]1OC(OC)[C@H](OC)[C@@H](OC)[C@H]1OC
Agent: COC1OC[C@@H](OC)[C@@H](O)[C@@H]1OC
Agent: COC[C@H]1OC(OC)[C@H](OC)[C@@H](OC)[C@@H]1OC
Product: COC1O[C@H](CO)[C@@H](OC)[C@H](OC)[C@H]1O

Procedure:
When it is subjected to methanolysis, it gives 1 mol each of methylglucoside, methylgalactoside, methylarabinoside and methylglucuronide. A completely methylated compound (C68H116O24) obtained by methylation of soyasaponin A2 with methyl iodide, dimethyl sulfoxide and sodium hydride gives 1 mol each of methyl 3,4-di-O-methylglucopyranoside, methyl 2,4-di-O-methylarabinopyranoside, methyl 2,3,4,6-tetra-O-methylgalactopyranoside and methyl 2,3,4,6-tetra-O-methylglucopyranoside as methylated sugar, and 1 mol of 3,22,24-tri-O-methyl soyasapogenol A as methylated sapogenol, when subjected to methanolysis after reduction.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][OH:14])[CH2:8]2)OCC1.F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].O>O1CCCC1>[N+:26]([C:17]1[CH:18]=[C:19]([S:22]([NH2:25])(=[O:23])=[O:24])[CH:20]=[CH:21][C:16]=1[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][C:7](=[O:3])[CH2:8]1)([O-:28])=[O:27]
Reactant: OCC1CCCC2(C1)OCCO2
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(OCC2CCCC(=O)C2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 250 mL round-bottomed flask was added sodium hydride (0.5 g) in tetrahydrofuran (10 mL) and then 1,4-dioxaspiro[4.5]decan-7-ylmethanol (0.5 g) was added. After the mixture stirred at room temperature for 20 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.65 g) was added. The mixture was stirred at room temperature for overnight. Water (20 mL) was added slowly. The aqueous layer was extracted by dichloromethane (3×20 mL). The combined organic layers were dried over Na2SO4. After filtration, and concentration of the filtrate, the residue was purified by reverse phase chromatography, eluting with 30-60% acetonitrile in water with 0.1% trifluoroacetic acid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23]C(=O)OC(C)(C)C)[N:10]=[C:9]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[C:8]=2[C:7]1=[O:37].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>>[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45].[NH2:23][C@@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]1[NH:16][C:11]1[N:10]=[C:9]([C:31]2[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=2)[C:8]2[C:7](=[O:37])[NH:6][CH2:14][C:13]=2[C:12]=1[F:15]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc(N[C@H]3CCCC[C@H]3N)c(F)c3c2C(=O)NC3)cn1
Temperature: 65 °C
Yield: 92 %

Procedure:
A mixture of tert-butyl (1R,2S)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (41.5 mg, 0.070 mmol) and TFA (2 mL) was heated at 65° C. for 3 h. Following reaction, the solvent was removed in vacuo. The residue was diluted with DMSO and MeOH (1/1), passed through a microfiltration frit, and purified via preparative HPLC. The fractions were collected and dried in vacuo to give a TFA salt of the title compound as a white solid (22 mg, 92%). 1H NMR (500 MHz, CD3OD) δ ppm 1.56-2.01 (m, 8 H), 3.85 (br s, 1 H), 3.94 (br s, 3 H), 4.45 (br s, 2 H), 4.67 (br s, 1 H), 8.31 (br s, 1 H), 8.81 (br s, 1 H). [M+H] calc'd for C17H21FN6O, 345; found, 345.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:28]3[CH2:29][CH2:30][CH2:31][N:25]([CH3:24])[CH2:26][CH2:27]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CN1CCCNCC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CO
Product: CN1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 1-methyl-1,4-diazepane (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 15-40% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (61 mg, 99%). 1HNMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H) 2.33 (d, J=1.77 Hz, 2 H) 2.91 (d, J=4.55 Hz, 3 H) 3.32-3.46 (m, 1 H) 3.51-3.64 (m, 2 H) 3.64-3.86 (m, 4 H) 4.65 (dd, J=15.54, 4.42 Hz, 1 H) 6.33 (d, J=2.27 Hz, 1 H) 7.32 (s, 1 H) 7.60 (d, J=8.59 Hz, 2 H) 7.99 (d, J=8.34 Hz, 2 H) 8.08 (d, J=2.27 Hz, 1 H) 9.62 (br. s., 1 H) 10.85 (s, 1 H). ESI-MS: m/z 409.3 (M+H)+.