Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH:16]=[CH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCCCCCCC.[OH-:27].[Na+].OO>C1COCC1.C(OCC)(=O)C>[OH:27][CH2:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]1
Reactant: [OH-]
Reactant: C=CCOC1CCN(C(=O)OC(C)(C)C)CC1
Agent: OO
Agent: [Na+]
Solvent: CCCCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCCCO)CC1
Temperature: 2.5 °C

Procedure:
To a solution of N-t-butoxycarbonyl-4-allyloxypiperidine (2.95 g) in THF (15 ml) was added 9-borobicyclo[3.3.1]nonane (9-BBN, 0.5M solution in THF) (51.3 ml) under ice-cooling with stirring, and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was cooled at 0-5° C., and 3M aqueous sodium hydroxide (20.4 ml) and 30% hydrogen peroxide aqueous solution (20.4 ml) were added the reaction mixture at 0-5° C. The mixture was stirred at ambient temperature for 1 hour. To a reaction mixture was added ethyl acetate (100 ml), and the solution was washed successively with saturated aqueous sodium chloride, 1N-hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of dichloromethane and methanol (9:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(3-hydroxypropyloxy)-N-t-butoxycarbonylpiperidine (3.83 g).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][C:8]1[CH:9]=[C:10]([C@@H:16]([CH2:20][C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]2)[C:17]([OH:19])=[O:18])[CH:11]=[CH:12][C:13]=1[S:14][CH3:15].[Mn]([O-])(=O)(=O)=[O:28].[K+].[OH2:33]>CO>[CH3:15][S:14]([C:13]1[CH:12]=[CH:11][C:10]([C@@H:16]([CH2:20][C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]2)[C:17]([OH:19])=[O:18])=[CH:9][C:8]=1[CH3:7])(=[O:28])=[O:33]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CSc1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)cc1C
Reactant: O
Agent: [K+]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Product: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
In a flask was placed sodium periodate (725 mg, 3.38 mmol) and water (6 mL). To this solution was then added (R)-2-(3-methyl-4-methylsulfanyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (525 mg, 1.80 mmol) in methanol (11 mL). The reaction was then stirred at 25° C. for 1 h after which time there was a white precipitate. The reaction was then filtered through a plug of celite and the celite pad washed with chloroform. The filterate was concentrated in vacuo and then azeotroped with acetonitrile. The residue was then dissolved in methanol (20 mL) and added slowly to a solution of potassium permanganate (425 mg, 2.70 mmol) in water (5 mL) and stirred at 25° C. for 1 h. After this time the reaction turned dark brown and the solids were filtered off and washed with methanol. The filterate was concentrated in vacuo and the residue was dissolved in acetonitrile with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40M column, silica gel, 20% methanol/ethyl acetate) to afford (R)-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (523 mg, 90%) as a white solid: [α]31589=−90.0° (c=0.15, methanol); ES-HRMS m/e calcd for C16H20O5S (M+H)+ 325.1104, observed 325.1104; 1H NMR (300 MHz, DMSO-d6) δ 1.48 (m, 1H, CH), 1.78-2.35 (m, 8H, 4×CH2), 2.63 (s, 3H, ArCH3), 3.20 (s, 3H, SO2CH3), 3.67 (t, J=7.6 Hz, 1H, ArCHCO), 7.42 (m, 2H, Ar), 7.85 (d, Jo=8.6 Hz, 1H, Ar), 12.64 (s, 1H, CO2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[C@@H:14]([CH3:28])[CH2:13]3)[C:11](=[NH:29])[NH:10][C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1.[CH:31]1(N)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[CH:31]1([NH:29][C:11]2[C@:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[C@@H:14]([CH3:28])[CH2:13]3)[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:9](=[O:30])[N:10]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C[C@H]1C[C@]2(CCN1C(=O)OCc1ccccc1)C(=N)NC(=O)N2c1cccc(F)c1
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H]1C[C@]2(CCN1C(=O)OCc1ccccc1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Temperature: 110 °C

Procedure:
Benzyl (5R,7S)-1-(3-fluorophenyl)-4-imino-7-methyl-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (27.2 g, 0.066 moles) was dissolved in 100 mL toluene, cyclohexylamine (60 mL, 0.523 moles) was added and the mixture was heated to 110° C. over the weekend in a 1 L roundbottom flask fitted with a condenser. The reaction was diluted with CHCl3 and MeOH until soluble and washed with 1 Normal HCl three times to remove excess cyclohexylamine. The organic was dried with MgSO4, filtered and concentrated to give the product which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)[Cl:21].C([O-])(O)=O.[Na+]>C(O)C>[Cl:21][CH2:20][CH:22]([OH:24])[CH2:23][N:17]1[CH2:16][CH2:15][N:14]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]1
Reactant: ClCC1CO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Diphenylmethylpiperazine (16.4 g, 0.065 mol) in ethanol (250 mL) was added dropwise to epichlorohydrin (5.1 mL, 0.065 mL) in ethanol (13 mL) with anhydrous NaHCO3 (0.065 mol, 5.46 g) at 0° C., over 45 min at room temperature under N2. After 17 h the NaHCO3 was removed by filtration via a sintered glass funnel and the ethanol removed from the filtrate in vacuo giving a white-yellow solid (21.5 g). This solid after triturating with Et2O (300 mL) gave a precipitate which was filtered and dried in vacuo to give the pure product (5.11 g, 22.8%) mp 114°-116° C. DCI/MS (M+1) 345. 400 MHz 1H NMR (CDCl3)δ:7.2-7.4 (m, 10H),4.2 (s,1H), 3.9 (m, 1H),3.55-3.7(m,2H),2.7(m,2H),2.45(m,8H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([OH:13])=[O:12])=[O:5]>ClCCl>[C:11]([C@H:7]1[CH2:8][CH2:9][CH2:10][N:6]1[C:4](=[O:5])[CH2:3][CH2:2][S:1][S:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([OH:13])=[O:12])=[O:5])([OH:13])=[O:12]
Reactant: O=C(O)[C@H]1CCCN1C(=O)CCS
Solvent: ClCCl
Product: O=C(O)[C@H]1CCCN1C(=O)CCSSCCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 8.7 %

Procedure:
0.9 g (4 mmol) 1-(3-mercapto-propionyl)-(R)-pyrrolidine-2-carboxylic acid (raw material) were dissolved in dichloromethane and extracted with 50 ml of an saturated aqueous solution of CuSO4. The aqueous phase was extracted twice with dichloromethane, the combined organic phases filtered, dried with magnesiumsulfate and evaporated. Chromatography with dichloromethane/acetone/formic acid 80/20/1 gave 70 mg (R)-1-[3-[3-[(R)-2-carboxy-pyrrolidin- 1-yl]-3-oxo-propyldisulfanyl]-propionyl]-pyrrolidine-2-carboxylic acid as a colorless oil. ISN -MS: 403 (M--H)-.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CS(C)=O>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:1][C@H:2]([CH2:3][CH2:4][OH:5])[C:6]([OH:8])=[O:7])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: N[C@H](CCO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@H](CCO)C(=O)O)ccc(C#N)c1Cl
Temperature: 80 °C
Reaction time: 17 h
Yield: 60.1 %

Procedure:
To a suspension of D-Homoserine (2.5 g, 20.99 mmol) and K2CO3 (5.8 g, 41.98 mmol) in DMSO (30 mL) was added 2-chloro-3-methyl-4-fluorobenzonitrile (3.56 g, 20.99 mmol) at room temperature. The reaction mixture was heated to 80° C. and stirred for 17 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (200 mL) and extracted with EtOAc (3×200 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The organic extracts were combined, washed with H2O (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a beige solid (3.39 g, 60%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.49 (d, J=9 Hz, 1H), 6.62 (d, J=9 Hz, 1H), 6.06 (br d, J=9 Hz, 1H), 4.49-4.41 (m, 1H), 3.83-3.80 (m, 2H), 2.29 (s, 3H), 2.27-2.20 (m, 1H) and 2.18-2.09 (m, 1H).
Reaction SMILES: [NH:1]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=3[O:19][CH3:20])[NH:11][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[NH:1]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][C:13]=3[O:19][CH3:20])[NH:11][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1nc2ccc(NC(C)=O)cc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(NC(C)=O)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 5-acetamino-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.
Reaction SMILES: C(N(C(=O)C1C=CC(O)=CC=1)C1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH2:44][CH3:45])[CH3:43])=O>>[CH2:44]([N:42]([CH2:40][C:39]1[CH:19]=[CH:18][C:17]([O:22][CH2:39][CH2:40][N:42]([CH2:44][CH3:45])[CH3:43])=[CH:16][CH:15]=1)[C:43]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:45]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCN(C)C(=O)CCl
Product: CCN(C)CCOc1ccc(CN(CC)c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 88.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-ethyl-N-methylacetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.6 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1([CH3:27])[C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:17]=2[NH:16][C:15](=[O:26])[O:14]1>>[CH3:12][C:13]1([CH3:27])[O:14][C:15](=[O:26])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:2]3[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=3)=[CH:19][C:18]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(S(N)(=O)=O)c3)cc21

Procedure:
Prepared according to procedure B from 3-bromobenzenesulfonamide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid: mp 242-244° C. (dec) 1H-NMR (DMSO-d6) δ10.28 (s, broad 1H), 8.07 (s, 1H), 7.9 (d, 1H, J=7.80 Hz), 7.78 (d, 1H, J=7.86 Hz), 7.64 (t, 1H, J=7.79 Hz), 7,59 (m, 2H), 7.42 s, broad 2H), 7.02 (d, 1H, J=8.86 Hz), 1.68 (s, 6H); MS m/z 331(M+H). Anal. Calc. For C16H16N2O4S: C, 57.82; H, 4.85; N, 8.43. Found: C, 57.49; H, 5.08; N, 8.05.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CO.O.[F:22][C:23]([F:39])([F:38])[C:24]([C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=1)[CH:35]=O)([OH:29])[C:25]([F:28])([F:27])[F:26].[OH-].[Na+]>C(Cl)(Cl)Cl>[F:28][C:25]([F:26])([F:27])[C:24]([C:30]1[CH:37]=[C:34](/[CH:35]=[C:8]2/[C:9](=[O:12])[C:10]3[C:6]([CH2:7]/2)=[CH:5][C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[C:3]([O:2][CH3:1])[CH:11]=3)[CH:33]=[N:32][CH:31]=1)([OH:29])[C:23]([F:39])([F:38])[F:22]
Reactant: O=Cc1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1)C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (0.1 g, 0.40 mmol)), MeOH/H2O (1:1), was added 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)nicotinaldehyde 259 (0.132 g, 0.485 mmol) and NaOH (0.032 g, 0.80 mmol). The reaction was stirred at RT for 6 h. The reaction mass was diluted with chloroform and washed with water (3×25 ml). The organic layer was dried over sodium sulphate and concentrated to get the crude 263, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid (E)-2-((5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)methylene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 263.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[Cl:27].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([Cl:27])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:25][CH3:26])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)c(Cl)c2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ncnc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 3.3 g (8.4 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-chloro-benzoic acid methyl ester using 1.06 g (25.2 mmol.) LiOH in 20 mL water and 100 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitated product is filtered off and washed with water and MeOH. After drying 2.5 g (89%) of the desired product are obtained as solid material.
Reaction SMILES: [CH3:1]N(C)C=O.[C:6]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=O)[CH3:7].[Br-].[CH2:16]([O:23][C:24]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[N:12]1[CH:13]=[CH:14][C:9]([C:6]([CH3:1])=[CH:7][C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Reactant: CC(=O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: CC(=CC(=O)OCc1ccccc1)c1ccncc1
Yield: 42 %

Procedure:
N,N-Dimethylformamide (33 ml) was added to a mixture of 4-acetylpyridine (2.00 g, 16.5 mmol) and (benzyloxycarbonyl)triphenylphosphonium bromide (8.94 g, 18.2 mmol), and the whole was stirred under ice-cooling. Potassium carbonate (9.12 g, 66.0 mmol) was added thereto, and the whole was stirred at an external temperature of 70° C. overnight. The reaction mixture was diluted with diethyl ether (100 ml), and the whole was washed with water (100 ml, twice) and saturated brine (50 ml) successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give benzyl 3-(4-pyridyl)-2-butenate (1.77 g, 42%: mixture of E body and Z body) as a pale yellow oily matter.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>O>[CH2:15]([S:22][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(SCc2ccccc2)c([N+](=O)[O-])c1
Yield: 92.1 %

Procedure:
In a similar fashion using route 38 general procedure 92, 1-chloro-4-methanesulfonyl-2-nitrobenzene (750 mg, 3.19 mmol), benzylmercaptan (450 ml, 3.82 mmol), Na2CO3 (439 mg, 4.14 mmol) and EtOH:water (25 ml: 18 ml) at 90° C. for 4 h gave the title compound (950 mg, 92%) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([NH:7][C:8]([C@@H:10]2[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]2C(OC(C)(C)C)=O)=[O:9])=[N:4][CH:3]=1.Cl.O1CCOCC1>CO>[F:1][C:2]1[S:6][C:5]([NH:7][C:8]([C@@H:10]2[CH2:14][C@H:13]([OH:15])[CH2:12][NH:11]2)=[O:9])=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)Nc1ncc(F)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1ncc(F)s1)[C@@H]1C[C@H](O)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4S)-tert-butyl 2-(5-fluorothiazol-2-ylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (1.42 g, 4.29 mmol) in MeOH (40 mL) was added 4N HCl in dioxane (10.71 mL, 42.9 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The residue was used for the next step without purification. LC/MS [M+H]+: 232; Ret time (Method F): 0.51 min.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8](OCC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>C1COCC1>[Cl:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[CH2:8][OH:9]
Reactant: CCOC(=O)c1c(C)nsc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nsc(Cl)c1CO
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A solution of 2.06 g (10.0 mmoles) of ethyl 5-chloro-3-methyl-isothiazole-4-carboxylate dissolved in 10 ml of THF was dropwise added at −30° C., to. a solution of 0.42 g (11.0 mmoles) of lithium aluminum hydride dissolved in 10 ml of THF. The mixture was stirred at the same temperature for 1 hour to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added to the reaction mixture. The resulting mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.50 g (yield: 91.5%) of (5-chloro-3-methyl-isothiazol-4-yl)-methanol.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[C:39]([N:42]1[C:50]2[C:45](=[CH:46][C:47]([NH2:51])=[CH:48][CH:49]=2)[CH2:44][CH2:43]1)(=[O:41])[CH3:40]>C(O)C>[C:39]([N:42]1[C:50]2[C:45](=[CH:46][C:47]([NH:51][C:7]3[N:8]=[CH:9][C:10]4=[C:2]([CH3:1])[N:3]=[C:4]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[N:5]4[N:6]=3)=[CH:48][CH:49]=2)[CH2:44][CH2:43]1)(=[O:41])[CH3:40]
Reactant: CC(=O)N1CCc2cc(N)ccc21
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: CC(=O)N1CCc2cc(Nc3ncc4c(C)nc(-c5ccccc5)n4n3)ccc21
Yield: 30.6 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), 1-acetyl-5-amino-2,3-dihydro-(1h)-indole (30.5 mg, 0.17 mmol) and ethanol (2.5 mL) to afford N-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (20 mg) as a yellow solid. MS m/z 385 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: OB(O)c1ccncc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccncc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (64 mg, 85%), MS (ISP) m/z=303.5 [(M+H)+], mp 278.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available pyridin-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@@H]([C@H]([C@H](C)O)O)O)O.O=C[C@@H]([C@H]([C@H]([C@@H](C(O)=O)O)O)O)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The teachings also provide a method of preparing the extracts. The methods comprise isolating a crude extract from Astragalus membranaceus and mildly treating the crude extract with an acid. The mildly treating includes applying the acid to the crude extract at a concentration ranging from about 0.05M to about 0.5M, at a temperature ranging from about 15° C. to 25° C., and for a time ranging from about 1 hour to about 24 hours. The temperature and time for applying the acid are selected to obtain an arabinose:galactose ratio greater than about 3.5:1; from about 5% to about 10% rhamnose; from about 15% to about 20% galactose; from about 10% to about 20% galacturonic acid; from about 10% to about 15% glucose; and a high yield. The high yield is substantially higher than a yield of an extract of the Astragalus membranaceus produced using a second process that includes applying the acid to the crude extract at a temperature and time selected to obtain an arabinose:galactose ratio of less than 3.5:1, 20%-35% galactose, and less than about 10% glucose. In some embodiments, the arabinose:galactose ratio can reduced to within a range of about 4.0:1 to about 4.5:1, about 3.75:1 to about 4.5:1, about 3.8:1 to about 4.25:1, or any range therein.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])(C)C)=[O:8])[CH2:3]1.[C:14](Cl)(=[O:17])[CH2:15][CH3:16].[CH2:19](N(CC)CC)[CH3:20]>C(Cl)Cl>[C:14]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH2:13][CH2:19][CH3:20])=[O:8])[CH2:3]1)(=[O:17])[CH2:15][CH3:16]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCCCOC(=O)N1CC[C@H](NC(=O)CC)C1
Reaction time: 2 h

Procedure:
tert-Butyl (3S)-3-aminopyrrolidine-1-carboxylate (0.09 mL, 0.5 mmol) was combined with propanoyl chloride (0.055 mL, 0.64 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, and dried over MgSO4, then concentrated. The resulting residue was purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give tent-butyl (3S)-3-(propionylamino)pyrrolidine-1-carboxylate, LCMS [M+Na] 265.2. The later was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give crude product (0.057 g) which was used directly in the next step. LCMS calculated for C7H15N2O (M+H)+: m/z=143.1; Found: 143.2.