Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:13]=1.C[O:31][B:32](OC)[O:33]C.Cl>C1COCC1>[B:32]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:13]=1)([OH:33])[OH:31]
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2ccccc21
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
A 1.7 M solution of tert-butyl lithium (t-BuLi) in pentane (3.8 ml; 6.45 mmol) was added over ~5 minutes, to a solution of the title product of Step (B) (1 g; 3 mmol) in THF at -100° C. The temperature was kept below -84° C. during the addition. After stirring 5 minutes at -100° C., trimethylborate was added in one portion and the reaction mixture was allowed to warm to room temperature over 4 hours. At this time, 10 ml of 10% HCl was added and the mixture was extracted with methylene chloride (3×30 ml). The combined organic layers were washed with water (3×30 ml) and brine (30 ml). Drying (MgSO4), decolorizing (Darco) and concentration afforded a tan foam. Due to apparent decomposition at room temperature, the foam was stored at -80° C. overnight. The residue was then partitioned between ether (20 ml) and 0.5 N NaOH (20 ml). The purple ether layer was extracted with 10 ml of 0.5N NaOH. The combined green basic layer was washed with ether (20 ml), acidified to pH 2 with saturated KHSO4 solution to afford a purple mixture, which was extracted with methylene chloride (2×30 ml). Drying (MgSO4) and concentration afforded 623 mg (69%) of the title product of this step as a purple foam.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Si](C)(C)C.[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:43](O)=[O:44])[CH:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:33]([OH:35])=[O:34])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[SiH3]OC(=O)[C@@H](COCC1C=CC=CC=1)N.Cl>CN(C)C=O.O1CCCC1.C(Cl)(Cl)Cl>[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:43]([NH:11][C@@H:10]([C:12]([OH:14])=[O:13])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:44])[CH:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:33](=[O:34])[OH:35])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N[C@H](COCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(N[C@H](C(=O)N[C@H](COCc1ccccc1)C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
O-Benzyl-D-serine (5.0 g, 25.6 mmole) was dissolved in dimethylformamide (50 ml), treated with chlorotrimethylsilane (3.053 g, 28.1 mmole) and the mixture stirred at room temperature until a homogeneous solution was obtained (approx. 1 hour). Meanwhile, N-benzyloxycarbonyl-β-benzyl-L-aspartic acid (9.14 g, 25.6 mmole) was dissolved in a 1:1 mixture of dimethylformamide and tetrahydrofuran, cooled to -15° C. and treated with N-methylmorpholine (2.81 ml, 25.6 mmole), followed by isobutyl chloroformate (3.32 ml, 25.6 mmole). After 10 minutes' activation, the precooled solution of O-benzyl-D-serine silyl ester was added, followed by dropwise addition of N-methylmorpholine (2.81 ml, 25.6 mmole), ensuring that the temperature of the reaction mixture was maintained at -15° C. The solution was allowed to warm to room temperature slowly and stirred for 4 hours before acidifying to pH 1-2 (with cooling) using aqueous hydrochloric acid. Chloroform was added, the phases separated and the aqueous layer re-extracted with chloroform. The combined organic extracts were washed with 1N hydrochloric acid (3×) and with saturated sodium chloride and dried (MgSO4) The solvent was evaporated under reduced pressure and the solid residue crystallized from ethyl acetate/hexanes to give Nα -benzyloxycarbonyl-β-benzyl-L-aspartyl-O-benzyl-D-serine (11.0 g), m.p. 107°-108° C., which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:23][C:24]([CH3:26])=O.[BH3-]C#N.[Na+]>>[CH:24]([NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2)([CH3:26])[CH3:23]
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Yield: 41 %

Procedure:
Using a method similar to Example 204, using 6-S-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 297 mg, 1.00 mmol), acetone (116 mg, 2.00 mmol), and NaBH3CN (125 mg, 2.00 mmol) gives the title compound (139 mg) as a white foam. Mass spectrum (ion spray): m/z=340 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.13 (d, 1H), 7.21-7.13 (m, 2H), 6.90-6.87 (m, 2H), 6.27 (br. s, 2H), 2.97 (m, 1H), 2.91-2.75 (m, 3H), 2.62-2.41 (m, 2H), 1.83-1.63 (m, 4H), 1.07 (d, 6H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH2:17][C@@H:18]([C:43]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:44]=1[F:50])[NH:19][C:20]([C@H:22]1[N:26]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:25][CH2:24][S:23]1)=[O:21])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.Cl.CS(O)(=O)=O>C(Cl)Cl.O1CCOCC1.C1COCC1>[NH2:8][C@H:9]([C:13]([O:15][CH2:16][CH2:17][C@@H:18]([C:43]1[C:44]([F:50])=[CH:45][CH:46]=[CH:47][C:48]=1[F:49])[NH:19][C:20]([C@H:22]1[N:26]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])=[CH:32][CH:31]=2)(=[O:28])=[O:29])[CH2:25][CH2:24][S:23]1)=[O:21])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2F)cc1)c1c(F)cccc1F
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2F)cc1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
Compound (3S)-3-(2,6-difluorophenyl)-3-[({(2S)-3-[(2′-fluorobiphenyl-4-yl)sulfonyl]-1,3-thiazolidin-2-yl}carbonyl)amino]propyl N-(tert-butoxycarbonyl)-L-valinate (3.04 g, 4.13 mmol) was dissolved in DCM (33 mL) at 0 degree and 66 mL of 4M HCl in dioxane was added. The reaction was stirred at 0 degree for 1 h and at r.t. for 3 h. The solvent was evaporated and the residue redissolved in DCM and washed with 10% NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a white foam. The foam was redissolved in THF and 1 eq of methanesulfonic acid (345 mg) was added, the precipitate was filtered and dried to give the desired product (3S)-3-(2,6-difluorophenyl)-3-[({(2S)-3-[(2′-fluorobiphenyl-4-yl)sulfonyl]-1,3-thiazolidin-2-yl}carbonyl)amino]propyl L-valinate as a white solid (2.53 g, 83.7% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO.CC#N.C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-aminonicotinic acid (1.00 g, 7.24 mmol) in MeOH (20 ml) and MeCN (10 ml) was added 10% solution of trimethylsilyldiazomethane in CH2Cl2 (25 ml) at room temperature. After stirring at room temperature for 0.5 h, the solvent was evaporated to give crude methyl 6-aminonicotinate as a yellow solid. Title compound was prepared from this crude methyl 6-aminonicotinate in 17% yield according to a procedure sinular to that described in Preparation 6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[CH2:14]3)=[O:12])[CH2:9][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C1=CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: Cc1ccccc1C1CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-(2-methylphenyl)-2,5-dihydro-1H-pyrrole (5 mg, 0.00001 mol) in methanol (1 mL, 0.02 mol) was added Pd/BaSO4 (reduced) and the mixture was stirred under an atmosphere of hydrogen at rt for 1 h. The crude product was purified using prep-HPLC. LCMS: m/z 340.4 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Li+].Cl>C(O)C.O>[Cl:15][C:12]1[C:11]([Cl:16])=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2
Reactant: CCOC(=O)c1cc2c(Cl)c(Cl)ccc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2c(Cl)c(Cl)ccc2[nH]1
Reaction time: 2 h
Yield: 60.6 %

Procedure:
4,5-Dichloro-1H-indole-2-carboxylic acid ethyl ester (0.5 g) was treated with 1 M lithium hydroxide in ethanol (3 mL) and heated, water bath, for 2 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethylacetate. The organic extracts were combined, dried over sodium sulfate and filtered, and solvent was evaporated to give 4,5-dichloro-1H-indole-2-carboxylic acid (0.27 g, 60%). This material was treated with -ethyl-3-(3′-dimethylaminopropyl)-carbodiimide hydrochloride (0.5 g), HOBT (0.4 g) and N,N-diisopropylethylamine (1 mL) in DMF (2 mL) and dichloromethane (2 mL) was treated with N-methylpiperazine (0.2 mL) stirred at ambient temperature for 18 h then diluted with water. The organic portion was separated, washed with brine, dried over sodium sulfate, and filtered. Solvent was removed under reduced pressure, and the residue was purified via silica gel chromatography (3-8% 2 M ammonia in methanol/dichloromethane) to give the title compound (0.15 g, 40%). 1H NMR (400 MHz, CDCl3): δ 10.2 (br.s, 1H), 7.25-7.16 (m, 2H), 6.75 (d, J=2 Hz, 1H), 3.92 (br.m, 4H), 2.47 (m, 4H), 2.30 (s, 3H). MS (electrospray): exact mass calculated for C14H15Cl2N3O, 311.06; m/z found, 312.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:12][OH:13])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:12]=[O:13])[CH2:9][O:10][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCC1(c2cccc(Cl)c2)COC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=CC1(c2cccc(Cl)c2)COC1
Reaction time: 0.5 h

Procedure:
The mixture of Example 86D (510 mg, 2.58 mmol) and Dess-Martin periodinane (1.3 g, 3.09 mmol) in 30 mL of dichloromethane was stirred under N2 atmosphere for 4 hours at room temperature. Then saturated NaHCO3 (120 mL) and Na2S2O3 (30 mL) was added with stirring for another 30 min. The mixture was extracted with dichloromethane (3×100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to provide the crude product which was directly used in the next step without further purification.
Reaction SMILES: [SH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C1COCC1>CO.C(OCC)(=O)C.C(O)C>[C:14]([S:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCCOCCOCCOCCS
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: OCCOCCOCCOCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To 2-{2-[2-(2-mercapto-ethoxy)-ethoxy]-ethoxy}-ethanol (310 mg, 1.47 mmol) and trityl chloride (452 mg, 1.62 mmol, 1.1 eq.) in a round bottomed flask was added simultaneously triethylamine (2.1 ml, 10 eq.) and THF (25 ml) under argon. The initial red colour faded upon stirring at ambient temperature for 1 hour. The reaction was monitored by TLC, ethyl acetate/ethanol (1:1) and was completed after 6 hours. Thereafter methanol (6 ml) was added to consume excess trityl chloride and the mixture stirred for 5 minutes before evaporation of the solvents. The residue was purified by flash chromatography using 100% ethyl acetate to afford the product (550 mg, 83%) as a colourless oil.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]([C:7]1([C:10]2[S:11][C:12]([C:15]3[CH:20]=[C:19]([NH:21][C:22]4[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=4)[CH:18]=[C:17]([CH3:32])[CH:16]=3)=[CH:13][N:14]=2)[CH2:9][CH2:8]1)=O)=[O:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:32][C:17]1[CH:18]=[C:19]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:20]=[C:15]([C:12]2[S:11][C:10]([C:7]3([C:5]4[O:2][CH:1]=[N:3][N:4]=4)[CH2:8][CH2:9]3)=[N:14][CH:13]=2)[CH:16]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(=O)NNC=O)CC3)s2)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(c4nnco4)CC3)s2)c1
Temperature: 100 °C
Yield: 22 %

Procedure:
The product from Step 1 (85 mg, 0.184 mmol) was taken up in THF (2 mL) in a microwave vial, and Burgess reagent (88 mg, 0.368 mmol) was added. The reaction was heated in the microwave at 100° C. for 30 min. The yellow reaction mixture was concentrated to dryness, and the resulting residue was purified by flash chromatography (25-100% ethyl acetate in hexanes) to afford N-(3-methyl-5-{2-[1-(1,3,4-oxadiazol-2-yl)cyclopropyl]-1,3-thiazol-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (18 mg, 22%) as a colorless solid. MS ESI: [M+H]+ m/z 445.0. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.23 (s, 1H), 8.81 (d, J=4.9, 1H), 7.97 (s, 1H), 7.96 (s, 1H), 7.46 (s, 1H), 7.26 (d, J=4.9, 1H), 7.15 (s, 1H), 2.29 (s, 3H), 1.94-1.82 (m, 4H). rhSYK activity=+++
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH2:30][OH:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:31][CH2:30][CH2:29][N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:11][N:8]([CH:37]3[CH2:38][CH2:39][C:34]([OH:33])([C:41]4[CH:42]=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=4)[CH2:35][CH2:36]3)[CH2:9]2)=[O:32])=[N:17]1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNc1nn(CCO)c2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(CCO)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in the previous step) and 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][OH:23]>ClCCl>[CH3:1][S:2]([O:23][CH2:22][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13])(=[O:4])=[O:3]
Reactant: OCCc1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Methanesulphonyl chloride (3.3 ml; 0.043 mol) and triethylamine (5.9 ml; 0.043 mol) were added to a solution of 2-(2,4-difluorophenyl)ethanol (6.4 g; 0.0426 mol) in dichloromethane (100 ml). The solution was cooled for 1 h at 0° C. and then brought to room temperature for 1 h. The reaction mixture was then treated by washing, successively, with 5N sulphuric acid (20 ml), water (50 ml), a 5% solution of NaHCO3 (50 ml) and water (50 ml). The organic phase was then dried over Na2SO4, filtered and concentrated at reduced pressure. The residue was taken up twice in CCl4, thus obtaining 6.42 g of 2-(2,4-difluorophenyl)ethyl methanesulphonate.
Reaction SMILES: [CH3:1][NH2:2].C[O:4][C:5](=O)[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1>CO>[CH:8]1([CH2:7][CH2:6][C:5]([NH:2][CH3:1])=[O:4])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1
Reactant: CN
Reactant: COC(=O)CCC1CC=CCC1
Solvent: CO
Product: CNC(=O)CCC1CC=CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Methyl amine (8 M in EtOH, 75 ml, 600 mmol) was added to a mixture of 3-cyclohex-3-enyl-propionic acid methyl ester (German patent DE 4023848 A1 19920130) (20.0 g, 119 mmol) in 75 mL of methanol. The mixture was stirred at room temperature for one day. Additional Methyl amine (8 M in EtOH, 40 ml, 320 mmol) was added to the mixture and stirring continued for one more day. The mixture was concentrated and the residue was taken up in ethyl acetate, washed with 0.5 M aqueous HCl, dried and stripped of the solvent to give the title compound (19.50 g, 98% yield, uncorrected) as a pale orange solid.
Reaction SMILES: [CH:1]1[C:2]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[C:13]([O:19][C@@H:20]4[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]([OH:29])[C@H:21]4[OH:30])[C:12]([OH:31])=[CH:11][C:10]=3[O:9][C:3]=2[CH:4]=[C:5]([OH:8])[C:6]=1[OH:7].CS(C)=O.[OH-].[Ca+2:37].[OH-].C(O)C>OCC(CO)O>[CH:1]1[C:2]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[C:13]([O:19][C@@H:20]4[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]([OH:29])[C@H:21]4[OH:30])[C:12]([OH:31])=[CH:11][C:10]=3[O:9][C:3]=2[CH:4]=[C:5]([OH:8])[C:6]=1[OH:7].[Ca:37]
Reactant: [Ca+2]
Agent: O=c1c2cc(O)c(O)cc2oc2cc(O)c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(O)c12
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Solvent: OCC(O)CO
Product: [Ca]
Temperature: 60 °C

Procedure:
mangiferin 4.2 g (0.01 mol) is dissolved into 80 ml DMSO, calcium hydroxide 1.48 g (0.02 mol) is dissolved in 200 g glycerol, calcium hydroxide solution is added slowly into mangiferin solution while mixing round, mixing round until it react completely. Appropriate quantity ethanol is added into the reaction solution, mixing round adequately. A lot of deposition is come into being in solution. The reaction solution is filtrated to get the deposition. This deposition is heated up no excess 60° C. to dry. The yellow green solid substance is mangiferin calcium. Its weight is 3.83 g, the productivity is 91.2%. The purity of mangiferin monopotassium is 63.8% detected by HPLC.
Reaction SMILES: ClC1C=C2C(C(NC3C=CC(C(N4CCN(C)CC4)=[O:18])=CC=3)=CC=N2)=CC=1.[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([NH:39][C:40]3[CH:60]=[CH:59][C:43]([C:44]([N:46]4[CH2:51][CH2:50][N:49]([C:52]5[CH:57]=[CH:56][C:55](Cl)=[CH:54][CH:53]=5)[CH2:48][CH2:47]4)=[O:45])=[CH:42][CH:41]=3)=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1.ClC1C=C2C(C(NC3C=CC(C(N4CCN(C5C=CC=C(OC)C=5)CC4)=O)=CC=3)=CC=N2)=CC=1.ClC1C=C2C(C(NC3C=CC(C(N4CCN(C5C=CC=C(C(F)(F)F)C=5)CC4)=O)=CC=3)=CC=N2)=CC=1.ClC1C2C(=CC(Cl)=CC=2)N=CC=1.NC1C=CC(C(N)=O)=CC=1>>[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([NH:39][C:40]3[CH:60]=[CH:59][C:43]([C:44]([N:46]4[CH2:51][CH2:50][N+:49]([O-:18])([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)[CH2:48][CH2:47]4)=[O:45])=[CH:42][CH:41]=3)=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: CN1CCN(C(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Agent: COc1cccc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)c1
Agent: Clc1ccc2c(Cl)ccnc2c1
Agent: NC(=O)c1ccc(N)cc1
Product: O=C(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CC[N+]([O-])(c2ccccc2)CC1

Procedure:
Similary, following the procedure of Example 1 above but replacing the 1-[p-[(7-chloro-4-quinolyl)amino]benzoyl]-4-methylpiperazine as used therein with 1-[p-[(7-chloro-4-quinolyl)amino]benzoly]-4-phenylpiperazine; 1-[p-[(7-chloro-4-quinolyl)amino]benzoyl]-4-(p-chlorophenyl)piperazine; 1-[p-[(7-chloro-4-quinolyl)amino]benzoyl]-4(m-methoxyphenyl)piperazine; 1-[p-[(7-chloro-4-quinolyl)amino]benzoly]-4-(o-tolyl)piperazine; and 1-[p-[(7-chloro-4-quinolyl)amino]-benzoyl]-4-(m-trifluoromethylphenyl)piperazine, respectively, all of which may be prepared by reacting 4,7-dichloroquinoline with an appropriate p-aminobenzamide of formula (IV), supra. according to the method of Morley et al., supra., there is obtained the corresponding 1-[p-[(7-chloro-4-quinolyl)amino]benzoyl]-4-phenylpiperazine-4-oxide; 1-[p-[(7-chloro-4-quniolyl)amino]benzoly]-4-chlorophenyl)-piperazine-4-oxide; 1-[p-[(7-chloro-4-quinolyl)amino]benzoyl]-4-(m-methoxyphenyl)piperazine-4-oxide; 1-[p-[(7-chloro-4-quinolyl)amino]benzoyl]-4-(o-tolyl)piperazine-4-oxide; and 1-[p-[(7-chloro-4 -quinolyl)amino]benzoyl]-4-(m-trifluoromethylphenyl)piperazine-4-oxide, respectively.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:19])=[N:14][CH:13]=[C:12]2[O:20]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:19])=[N:14][CH:13]=[C:12]2[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnc(Cl)c2ccc(SCc3ccccc3)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cnc(Cl)c2ccc(SCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-(benzylthio)-1-chloro-4-methoxyisoquinoline (Intermediate VVV; 0.400 g, 1.267 mmol) was dissolved in DCM (12.67 ml) and cooled to 0° C. Boron tribromide (0.487 ml, 5.06 mmol) was added and the reaction was stirred for 30 minutes, then warmed to room temperature and stirred overnight. The reaction was cooled to 0° C. and carefully quenched with saturated sodium bicarbonate solution. The reaction was diluted with ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford crude 6-(benzylthio)-1-chloroisoquinolin-4-ol as an orange solid. (ESI) 302.1 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:23][CH:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32]C2CCCCO2)=[CH:28][CH:27]=1)[CH3:25])(=[O:22])[CH2:19][CH2:20][CH3:21]>CO>[C:18]([O:23][CH:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH3:25])(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=O)OC(C)c1ccc(OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CCCC(=O)OC(C)c1ccc(O)cc1
Yield: 13 %

Procedure:
In 150 ml of methanol was dissolved 0.1 mole of the S-form of 1-(4-(tetrahydro-2-pyranyloxy)phenyl)ethyl butyrate, 1.1 g of pyridinium p-toluenesulfonate was added thereto, and the mixture was subjected to reaction at room temperature for 2 hours. Then, methanol was distilled under reduced pressure, to which 200 ml of ether was added, and the mixture was washed with water. The resulting ether layer was dried with anhydrous magnesium sulfate, and ether was distilled under reduced pressure to give S-form of 1-(4-hydroxyphenyl)ethyl butyrate (yield: 13%).