Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: COCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(COC)cc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
Ethyl 4-iodobenzoate (5.5 g), tetrakis(triphenylphosphine)palladium (1.2 g), and cesium carbonate (9.8 g) were added to an ethanol (0.10 L) solution of 2-[4-(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.1 g), as obtained in Example 3-(1). The mixture was stirred for 30 minutes at 80° C., and then the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (hexane/ethyl acetate=85/15) to obtain ethyl 4′-(methoxymethyl)biphenyl-4-carboxylate (light yellow solid) (3.5 g, 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1B(O)O>>[CH3:17][O:16][C:12]1[C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:8])=[C:10]([Cl:9])[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(Cl)c1B(O)O
Reactant: Clc1ccccc1Br
Product: COc1cccc(Cl)c1-c1ccccc1Cl
Yield: 73.5 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (15.6 g, 80.64 mol) generally according to the procedure described for Intermediate 37 afforded 5.0 g (73%) of 6-chloro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (60 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (1.05 g, 26.35 mmol) and allyl bromide (3.19 g, 26.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol (2.8 g, 10.03 mmol) with m-chloroperoxybenzoic acid (4.6 g, 15.0 mmol, 77%) and potassium carbonate (1.6 g, 12.0 mmol) generally according to the procedure described for Intermediate 9 afforded 2.2 g (74%) of (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.6 g, 5.42 mmol) with p-toluenesulfonyl chloride (1.55 g, 8.13 mmol) generally according to the procedure described for Intermediate 10 gave 2.1 g (86%) of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.44 mmol) with sodium azide (0.2 g, 3.08 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.43 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.3 g, 1.14 mmol) generally according to the procedure described for Example 154 provided 0.036 g (24%) of (±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 221-223° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[S:10](Cl)(=[O:12])=[O:11])#[N:2].[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1.O.Cl>C1COCC1>[F:9][C:8]1[C:3]2[C:1](=[NH:2])[N:18]([CH2:17][CH:14]3[CH2:16][CH2:15]3)[S:10](=[O:11])(=[O:12])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CC1
Reactant: N#Cc1c(F)cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N=C1c2c(F)cccc2S(=O)(=O)N1CC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 mg of 2-cyano-3-fluoro-benzenesulfonyl chloride (EP33984 A1 19810819) is added to a solution of 0.85 ml of cyclopropylmethylamin in 3.5 ml of THF. After stirring for 3 hours at room temperature the reaction mixture is poured into water. The mixture is acidified with hydrochloric acid (˜pH3) and extracted three times with methylenchloride. The combined organic phases are dried (Na2SO4), filtered and concentrated. Preparative HPLC affords 16 mg of 4-fluoro-2-cyclopropylmethyl-1,2-benzisothiazol-3(2H)-imine 1,1-dioxide as an orange solid (m.p. 90-93° C.).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C@@H:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19])[CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])C>C(O)C>[C:6]([C@@H:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19])[CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([OH:7])=[O:5]
Reactant: CCCCCCSC[C@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCSC[C@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A 3.2 ml quantity of a 1N aqueous solution of sodium hydroxide was added with ice cooling and stirring to a solution of 600 mg of the N-[(R)-1-ethoxycarbonyl-2-hexylthioethyl]-alanyl-(S)-proline (α-isomer) obtained in Example 4 in 8 ml of ethanol. The mixture was stirred at room temperature for 2.5 hours, and applied to a column (Dowex 50W-X8(H+)). The reaction product was sufficiently washed with water, and eluted with a 4% aqueous solution of pyridine. Fractions of the title compound were collected and lyophilized. The powder thus obtained was reprecipitated with ethanolether, giving the title compound. Yield 270 mg.
Reaction SMILES: C1(CC(CC(=O)NCCC2C=CC=CC=2)C(N(C(=O)[C@H](CC2N=CNC=2)N)N)=O)C2C(=CC=CC=2)C=CC=1.Cl.N(OCCC(C)C)=O.[C:48]1([CH2:58][CH:59]([CH2:75][C:76](=[O:86])[NH:77][CH2:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:60]([NH:62][C@H:63]([C:70]([N:72]=[N+]=[N-])=[O:71])[CH2:64][C:65]2[N:69]=[CH:68][NH:67][CH:66]=2)=[O:61])[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1.[N-]=[N+]=[N-].Cl.Cl.[CH2:92]([NH:99][CH2:100][CH:101]([OH:108])[C@@H:102](N)[CH2:103][CH:104]([CH3:106])[CH3:105])[C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1>CN(C)C=O.C(N(CC)CC)C>[CH2:92]([NH:99][CH2:100][CH:101]([OH:108])[C@@H:102]([NH:72][C:70](=[O:71])[C@H:63]([CH2:64][C:65]1[N:69]=[CH:68][NH:67][CH:66]=1)[NH:62][C:60](=[O:61])[CH:59]([CH2:58][C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1)[CH2:75][C:76](=[O:86])[NH:77][CH2:78][CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)[CH2:103][CH:104]([CH3:105])[CH3:106])[C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1
Reactant: CC(C)C[C@H](N)C(O)CNCc1ccccc1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Agent: CC(C)CCON=O
Agent: Cl
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)N(N)C(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12)C(O)CNCc1ccccc1

Procedure:
To a suspension of 66 mg of N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide in 5 ml of dry N,N-dimethylformamide were added successively 0.08 ml of a dry 5.1N-hydrogen chloride in N,N-dimethylformamide solution and 0.02 ml of isoamyl nitrite at -20° C. with stirring, and the mixture was stirred under ice-cooling. After disappearance of hydrazide compound, the reaction mixture was cooled to -30° C., and neutralized by adding 0.06 ml of triethylamine to prepare a solution of N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine azide. The azide solution was added dropwise to a solution of 40 mg of (3S)-N-benzyl-3-amino-2-hydroxy-5-methylhexylamine dihydrochloride and 0.018 ml of triethylamine in 2 ml of dry N,N-dimethylformamide under ice-cooling, and the mixture was stirred for 16 hours under ice-cooling. The reaction mixture was evaporated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=15/1 by volume) to obtain 33 mg of (2RS, 3S)-N-benzyl-3-{N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexylamine as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][C:10]1[O:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:12][CH:11]=1
Reactant: Cc1cccc(-c2ccco2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(-c2ccc(Br)o2)c1
Reaction time: 18 h
Yield: 91.7 %

Procedure:
A stirred solution of 10.0 g (0.063 mol) of 2-(3-methylphenyl)furan in 250 mL of carbon tetrachloride was heated to reflux, and 0.1 g of benzoyl peroxide was added. The solution was heated at reflux for ten minutes, then an additional 0.1 g of benzoyl peroxide followed by 11.2 g (0.063 mol) of N-bromosuccinimide, were added. Upon complete addition, refluxing was continued for an additional 18 hours. The reaction mixture was cooled, filtered, and the filtrate washed with 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 13.7 g of 2-bromo-5-(3-methylphenyl)furan.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=1>>[CH3:22][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:20])=[CH:15][CH:14]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1

Procedure:
Racemic phenylalanine and p-toluoyl chloride were processed as described in Example 26A to provide the desired product.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][C:18]([O:20]C)=O)[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.CO.C(O)(=O)C.[NH3:28]>O>[C:18]([CH2:17][CH:6]([CH2:5][SH:4])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:20])[NH2:28]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: N
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
2.1 g. of the product from Example 81 is dissolved in a mixture of water (40 ml.) and concentrated ammonia (40 ml.). After one hour the reaction mixture is concentrated to 1/3 volume, and applied to a column of Dowex 50 resin in the hydrogen cycle. The product is eluted with water. The aqueous is extracted with ethyl acetate and then concentrated to dryness to yield 1.4 g. of the named product Rf 0.50 (silica gel-Chloroform:methanol:acetic acid:water).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:13][CH2:14][C@H:15]1[CH2:17][C@@H:16]1[CH2:18]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[C-:21]#[N:22].[K+]>C1COCC1>[CH2:6]([O:13][CH2:14][C@H:15]1[CH2:17][C@@H:16]1[CH2:18][C:21]#[N:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC[C@H]1C[C@@H]1COCc1ccccc1
Reactant: [C-]#N
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC[C@H]1C[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Methanesulfonyl chloride (443 μL, 5.72 mmol) was added to a solution of ((1S,2S)-2-((benzyloxy)methyl)cyclopropyl)methanol (1.00 g, 5.20 mmol) and TEA (797 μL, 5.72 mmol) in THF (15 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water (80 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in DMF (15 mL), and potassium cyanide (0.677 g, 10.40 mmol) was added thereto at room temperature. The reaction mixture was stirred at 60° C. for 2 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 17→38% ethyl acetate/hexane) to give 2-((1R,2S)-2-((benzyloxy)methyl)cyclopropyl)acetonitrile (782 mg, 3.89 mmol, 75%) as a colorless oil.
Reaction SMILES: [OH:1][CH:2](CN1CCC(COC2C=CC=CC=2)CC1)COC1C=CC(C)=C([N+]([O-])=O)C=1[N+]([O-])=O.C(N)CC.[OH:37][CH:38]([CH2:55][N:56]1[CH2:61][CH2:60][CH:59]([CH2:62][O:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:58][CH2:57]1)[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[C:43]([N+:48]([O-])=O)[C:42]=1[NH:51][CH2:52][CH2:53][CH3:54]>[Pt]=O>[OH:37][CH:38]([CH2:55][N:56]1[CH2:61][CH2:60][CH:59]([CH2:62][O:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:58][CH2:57]1)[CH2:39][O:40][C:41]1[C:42]2[N:51]([CH2:52][CH2:53][CH3:54])[C:2](=[O:1])[NH:48][C:43]=2[C:44]([CH3:47])=[CH:45][CH:46]=1
Reactant: CCCNc1c(OCC(O)CN2CCC(COc3ccccc3)CC2)ccc(C)c1[N+](=O)[O-]
Reactant: Cc1ccc(OCC(O)CN2CCC(COc3ccccc3)CC2)c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCCN
Product: CCCn1c(=O)[nH]c2c(C)ccc(OCC(O)CN3CCC(COc4ccccc4)CC3)c21

Procedure:
15.0 g. 1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-4-methyl-2,3-dinitrobenzene (see preparation of the starting material for Example (4a) are heated under reflux in 12 ml. n-propylamine for 3.5 hours. After cooling, there are isolated 8.8 g. (59% of theory) crystalline 1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-4-methyl-2-propylamino-3-nitrobenzene; m.p. 91°-93° C. This compound is hydrogenated in the presence of platinum oxide to give the desired 3-amino-1-[2-hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-4-methyl-2-propylaminobenzene.
Reaction SMILES: [O:1]1[C:9]2[C:8]([OH:10])=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[N+:11]([O-])([OH:13])=[O:12]>>[N+:11]([C:7]1[N:6]=[CH:5][C:4]2[CH:3]=[CH:2][O:1][C:9]=2[C:8]=1[OH:10])([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Oc1cncc2ccoc12
Product: O=[N+]([O-])c1ncc2ccoc2c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
The reaction was conducted with 1 g starting material/10 mL 90% aq. nitric acid ratio. Reactions were run at 2×200 mg, 500 mg, 4×1.05 g scales. The nitric acid was cooled down to 0° C. and furo[3,2-c]pyridin-7-ol was added in portions slowly. The color of the reaction mixture turned to deep orange/red. The reaction mixture was stirred at 0° C. for 30 min. LC-MS showed complete consumption of the starting material. The mixture was poured into crashed ice to quench reaction, then extracted with DCM (3×10 mL for 200 mg scale). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The resulting yellow solid (1.83 g, 26% yield) was directly used in the next step. 1H NMR (CD3OD, 400 MHz): δ=7.16 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.39 (s, 1H). MS (ES+): 181.01 [MH+].
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:15]3[CH:14]=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30].C(N(CC)CC)C>CN(C=O)C>[CH2:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[N:13]=[CH:14][C:15]=23)[CH2:23][CH2:24]1)=[O:30])[CH2:33][CH2:34][CH3:35]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Reactant: CCCCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (0.17 mmol, 60 mg), n-butyl chloroformate (0.19 mmol, 24 μL) and triethylamine (0.51 mmol, 71 μL) were dissolved in DMF (2 mL) and stirred for 60 minutes at room temperature. The reaction mixture was quenched with water followed by an extraction with ethylacetate. Removal of organic solvents in vacuo provided Compound A48 as a white solid (40 mg, 50%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.67 (s, 1H); 8.62 (d, 2H); 8.26 (s, 1H); 8.11 (d, 2H); 5.62 (h, 1H); 4.12 (t, 2H); 3.92 (m, 2H); 3.39 (m, 2H); 3.10 (s, 3H); 2.11 (m, 2H); 1.65 (m, 2H), 1.56 (p, 2H); 1.42 (s, 2H); 0.97 (t, 3H). Exact mass calculated for C22H27N5O5S 473.55, found 474.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[CH2:6][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
3-(4-Benzyloxy-phenyl)-3-hydroxy-2,2-dimethyl-propionic acid ethyl ester (1.5 g, 4.57 mmol) obtained in Step B was dissolved in DCM (20 mL). Triethylsilane (0.81 mL, 5.03 mmol) was added thereto, and the reactant was cooled to 0˜5° C. After boron trifluoride diethylether (0.62 mL, 5.03 mmol) was added thereto at 0˜5° C., the mixture was heated to room temperature and stirred for 2 hours. Saturated sodium bicarbonate was added thereto, and the reactant was stirred. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (1.34 g, 94%).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].CO[C:13](OC)([CH3:15])[CH3:14]>CC(C)=O.[Cu](Cl)Cl>[CH3:14][C:13]1([CH3:15])[O:1][C@@H:2]([C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: COC(C)(C)OC
Reactant: C[C@@H](C(=O)O)[C@H](O)C(=O)O
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: C[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
To a solution of (2S,3R)-2-hydroxy-3-methylsuccinic acid (2.40 g; 16.2 mmol; 1.0 eq.) in acetone (80.0 mL) was added 2,2-dimethoxypropane (3.98 g; 32.4 mmol; 2.0 eq.) and copper(II) chloride (218 mg; 1.62 mmol; 0.1 eq.). The resulting reaction mixture was stirred for 4 h at RT. The reaction mixture was evaporated and the residue taken up in CHCl3. Activated charcoal is added and the resulting mixture stirred for one hour. Filtration on a pad of celite gave the title product (mixture of diastereoisomers) as a greenish oil (2.48 g, 82%) used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5990.1 %

Procedure:
To a stirred solution of 2-chloroisonicotinic acid (3.15 g, 20 mmol) in anhydrous THF (40 ml) cooled in an ice bath, was added borane-methyl sulfide complex (6 mL, 60 mmol). After 1 hr, the mixture was stirred for 48 hr at room temperature. The mixture was cooled in an ice bath and conc. HCl (30 ml) was added and stirred for 30 min. The mixture was then basified by addition of 50% aqueous NaOH (30 ml). The product was extracted with dichloromethane, dried with anhydrous potassium carbonate, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (5:1)) to afford 172 g (60%) of 2-chloro-4-pyridinemethanol as a white solid. m.p. 77-79° C.; 1H NMR (200 MHz, CDCl3) δ 2.97 (1H, br. s), 4.74 (2H, s), 7.20 (1H, d, J=5.7 Hz), 7.36 (1H, s), 8.28 (1H, d, J=5.7 Hz).
Reaction SMILES: [CH3:1][CH:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][N:11]([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:19][Sb-:20]([F:25])([F:24])([F:23])([F:22])[F:21].[Na+]>CO>[F:19][Sb-:20]([F:25])([F:24])([F:23])([F:22])[F:21].[CH3:1][CH:2]([N+:11]([CH3:18])([CH3:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(Cl)c1ccccc1
Reactant: CN(C)c1ccccc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Product: CC(c1ccccc1)[N+](C)(C)c1ccccc1

Procedure:
4.218 g (0.03 mol) of α-methylbenzyl chloride and 3.638 g (0.03 mol) of N,N-dimethylaniline were reacted in 40 ml of methanol at 40° C. for 3 days. After the reaction, the solvent was evaporated in vacuo and ether-water was added to the residue to extract unreacted reactants in the etherial layer. To the aqueous layer was added 7.77 g (0.03 mol) of sodium hexafluoroantimonate. The resulting crystals were suction filtered, washed and dried to give the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].C(N(CC)CC)C.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:2]([O:4][C:5](=[O:9])[CH:6]([NH:7][C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:21])[CH3:8])[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C)NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of L-alanine ethyl ester hydrochloride (50 g, 325 mmol) in anhydrous dichloromethane (800 mL) added triethylamine (65.8 g, 650 mmol) and stirred at room temperature for 30 minutes. To the reaction mixture cyclopropanecarbonyl chloride (50.96 g, 0.487 mole) was slowly added and stirred at room temperature for overnight. The reaction mixture was then poured into a cold solution of saturated aqueous sodium bicarbonate, and the crude product extracted with dichloromethane, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using a mixture of ethyl acetate:hexane (1:1) as eluant to give 2-(cyclopropanecarbonyl-amino)-propionic acid ethyl ester (163) (58.0 g, 96% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2>C(Cl)(Cl)Cl>[N:1]1([CH2:8][C:9]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc(CCl)c2cccnc12
Reactant: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: Oc1ccc(CN2CCCCC2)c2cccnc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.8 %

Procedure:
Piperidine (2 ml; 20.26 mmol) was added to a solution of 5-chloromethyl-8-hydroxyquinoline (1.87 g; 8.13 mmol) in CHCl3 (50 ml) at 5° C. The mixture was stirred for two days at room temperature. Then the mixture was evaporated under vacuum to dryness. The residue was dissolved in CHCl3, washed with 5% NaHCO3 (2×50 ml), followed by brine (50 ml), dried over Na2SO4 and evaporated to dryness. The residue was crystallized from hexane to give 1.0 g of the title product (50%). M.p. 96° C. TLC (CHCl3; MeOH; NH3=8:2:0.5). Rf=0.63.