Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C@H:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:11]([CH2:32][OH:33])[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1.CO>CN(C=O)C>[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@H:12]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:11]([CH2:32][O:33][CH2:39][C:38]2[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=2)[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5]
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO)[C@H]2OCc2ccccc2)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](COCc3ccc(Cl)cc3)[C@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A suspension of sodium hydride (71 mg, 1.8 mmol) in dry DMF (5 mL) was cooled to 0° C., and a solution of methyl 2-azido-4-O-benzyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (33) (680 mg, 1.5 mmol) in dry DMF (5 mL) was added dropwise in 30 minutes. The resulting solution was stirred at room temperature for 30 minutes and 4-chlorobenzyl chloride (295 mg, 1.5 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 4.5 hours, cooled at 0° C. and dry methanol (1 mL) was added dropwise. The reaction mixture was concentrated under reduced pressure, then xylene (10 mL) was co-evaporated from the residue. The residue was treated with hexane (10 mL) and filtered to give methyl 2-azido-4-O-benzyl-6-O-(4-chlorobenzyl)-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (34) (620 mg, 71%).
Reaction SMILES: [CH2:1]([C:4]12[CH2:11][O:10][C:7]([CH2:12][C:13]([O-:15])=[O:14])([O:8][CH2:9]1)[O:6][CH2:5]2)[CH2:2][CH3:3].[Na+].[CH2:17](Br)[C:18]#[CH:19].O>CN(C)C=O>[CH2:1]([C:4]12[CH2:9][O:8][C:7]([CH2:12][C:13]([O:15][CH2:19][C:18]#[CH:17])=[O:14])([O:6][CH2:5]1)[O:10][CH2:11]2)[CH2:2][CH3:3]
Reactant: CCCC12COC(CC(=O)[O-])(OC1)OC2
Reactant: C#CCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOC(=O)CC12OCC(CCC)(CO1)CO2
Reaction time: 24 h

Procedure:
A mixture of sodium 2-{4-n-propyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl}acetate (1.0 g) and propargyl bromide (1.8 ml of 80% solution in toluene, supplied by Aldrich) in dry dimethylformamide (30 ml) was stirred at 20° for 24 hours. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was chromatographed on silica (pre-eluted with 1:3 dichloromethane:hexane containing 3% triethylamine) and eluting with 1:3 dichloromethane:hexane containing 3% triethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(Cl)cc3C2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2cc(Cl)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 42 %

Procedure:
The title compound was prepared from 8-chloro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.6 g, 1.50 mmol), cyclohexene (0.304 mL, 3.75 mmol), and 1.0 M boron tribromide in dichloromethane (9.0 mL, 9.0 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting with dichloromethane to yield 4-[(8-chloro-6-methylphenanthridin-5(6H)-yl)sulfonyl]phenol (0.24 g, 0.63 mmol, 42%) as a white solid, m.p. 176-178° C.;
Reaction SMILES: C([Si](CC)(CC)[O:4][C:5]1([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1)C.Cl.C(O)C>O>[OH:4][C:5]1([C:12]([F:13])([F:14])[F:15])[CH:6]=[CH:7][C:8](=[O:11])[CH:9]=[CH:10]1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=CC(=O)C=C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1C=CC(O)(C(F)(F)F)C=C1
Yield: 90 %

Procedure:
A mixture of 200 mg (0.68 mmol) of 4-triethylsiloxy-4-trifluoromethyl-2,5-cyclohexadien-1-one and 1 mL of a solution of 1 part 37% hydrochloric acid in 9 parts absolute ethanol was heated at reflux overnight and poured into 10 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of dichloromethane. Combination, drying (MgSO4), and concentration of the organic layers afforded a residue which was purified by PTLC (one 2 mm silica gel plate eluted with 1% methanol - 99% dichloromethane) to give 109 mg (89% yield) of 4-hydroxy-4-trifluoromethyl-2,5-cyclohexadien-1-one. An analytical sample was obtained by crystallization from dichloromethane-hexane: mp 84°-86° C.; 1H NMR (CDCl3) δ 3.40 (broad s,1H), 6.40 (d, 2H, J=10 Hz), 6.89 (d, 2H, J=10 Hz); 13C NMR (CDCl3) 70.2 (q, JCF =30 Hz), 125.0 (q, JCF =286 Hz), 132.2 (d), 142.7 (d), 184.5 (s) ppm; 19F NMR (CDCl3) relative to CFCl3) -79.6 ppm (s); IR (KBr) 3374, 3105, 3022, 2919, 1693, 1671, 1632, 1620, 1396, 1249, 1235, 1195, 1174, 1089, 1078, 1003, 988, 980, 973, 863, 698 cm-1 ; mass spectrum (70 eV) m/z (relative intensity) 178 (5, M+), 109 (100), 81 (34), 53 (36). Anal. Calcd. for C7H5F3O2 : C, 47.20; H, 2.83. Found: C, 47.42; H, 2.80.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:22]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[Si:26]([O:1][CH2:2][CH2:3][C:4]#[N:5])([C:22]([CH3:25])([CH3:24])[CH3:23])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N#CCCO
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxypropanenitrile (1 g, 14.1 mmol), dimethylaminopyridine (0.34 g, 2.8 mmol), and triethylamine (2.9 ml, 21 mmol) in tetrahydrofuran (38 ml) was added tert-butyl(chloro)diphenylsilane (4.3 ml, 16.9 mmol). The mixture was stirred at room temperature overnight. The resulting white slurry was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified via flash chromatography (silica, 0-17% ethyl acetate in hexane) to afford the title compound. 1H NMR (600 MHz, d6-DMSO): δ 7.65 (dd, 4H), 7.43 (dt, 2H), 7.40 (d, 4H), 3.82 (t, 2H), 2.52 (t, 2H), 1.10 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([O:15][C:16]([C:18]1[CH:48]=[CH:47][C:21]([CH2:22][C:23]([CH2:36][CH2:37][C:38]2([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:40][CH2:39]2)(C(OCC=C)=O)[C:24]([O:26]CC=C)=[O:25])=[CH:20][CH:19]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([O:15][C:16]([C:18]1[CH:48]=[CH:47][C:21]([CH2:22][CH:23]([CH2:36][CH2:37][C:38]2([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:40][CH2:39]2)[C:24]([OH:26])=[O:25])=[CH:20][CH:19]=1)=[O:17])([CH3:13])([CH3:12])[CH3:14]
Reactant: C=CCOC(=O)C(CCC1(CC(=O)OCC)CC1)(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CCOC(=O)CC1(CCC(Cc2ccc(C(=O)OC(C)(C)C)cc2)C(=O)O)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
At room temperature, a solution of 7.42 ml (53.56 mmol) of triethylamine and 1.53 ml (40 mmol) of formic acid in 25 ml of dioxane is added to a solution of 8.58 g (16.2 mmol) of diallyl [4-(tert-butoxycarbonyl)benzyl]{2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}malonate, 298 mg (1.14 mmol) of triphenylphosphine and 73 mg (0.33 mmol) of palladium acetate in 75 ml of dioxane. The reaction mixture is then stirred at 100° C. for 2 hours. After complete conversion, the reaction solution is cooled and the solvent is removed under reduced pressure. The residue is then taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid (pH 4-5), and the organic phase is separated off. The aqueous phase is extracted three more times with ethyl acetate, and the organic phases are then combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated under reduced pressure. The crude product obtained is purified by flash chromatography on silica gel (700 g; mobile phase: petroleum ether/ethyl acetate 1:1). This gives 4.9 g (74.6% of theory) of a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=2)[CH:21]=[N:20]1>>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:2]3[CH:17]=[C:6]4[C:7]5[C:12]([CH2:13][CH2:14][N:5]4[C:4](=[O:18])[N:3]=3)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=5)[CH:26]=2)[CH:21]=[N:20]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2ccc3cn[nH]c3c2)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 1H-indazol-6-ylamine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 12.95 (br, 1H), 9.76 (s, 1H), 8.60 (s, 1H), 7.96 (s, 1H), 7.72-7.60 (2H), 7.15-6.95 (3H), 6.42 (s, 1H), 4.01 (t, 2H), 3.85 (s, 3H) and 2.98 (t, 2H); MS (ESI) (M+H)+ 360.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][C:8]2[C:10]([CH3:24])=[C:11]([O:16]CC3C=CC=CC=3)[C:12]([CH3:15])=[C:13]([CH3:14])[C:7]=2[O:6]1.[K+].[Br-]>>[ClH:1].[NH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][C:8]2[C:10]([CH3:24])=[C:11]([OH:16])[C:12]([CH3:15])=[C:13]([CH3:14])[C:7]=2[O:6]1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCN)O2
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: Cc1c(C)c2c(c(C)c1O)CC(CCN)O2

Procedure:
The de-benzylization of the 2-(RS)-(2-aminoethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethylbenzofurane hydrochloride is done with the same process as described in example 15. A white solid is obtained. m.p. 198°-199° C.; IR (KBr): 3410 (νOH), 3059 cm-1 (νNH3 +); 1H-NMR (D2O): δ3.4-2.7 (4H,m), 2.3-2.1 (2H,m), 2.1 (6H,s), 2.0 (3H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:29][CH3:30])[C:8]=2[C:7]1=[O:31].[H-].[Na+].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH:20]=[C:19]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:39]([CH3:38])(=[O:41])=[O:40])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:29][CH3:30])[C:8]=2[C:7]1=[O:31]
Reactant: COc1c2n(c3c(NC(=O)OC(C)(C)C)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c2n(c3c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Reaction time: 1 h

Procedure:
A cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-10-methoxy-4-(N-tert-butoxylcarbonyl-amino)-8-methyl-7,8-dihydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (0.74 g, 1.70 mmol) in anhydrous DMF (3 mL) was treated with sodium hydride (7 mg, 0.30 mmol). The resultant mixture was stirred at the same temperature for 30 minutes, and treated with methanesulfonyl chloride (34 mg, 0.30 mmol). After stirring at 0° for 1 hour, the product mixture was concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: NC1SC2C=C(C)C=CC=2C=1C(OCC)=O.FC1C=CC=CC=1[N+]([O-])=O.[CH3:27][C:28]1[CH:29]=[CH:30][C:31]2[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:34]([NH:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[N+:48]([O-])=O)[S:33][C:32]=2[CH:51]=1.Cl.O.O.[Sn](Cl)Cl>C(O)C.CS(C)=O>[NH2:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[NH:41][C:34]1[S:33][C:32]2[CH:51]=[C:28]([CH3:27])[CH:29]=[CH:30][C:31]=2[C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2cc(C)ccc12
Agent: CCOC(=O)c1c(N)sc2cc(C)ccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CS(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(Nc2ccccc2N)sc2cc(C)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-amino-6-methylbenzo[b]thiophene-3-carboxylate (4.18 g), 2-fluoronitrobenzene (2.5 g) and dimethyl sulfoxide (50 ml), crude crystals (7.5 g) of ethyl 6-methyl-2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Starting Material Synthesis Example 21 and using ethanol (50 ml), 18% hydrochloric acid (70 ml) and tin(II) chloride-dihydrate (16 g), ethyl 2-(2-aminoanilino)-6-methylbenzo[b]thiophene-3-carboxylate (3.7 g) was obtained.
Reaction SMILES: [Mg].Br[CH:3]([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6].Cl[C:11]1[N:16]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:15]2[N:14]=[C:13]([CH3:21])[CH:12]=1.[Cl-].[NH4+]>C1COCC1.BrC(CCC)CCC.II>[CH2:4]([CH:3]([C:11]1[N:16]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:15]2[N:14]=[C:13]([CH3:21])[CH:12]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:6]
Reactant: CCCC(Br)CCC
Reactant: Cc1cc(Cl)n2nc(C)cc2n1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(CCC)c1cc(C)nc2cc(C)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 1086.8 %

Procedure:
Heat a mixture of magnesium turnings (3.5 g, 144 mmol) and a catalytic amount of iodine (100 mg) in THF (100 mL) to 65° C. under a nitrogen atmosphere. Add a few drops of neat 4-bromoheptane and heat the mixture until the reaction starts. Then add a solution of 4-bromoheptane (17.6 mL, 94 9 mmol) in THF (42 mL) keeping the temperature at 65-70° C. over 2 h. Reflux the mixture for an additional hour and then cool the reaction to 22° C. Add the prepared Grignard reagent to a solution of 7-chloro-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (10.2 g; 53 3 mmol) in THF (60 mL) cooled to 0° C. under a nitrogen atmosphere. Add the magnesium reagent solution via cannula over 45 min while keeping the temperature below 10° C. Then stir the mixture for an additional 30 min at 5° C. Add to this mixture a 10% aqueous ammonium chloride solution (wt/wt) (125 mL) and stir at 22° C. for 30 min. Separate the organic layer and extract the aqueous layer with ethyl acetate (2×25 mL). Combine the organic layers and dry over sodium sulfate. Filter the mixture and evaporate the solvent. Purify the crude material by silica gel flash chromatography using an eluent of hexanes/ethyl acetate (5/1) to provide the title compound (8 g, 62%). ES/MS m/z 246 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[C:4]([Cl:13])[N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:13][C:4]1[N:3]=[C:2]([NH:23][C@H:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH3:22])[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=1
Reactant: Clc1cc(OCC2CC2)cc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cc(OCC2CC2)cc(Cl)n1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
130 mg of 2,6-dichloro-4-(cyclopropylmethoxy)pyridine, 92 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 36 mg 2-(di-t-butylphosphino)biphenyl, 144 mg of sodium t-butoxide and 14 mg of palladium acetate were added in turn to 2 ml of degassed toluene, and the mixture was stirred at 80° C. for 15 minutes under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 122 mg of the objective compound as colorless oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([O:7][N:8]([CH:21]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:24]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH:23]=[C:22]1[CH2:43]OS(C)(=O)=O)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH2:6]>O.CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:4]([O:7][N:8]([CH:21]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C@H:24]([CH2:34][O:35][Si:36]([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:38])[CH3:37])[CH:23]=[C:22]1[CH2:43][C:1]#[N:2])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[CH:5]=[CH2:6]
Reactant: [C-]#N
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COS(C)(=O)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CC#N)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of sodium cyanide (4.94 g, 100.85 mmol) in water (20.0 mL) was added (2S)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(((methylsulfonyl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (crude, 20.17 mmol) in DMF (100 mL). The mixture was then stirred at room temperature for 15 h. It became a dark orange solution. It was then diluted with sat. NaHCO3 and water and extracted with ethyl acetate, dried over MgSO4. The crude was subjected to silica gel column eluting with 0-100% ethyl acetate/hexanes to give a pale yellow oil, 5.92 g, 47.1%.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[N:19]=[N:20][NH:21][CH:22]=3)=[C:9]([O:23]CC3C=CC=CC=3)[C:8]2=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=O)C=CC=CC=1>C1COCC1>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[N:19]=[N:20][NH:21][CH:22]=3)=[C:9]([OH:23])[C:8]2=[O:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c(OCc2ccccc2)c(CCCCCc2c[nH]nn2)ccn1-c1ccccc1
Agent: O=c1c(O)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Solvent: C1CCOC1
Product: O=c1c(O)c(CCCCCc2c[nH]nn2)ccn1-c1ccccc1
Yield: 69.4 %

Procedure:
Reaction of 158d (0.085 g, 0.20 mmol) in anhydrous THF as described for synthesis of 159b gave 159d (0.045 g, 68%) of pure product. 1H NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.43 (t, J=7.7 Hz, 2H), 7.32 (t, J=7.4 Hz, 1H), 7.10 (dd, J=6.8, 1.6 Hz, 1H), 6.65 (dd, J=7.2, 1.5 Hz, 1H), 6.05 (1, J=7.0 Hz, 1H), 4.38 (t, J=7.0 Hz, 2H), 3.89 (t, J=7.2 Hz, 2H), 1.89 (m, 2H), 1.67 (m, 2H), 1.25 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 158.44, 147.67, 146.61, 130.51, 128.72, 128.01, 126.71, 125.57, 119.54, 113.81, 106.86, 49.86, 49.38, 29.58, 28.31, 23.19. HRMS (FAB) calcd for C18H21N4O2 [M+H]+ 325.1664. found 325.1683.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])/[CH:31]=[CH:32]/C)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.NC1N=CN=C2N(C3CCCN(S(C=C)(=O)=O)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N(C3CCCN(C(=O)C#C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N(C3CCN(C(=O)C=C)CC3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N([C@@H]3CCN(C(=O)C=C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.NC1N=CN=C2N([C@H]3CCN(C(=O)C=C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12.C(=O)C=C.NC1N=CN=C2N(C3CCCN(C(=O)/C=C/CN(C)C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3)C=12>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[CH:31]=[CH2:32])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: C/C=C/C(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: C#CC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: C=CC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Agent: C=CC(=O)N1CC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Product: C=CC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1

Procedure:
(E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)but-2-en-1-one (Compound 5); 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)sulfonylethene (Compound 6); 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one (Compound 8); 1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 9); N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)acrylamide (Compound 10); 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 11); 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 12); 1-(R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 13); 1-(S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 14); and (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Compound 15).