Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:40]1[C@@H:44]([CH:45]([CH3:47])[CH3:46])[CH2:43][O:42][C:41]1=[O:48])[C@H:3]([CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC([C@H]1COC(=O)N1C(=O)CCC1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C.BrCC(OCC1C=CC=CC=1)=O>>[O:1]=[C:2]([N:40]1[C@@H:44]([CH:45]([CH3:46])[CH3:47])[CH2:43][O:42][C:41]1=[O:48])[CH:3]([CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:20]=1)[CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OCc1ccccc1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)[C@H]1COC(=O)N1C(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C(CBr)OCc1ccccc1
Product: CC(C)[C@H]1COC(=O)N1C(=O)C(CC(=O)OCc1ccccc1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
3-{1,4-Dioxo-4-(phenylmethoxy)-2(R)-{[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butyl}-4(S)-(1-methylethyl)-2-oxazolidinone: By following the procedure of example 2, section (f), but replacing the product of section (e) of that example with 4(S)-(1-methylethyl)-3-{1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl}-2-oxazolidinone of section (b) of this example, and replacing tert-butyl 2-bromoacetate with benzyl 2-bromoacetate, 3-{1,4-dioxo-4-(phenylmethoxy)-2-{[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butyl}-4(S)-(1-methylethyl)-2-oxazolidinone was obtained as a mixture of 2(R)- and 2(S)-epimers in a 8 to 1 ratio by weight. Separation of the epimers by flash chromatography (SiO2, eluent: hexane-EtOAc, 1:2) yielded the desired 2(R)-epimer (Rf=0.25, eluent: hexane-EtOAc,1:2). The 1H NMR(CDCl3) of the 2(R)-epimer showed δ7.34-7.28 (m,15H), 7.13-7.08 (m,6H), 6.59 (d, J=1.3 Hz,1H), 5.06 (s,2H), 4.55-4.45 (m,1H), 4.38 (td, J=3.9 Hz,5.4 Hz,1H), 4.15-4.10 (m,2H), 2.97 (dd, J=10.3 Hz,16.9 Hz,1H), 2.88 (dd, J=6.3 Hz,14.3 Hz,1H), 2.73 (dd, J=7.0 Hz,14.3 Hz,1H), 2.59 (dd, J=4.4 Hz,16.9 Hz,1H), 2.32 (hept d, J=3.9 Hz,7.0 Hz,1H), 0.87 (d, J=7.1 Hz,3H), 0.85 (d, J=6.8 Hz,3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][C:22]1[N:23]=[C:24]([NH:29][CH2:30][CH2:31][NH2:32])[S:25][C:26]=1[C:27]#[N:28]>CS(C)=O>[NH2:21][C:22]1[N:23]=[C:24]([NH:29][CH2:30][CH2:31][NH:32][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=[C:2]([Br:1])[N:3]=2)[S:25][C:26]=1[C:27]#[N:28]
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: N#Cc1sc(NCCN)nc1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1sc(NCCNc2nc(Br)cn3ccnc23)nc1N
Temperature: 140 °C

Procedure:
300 mg (1.08 mmol) of 6,8-dibromoimidazo[1,2-a]pyrazine were dissolved in 10 ml of DMSO, and 0.6 ml (4.3 mmol) of triethylamine and 360 mg (1.3 mmol) of 4-amino-2-[(2-aminoethyl)amino]-1,3-thiazole-5-carbonitrile dihydrochloride (Example 8A) were added. The mixture was heated at 140° C. in a microwave for 1 h. Purification by preparative HPLC gave 376 mg (83% of theory) of the product as a solid.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([NH:13][CH2:14][C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=3C)[C:7]2=[N:6][C:5]=1[CH3:23])(=[O:3])[CH3:2].[CH3:24]O.[BH4-].[Na+]>O1CCCC1>[CH3:21][C:20]1[C:19]([CH3:24])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:14][NH:13][C:12]1[C:7]2[N:8]([C:4]([CH:1]([OH:3])[CH3:2])=[C:5]([CH3:23])[N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)c1c(C)nc2c(NCc3c(C)cccc3C)cccn12
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CNc2cccn3c(C(C)O)c(C)nc23)c1C
Reaction time: 1 h

Procedure:
To a mixture of 3-acetyl-8-(2,6-dimethylbenzylamino)-2-methylimidazo[1,2-a]pyridine (500 mg, 1.63 mmol) and methanol (20 ml) was sodium borohydride (62 mg, 1.63 mmol) added in portions. Tetrahydrofurane was added and the mixture stirred for 1 hour. TLC showed starting material and sodium borohydride (62 mg, 1.63 mmol) was added and the mixture stirred for 1.5 hour. The solvent was removed under reduced pressure and to the residue, methylene chloride and water was added. pH was adjusted to pH=3 with hydrogen chloride (conc.) and thereafter alkaline with sodium bicarbonate. The methylene chloride layer was separated washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was treated with ethanol/ethyl acetate and after filtration (410 mg, 81%).
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([N:17]1[C:21](=O)[C@@H:20]([OH:23])[C@H:19]([OH:24])[C:18]1=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].Cl.[F-].[Na+].[OH-].[Na+]>COCCOCCOC>[CH2:10]([N:17]1[CH2:21][C@@H:20]([OH:23])[C@H:19]([OH:24])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1[C@@H](O)[C@H](O)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Boron trifluoride ethyl etherate (36 ml, 0.29 mol) in diglyme (150 ml) was cooled to 0+ C. (3S,4S)-1-Benzyl-3,4-dihydroxy-2,5-dioxopyrrolidine (16 g, 72 mmol) and sodium borohydride were added slowly. The mixture was stirred at 70° C. for 2 hours. 6 N hydrochloric acid (100 ml) was added slowly and the mixture was heated at 70° C. for 15 minutes. Sodium fluoride (44.5 g, 1 mol) was added and the mixture was heated at reflux temperature for 1/2 hour. The mixture was cooled to room temperature. 20% Aqueous sodium hydroxide (85 ml) was added and the resulting mixture was filtered. The organic phase was isolated and evaporated to dryness. The residue was partitioned between water and diethyl ether. The water phase was extracted with ether (4×500 ml). The collected organic phases were dried over magnesium sulphate and evaporated to dryness. Recrystallization from ethyl acetate (25 ml) gave (3R,4R)-1-benzyl-3,4-pyrrolidinediol (12.3 g, yield: 88%) as white crystals.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:14][CH2:15][CH3:16]>>[CH2:18]([N:17]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCNCCCCCCNCCCC
Reactant: CCCCCCCCCC1CO1
Product: CCCCCCCCCC(O)CN(CCCC)CCCCCCN(CCCC)CC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and N,N'-dibutylhexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-butyl-2-hydroxyundecylamine] (I: R= CH3 (CH2)8, R' = CH3 (CH2)3, X= (CH2)6, Z= H).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([CH3:22])=[O:21]>O.C(#N)C>[C:20]([C:16]1[O:15][C:19]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)(=[O:21])[CH3:22]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(=O)c1ccco1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(C#N)cc2)o1
Reaction time: 0.75 h
Yield: 18 %

Procedure:
A mixture of 50 g (0.42 mole) of p-aminobenzonitrile, 146 ml of concentrated hydrochloric acid, and 106 ml of H2O was heated at 80° for for 20 minutes and then cooled to 0°. A solution of 29 g (0.42 mole) of sodium nitrite in 105 ml of H2O was added dropwise while maintaining the temperature at 0°-5° by means of an ice bath. The reaction was kept at 0° for 45 minutes. A solution of 47 g (0.42 mole) of methyl 2-furyl ketone in 43 ml of acetonitrile was added followed by a solution of 10 g of CuCl2 .2H2O in 50 ml of water. The reaction became exothermic and was controlled below 40°. The reaction was allowed to stand overnight. The aqueous layer was decanted and the residual semisolid was extracted with 6000 ml of refluxing hexane. The hexane was cooled and the resulting precipitate was filtered and air dried to yield 16 g (18%) of p-(5-acetyl-2-furyl)benzonitrile. An analytical sample was prepared by recrystallizing a sample from hexane/charcoal, m.p. 115°-116°.
Reaction SMILES: OC1(C2C=CC=CC=2)[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:19][C:18]=3[C:28]([F:31])([F:30])[F:29])=[O:16])=[CH:10][CH:9]=2)CC1.N[C:39]1C=C2C(=NC=1)NC=C2>>[NH:5]1[C:8]2=[N:13][CH:12]=[C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([CH3:39])[CH2:23]4)=[N:19][C:18]=3[C:28]([F:30])([F:31])[F:29])=[O:16])[CH:10]=[C:9]2[CH:7]=[CH:6]1
Reactant: O=C(Nc1ccc(N2CCC(O)(c3ccccc3)CC2)nc1)c1oc(N2CCCCC2)nc1C(F)(F)F
Reactant: Nc1cnc2[nH]ccc2c1
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3cnc4[nH]ccc4c3)o2)C1

Procedure:
Compound 54 was prepared by the general procedure for compound 1, by using compound A-10 and 5-amino-7-azaindole as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 11.67 (s, 1H), 10.21 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 7.50 (s, 1H), 6.46 (m, 1H), 4.13 (m, 2H), 3.07 (m, 1H), 2.75 (t, 1H, J=11.7 Hz), 1.77 (m, 2H), 1.67 (m, 1H), 1.54 (m, 1H), 1.15 (m, 1H), 0.94 (d, 3H, J=6.3 Hz). MS (M+1): 394.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[S:30]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1c(Cl)cccc1Cl

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 2,6-dichlorophenylsulfonyl chloride in presence of N,N-diisopropyl ethyl amine in dichloromethane to give 2,6-dichloro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless oil. MS: 549.3 ([M+NH4]+)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(SCCCCO)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(SCCCCOCc2ccccc2)cc1

Procedure:
A mixture of 4-(4-nitrophenylthio)-1-butanol (10 mmol) and potassium carbonate (20 mmol) in acetone (100 mL) is treated with a solution of benzylbromide (11 mmol) in acetone (50 mL). When the addition is completed the mixture is heated at reflux temperature for 18 hrs, cooled, filtered, and the filtrate is concentrated to obtain the title compound.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH2:7]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.C(Cl)Cl>[N:23]([CH:6]1[CH2:9][N:8]([C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH2:7]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: [N-]=[N+]=NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl methanesulfonate (200 mg, 0.61 mmol) was dissolved in DMSO (4 ml) and sodium azide (157 mg, 2.41 mmol) was added. The reaction was heated at 80° C. for 48 hours and then diluted with DCM (30 ml) and washed with water (10 ml), dried (MgSO4), filtered and concentrated at reduced pressure giving a yellow solid (140 mg, 83%), which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C:27](=[O:38])[C@@H:26]([CH3:39])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:40].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:30][C@H:28]1[C:27](=[O:38])[C@@H:26]([CH3:39])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:40])=[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:14]=2)[CH2:29]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)C1=O
Yield: 98 %

Procedure:
Tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate was treated with 25% TFA/CH2Cl2 for 30 minutes. The volatiles were removed in vacuo, the residue was dissolved in DMSO and purified by reverse phase HPLC to yield N-(4-((1R,3R,5S)-3-amino-5-methyl-4-oxocyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 98% yield. LC/MS (m/z)=455.1 (MH+), Rt=0.57 min. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.55 (s, 1H), 8.55 (s, 1H), 8.47 (d, J=4.0, 1H), 8.37 (dd, J=8.0, 4.0, 1H), 8.21 (t, J=8.0, 1H), 8.16 (broad doublet, J=4.0, 2H), 7.67-7.74 (m, 1H), 7.40 (d, J=8.0, 1H), 7.36 (t, J=8.0, 2H), 4.20-4.26 (m, 1H), 3.50-3.70 (m, 2H), 2.76-2.82 (m, 1H), 2.49-2.54 (m, 1H), 2.32-2.36 (m, 1H), 2.16-2.18 (m, 1H), 1.91 (q, J=12, 1H), 1.65 (q, J=12, 1H), 0.97 (d, J=8.0, 3H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:22])[CH2:7][C:8]([NH:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)=[O:9])C>C1COCC1.O>[C:16]1([C:13]2[CH:12]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][C:6]([OH:22])=[O:5])[O:15][N:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(-c2ccccc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(=O)Nc1cc(-c2ccccc2)no1
Reaction time: 8 h
Yield: 65.3 %

Procedure:
NaOH (57 mg, 1.4 mmol) was added to a stirred solution of N-(3-phenyl-isoxazol-5-yl)-malonamic acid ethyl ester (78 mg, 0.28 mmol) in a mixture of THF (12 mL) and H2O (12 mL) and stirring was continued at ambient temperature overnight. The reaction mixture was concentrated. The residue was diluted with water, washed with diethyl ether, acidified with concentrated HCl. The precipitate was filtered to afford 45 mg (64.28% Yield) of N-(3-phenyl-isoxazol-5-yl)-malonamic acid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:17]1([C:22]2[CH:26]=[C:25]([NH2:27])[N:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[N:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:17]1([C:22]2[CH:26]=[C:25]([NH:27][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])[N:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[N:23]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Cc1ccccc1-n1nc(C2CCCC2)cc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1nc(C2CCCC2)cc1Nc1ncccc1C(=O)O
Temperature: 150 °C
Yield: 22.9 %

Procedure:
A mixture of 2-chloronicotinic acid (113 mg, 0.72 mmol), potassium carbonate (199 mg, 1.44 mmol), 3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (174 mg, 0.72 mmol) (Intermediate E), and copper (II) acetate (6.5 mg, 0.04 mmol) in DMF (3 mL) was heated (150° C.) in a sealed tube for 16 h. The mixture was cooled to rt, filtered through a silica gel plug using ethyl acetate as eluent, concentrated to dryness, and subjected to HPLC purification using a gradient elution from 30% to 90% acetonitrile in water to afford 59.7 mg (23%) of the desired product.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]([CH3:8])[O:5][C:6]=1[CH3:7].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(Cl)Cl>[CH3:7][CH:6]1[C:2](=[O:1])[C:3]([O:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH3:8])[O:5]1
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C(OC(=O)C(C)(C)C)C(=O)C(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Hydroxy-2,5-dimethyl-3(2H)-furanone (1.0 g, TOKYO KASEI KOGYO CO., LTD.) and 4-dimethylaminopyridine (0.05 g) were dissolved in a mixture solution of pyridine (10 ml) and methylene chloride (10 ml) under an argon stream in a 50 ml two-necked flask. To the resulting solution, pivaloyl chloride (1.06 ml) was added dropwise under cooling with ice and the mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture solution was mixed with a 0.5N ice-cooled aqueous solution of HCl (10 ml) and subjected to extraction with diethyl ether (30 ml). The ether-extraction was repeated 3 times. The ether layer was washed 3 times with a 0.5N aqueous solution of HCl, twice with a saturated aqueous solution of sodium bicarbonate and once with a saturated saline solution and dried over sodium sulfate. The ether layer was then concentrated under a reduced pressure and applied to a silica gel column for separation and purification. Thus, 2,5-dimethyl-4-pivaloyloxy-3(2H)-furanone (1.40 g) was obtained.
Reaction SMILES: C(O)(=O)C.O.S(=O)(=O)(O)O.[Cl:11][C:12]1[CH:37]=[CH:36][C:15]([CH2:16][O:17][C@H:18]2[C@H:22]([F:23])[CH:21]([O:24]C)[O:20][C@@H:19]2[CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:14][CH:13]=1>CCCCCC.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C@@H:18]2[C@@H:19]([CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[O:20][CH:21]([OH:24])[C@H:22]2[F:23])=[CH:36][CH:37]=1
Reactant: COC1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccc(Cl)cc2)[C@@H]1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: OC1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccc(Cl)cc2)[C@@H]1F
Temperature: 70 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
27 mL of acetic acid, 6.6 mL of water and 1.06 mL of concentrated sulfuric acid were added to 3.32 g of (2R,3R,4S)-3-((4-chlorobenzyl)oxy)-2-(((4-chlorobenzyl)oxy)methyl)-4-fluoro-5-methoxyoxolane, and the obtained mixture was then stirred at 70° C. for 2 hours. Thereafter, 4.5 mL of water and 0.53 mL of concentrated sulfuric acid were added to the reaction mixture, and the obtained mixture was then stirred at 70° C. for 5 hours. Thereafter, ethyl acetate and hexane were added to the reaction mixture, and the thus obtained mixture was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 30/70), so as to obtain 2.92 g of (3S,4R,5R)-4-((4-chlorobenzyl)oxy)-5-(((4-chlorobenzyl)oxy)methyl)-3-fluorooxolan-2-ol in the form of a colorless oily product.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(NCCN3CCOCC3)nc21
Reactant: NCc1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccccc3Cl)n2)c2cnc(NCCN3CCOCC3)nc21
Temperature: 102 °C
Reaction time: 15 h

Procedure:
A sealed tube was charged with [3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 32 supra) (350 mg, 0.655 mmol), 2-chlorobenzylamine (130 mg, 0.918 mmol), Pd2(dba)3 (38 mg, 0.066 mmol), DavePhos (52 mg, 0.132 mmol), t-BuONa (88 mg, 0.917 mmol) and dioxane (16 mL). The mixture was stirred at 102° C. under an atmosphere of N2 for 15 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20 g, 200-300 mesh, eluting with dichloromethane:MeOH, 80:1) to give [3-[6-(2-chloro-benzylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 276 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:27][C:28]1[S:29][C:30]([C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[C:31]([CH3:33])[N:32]=1>O1CCCC1>[CH2:37]([NH:36][C:34]([C:30]1[S:29][C:28]([NH:27][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][N:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:32][C:31]=1[CH3:33])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1cc(C(=O)O)ccn1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)Nc2nc(C)c(C(=O)NCc3ccccc3)s2)ccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
To a solution of 2-methoxyisonicotinic acid (0.25 g, 1.01 mmol) in anhydrous tetrahydrofuran (10 mL) was added 4-methyl morpholine (0.15 g, 1.45 mmol), followed by the dropwise addition of isobutylchloroformate (0.19 g, 1.36 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 6 hours. Then a solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide in tetrahydrofuran (10 mL) was added to it. The reaction mixture was stirred at ambient temperature for another 6 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with diluted hydrochloric acid solution (10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was recrystallized from ethyl acetate and hexane to yield the title compound as a colorless solid in 83% yield (0.32 g); m.p. 188-190° C.; 1H NMR (CDCl3, 300 MHz) δ 8.32 (d, J=5.3 Hz, 1H), 7.37-7.25 (m, 7H), 7.17 (s, 1H), 5.99 (t, J=5.0 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 3.96 (s, 3H), 2.55 (s, 3H); 1H NMR (CDCl3, 75 MHz) δ 164.9, 163.7, 161.9, 157.1, 151.3, 148.4, 141.5, 137.6, 128.8, 127.8, 127.8, 119.4, 113.8, 109.4, 54.0, 44.2, 16.7; MS (ES+) m/z 383.5 (M+1).