Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[N:21][C:20]([O:19][CH3:18])=[N:25][CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2cc(F)cc3c(C)c4n(c23)CCNC4=O)cn1

Procedure:
The title compound, white solid (50 mg, 61%), MS (ISP) m/z=327.5 [(M+H)+], mp 271° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2-methoxy-pyrimidin-5-ylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][NH:12][C:11](=[O:14])[CH2:10]1.[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16].[F-].[Cs+]>CN(C=O)C.O.[Cu]I.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>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[C:2]([CH:15]=[CH2:16])[CH:7]=1
Reactant: O=C1C[C@H](c2ccc(Cl)cc2I)CN1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cc(Cl)ccc1[C@@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 87.7 %

Procedure:
To a solution of (4R)-4-(2-iodo-4-chlorophenyl)pyrrolidin-2-one (600 mg, 1.8 mmol), copper(I) iodide (36 mg, 0.18 mmol) and Pd(Ph3P)4 (103 mg, 0.09 mmol) in DMF (5 mL) under a nitrogen atmosphere was introduced vinyl tributyl tin (0.68 g, 2.16 mmol) followed by CsF (54 0 mg, 3.6 mmol). The reaction mixture was heated overnight at 100° C. After the reaction mixture was cooled to room temperature, it was diluted with water and extracted with ethyl ether (3×30 mL). The combined organic phases were washed with a 1N HCl aq. solution, a saturated sodium bicarbonate aqueous solution, and brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo to provide (4R)-4-(4-chloro-2-vinylphenyl)pyrrolidin-2-one (0.35 g, 85% crude yield); MS (ESI) m/z 222.04 (M+H)+. (4R)-4-(4-Chloro-2-vinylphenyl)pyrrolidin-2-one (75 mg, 0.33 mmol) was treated overnight with a 6N HCl aq. solution at 90° C. The product was purified by HPLC to provide the title compound. MS (ESI) m/z 240.06 (M+H)+.
Reaction SMILES: OC[C:3]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][N:4]=1.Cl.NCCS>>[CH:5]1[N:4]=[CH:3][N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]=12
Reactant: OCc1ncc2n1CCCC2
Agent: Cl
Agent: NCCS
Product: c1ncn2c1CCCC2

Procedure:
Reacting 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine with cysteamine hydrochloride by the procedure of Example 1 gives 3-[2-aminoethyl)thiomethyl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.
Reaction SMILES: [C@H:1]12[N:8]([C:9]([C:11]3[C:16]([N:17]4[N:21]=[CH:20][CH:19]=[N:18]4)=[CH:15][CH:14]=[CH:13][C:12]=3[F:22])=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C@H]12NC[C@H]1CCN(C(OC(C)(C)C)=O)C2>>[C@@H:1]12[N:8]([C:9]([C:11]3[C:16]([N:17]4[N:18]=[CH:19][CH:20]=[N:21]4)=[CH:15][CH:14]=[CH:13][C:12]=3[F:22])=[O:10])[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2
Reactant: O=C(c1c(F)cccc1-n1nccn1)N1C[C@H]2CCNC[C@H]21
Agent: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Product: O=C(c1c(F)cccc1-n1nccn1)N1C[C@@H]2CCNC[C@@H]21

Procedure:
The title compound was prepared in a manner analogous to Intermediate 28, substituting (1R,6S)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate for (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate. MS (ESI) mass calcd. C15H16FN5O, 301.32; m/z found 302.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Cl.[N:9]1([CH2:15][CH2:16][CH2:17]Cl)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:17][CH2:16][CH2:15][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1nnc(SCCCN2CCCCC2)s1
Yield: 57.9 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (13.3 g), piperidinopropylchloridehydrochloride (18.4 g), and potassium hydroxide (11.2 g) were stirred in methanol (300 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 13.9 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[CH:17][N:18]([CH3:20])[CH3:19])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Product: CCOC(=O)C(=CN(C)C)c1ccc(Cl)nc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
3.99 g (20.0 mmol) of the compound from Example 1A are dissolved in 13.7 ml of dimethylformamide diethyl acetal, and the mixture is stirred with microwave irradiation at 90° C. for 30 min. The mixture is then concentrated on a rotary evaporator, and the residue is chromatographed on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol 20:1).
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.[C:26]([CH2:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30])#[N:27].C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O>>[C:26]([CH2:28][S:29]([CH2:32][C:33]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:34])(=[O:31])=[O:30])#[N:27]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: N#CCS(=O)(=O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)(=O)CC#N)[C@H]2SC1

Procedure:
t-Butyl 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate (5.75 g, 15 mmol), cyanomethylsulfonylacetic acid (2.45 g, 15 mmol), and dicylohexylcarbodiimide (3.1 g, 15 mmol) were reacted as in Example 6. The t-butyl ester was treated with trifluoroacetic acid for 20 minutes as in Example 6, to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22](=[O:40])[N:23]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39])[C:24]([CH2:30]Cl)=[N:25]2>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH2:30][C:24]3[N:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][CH3:39])[C:22](=[O:40])[C:21]4[C:26](=[CH:27][CH:28]=[CH:29][C:20]=4[Cl:19])[N:25]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(Cn2ccc(=O)c3c(N)ncnc32)nc2cccc(Cl)c2c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.1 g, 0.616 mmol), Cs2CO3 (0.3013 g, 0.925 mmol, 1.5 eq), and KI (0.0102 g, 0.0616 mmol, 0.1 eq) in DMF (2 mL) was added 5-chloro-2-(chloromethyl)-3-(2-methoxyphenyl)quinazolin-4(3H)-one (0.2273 g, 0.678 mmol, 1.1 eq) and the mixture was stirred at 100° C. for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of :MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min as eluent to provide 4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one as yellow solid (0.1707 g, 60%). The yellow solid was triturated with MeOH and filtered to provide 4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one [PI3Kδ IC50=13 nM] as yellow solid. 1H NMR (DMSO-d6) δ ppm 9.53 (1 H, d, J=4.7 Hz), 8.20 (1 H, s), 8.14 (1H, d, J=4.7 Hz), 7.88 (1 H, d, J=7.8 Hz), 7.65-7.72 (1 H, m), 7.49-7.59 (3 H, m), 7.37 (1 H, dd, J=8.2, 1.2 Hz), 7.31 (1 H, dd, J=8.6, 1.2 Hz), 7.15-7.21 (1 H, m), 6.20 (1 H, d, J=8.2 Hz), 4.91-5.13 (2 H, m), 3.85 (3 H, s). Mass Spectrum (ESI) m/e=461.0 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([NH:34][CH:35]=[O:36])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][C:32]([NH:34][CH:35]=[O:36])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(NC=O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(NC=O)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-formylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:25][C:26]2([OH:43])[C:30](=[O:31])[O:29][C@H:28]3[C:32]4[C@@:37]([CH3:40])([CH2:38][CH2:39][C:27]23[OH:42])[CH2:36][CH2:35][CH2:34][C:33]=4[CH3:41])(=O)=O)=CC=1>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:25][C:26]2([OH:43])[C:30](=[O:31])[O:29][C@H:28]3[C:32]4[C@@:37]([CH3:40])([CH2:38][CH2:39][C:27]23[OH:42])[CH2:36][CH2:35][CH2:34][C:33]=4[CH3:41])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C2[C@@H]3OC(=O)C(O)(COS(=O)(=O)c4ccc(C)cc4)C3(O)CC[C@@]2(C)CCC1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCO
Product: CC1=C2[C@@H]3OC(=O)C(O)(CN4CCN(Cc5ccccc5)CC4)C3(O)CC[C@@]2(C)CCC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Benzyl piperazine (190 mg, 1.078 mmol) was added to the solution of compound of example 5 (470 mg, 1.078 mmol) in ethanol (15 mL), and stirred at 50° C. under nitrogen atmosphere for 6 hours. The reaction mixture was concentrated, and dissolved in water (25 mL) and was extracted using ethyl acetate (3×50 mL). Ethyl acetate layer was washed with water and brine, dried over sodium sulfate. Solvent was removed and crude product was purified by column chromatography (silica gel, using 12.5% ethyl acetate in petroleum ether). Semi-pure product was crystallized using ethyl acetate/petroleum ether to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Cl:10][C:11]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([Cl:27])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:28]([C:30]3[O:34][N:33]=[C:32]([CH3:35])[CH:31]=3)=[O:29])[CH:17]=2)[N:12]=1.[Li]CCCC>C1COCC1>[Cl:10][C:11]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([Cl:27])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:28]([C:2]3[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)([C:30]3[O:34][N:33]=[C:32]([CH3:35])[CH:31]=3)[OH:29])[CH:17]=2)[N:12]=1
Reactant: Cc1cc(C(=O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)on1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)c2cc(C)no2)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-methoxypyridine (0.019 mL, 0.15 mmol) was added to a solution of (2,4-dichloro-3-phenylquinolin-6-yl)(3-methylisoxazol-5-yl)methanone (44.1 mg, 0.115 mmol, Intermediate 3: step b) in THF (1 mL) under a nitrogen atmosphere. The mixture was cooled to −78° C. and n-BuLi (1.6 M in hexane, 0.094 mL, 0.150 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 minutes, then moved to an ice bath and stirred for 30 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl and was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by RP-HPLC (10-90% CH3CN—H2O, 0.1% TFA) to afford the title compound along with the intended product (2,4-dichloro-3-phenylquinolin-6-yl)(6-methoxypyridin-3-yl)(3-methylisoxazol-5-yl)methanol. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.06 (d, J=8.80 Hz, 1H), 7.93 (d, J=8.80 Hz, 1H), 7.47-7.60 (m, 3H), 7.38-7.47 (m, 2H), 6.55 (br. s., 1H), 6.33 (s, 1H), 2.22-2.36 (m, 2H), 2.20 (s, 3H), 1.17-1.36 (m, 3H), 0.92-1.10 (m, 1H), 0.81 (t, J=6.97 Hz, 3H); MS m/e 441.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[C:14]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])[CH:15]=[CH:16][C:17]=1N1CCN(S(C2SC=CC=2)(=O)=O)CC1>>[F:34][C:33]([F:35])([F:36])[C:32]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:13]=1)([OH:41])[C:37]([F:38])([F:40])[F:39]
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Product: Oc1ccc(-c2cccc(C(O)(C(F)(F)F)C(F)(F)F)c2)cc1

Procedure:
Following the procedure outlined for Example 69, 4-hydroxyphenylboronic acid (19.2 mg, 0.139 mmol) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol, the reaction mixture was filtered, concentrated, and the residue was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini-NX (C18 110 A column (100×21 mm, 5 μm) eluting with 0.1% NH4OH in CH3CN/H2O (5% to 95% over 8 min)) to afford 2′44-(2-thiophenylsulfonyl)-1-piperazinyl)-5′-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-4-biphenylol. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=5.3 Hz, 1H), 7.65 (d, J=4.0 Hz, 1H), 7.53-7.46 (m, 1H), 7.38 (s, 1H), 7.36-7.25 (m, 3H), 7.13 (d, J=8.8 Hz, 1H), 6.72 (d, J=8.8 Hz, 2H), 2.89 (br. s, 8H). m/z (ESI, +ve ion) 567.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=1.47 μM; GK-GKRP EC50 (LC MS/MS)=1.37 μM.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][NH:38]2)=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][N:38]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:29])=[CH:34][CH:33]=1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: COc1ccc2c(c1)NCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)N(C(=O)c1cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn1)CC2

Procedure:
83 mg (0.20 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 30 mg (0.20 mmol) 6-methoxy-2,3-dihydro-1-H-indole, 51 μL (0.36 mmol) TEA and 70 mg (0.22 mmol) TBTU in 1.5 mL DMF were stirred for 1 h at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[OH:13][C@H:14]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16]>[OH-].[OH-].[Pd+2]>[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[OH:13][C@@H:14]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16]
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd+2]
Agent: O=C(O)c1cc(O)c(O)c(O)c1
Agent: [OH-]
Product: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Next, hydrogenation was carried out using a palladium hydroxide charcoal catalyst for deprotection of benzyl groups. Thus, a mixture of α-glucose gallate and β-glucose gallate was obtained. Palladium hydroxide was removed via Celite filtration. The obtained mixture was subjected to separation using 10% liquid B comprising eluent A (a 0.1% acetic acid aqueous solution) and eluent B (a 90% methanol aqueous solution) by fractionation HPLC (Develosil C30; 10×250 mm; Nomura Chemical) (for 40 minutes). Accordingly, 1-O-α-galloyl glucose and 1-O-β-galloyl glucose were separately obtained: Molecular MS [M+Na]+ m/z 354.9, α-1H NMR (400 MHz, CD3CD): δ 7.10 (2H, s, H-2, 6), 6.25 (1H, d, H-Glc1, J=3.66), 3.82-3.32 (5H, m, H-Glc), β-1H NMR (400 MHz, CD3CD): δ 7.10 (2H, s, H-2, 6), 5.63 (1H, d, H-Glc1, J=7.79), 3.84-3.32 (5H, m, H-Glc).
Reaction SMILES: [OH-:1].[K+].[NH2:3][C:4]1[C:9](Br)=[CH:8][C:7]([Cl:11])=[CH:6][N:5]=1.Cl>[Cu].O>[NH2:3][C:4]1[C:9]([OH:1])=[CH:8][C:7]([Cl:11])=[CH:6][N:5]=1
Reactant: [OH-]
Reactant: Nc1ncc(Cl)cc1Br
Agent: [Cu]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Nc1ncc(Cl)cc1O
Temperature: 170 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
A mixture of 12 parts of potassium hydroxide (85%), 200 parts of water, 10.4 parts of 2-amino-3-bromo-5-chloropyridine and 0.5 part of copper powder is stirred under nitrogen in an autoclave for 10 hours at 170° C. The aqueous solution is afterwards neutralised with concentrated hydrochloric acid and the water is largely evaporated off. While still moist the residue is extracted in the hot state twice with ethyl acetate. The combined extracts are purified with active charcoal, and the solvent is then evaporated off to leave 5 parts (70% of theory) of 2-amino-3-hydroxy-5-chloropyridine, m.p. 196°-201° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[C:8]([NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:9])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:21][C:20]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[O:9])=[CH:6][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)Oc1cc(C(=O)NC2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Yield: 95.3 %

Procedure:
To a solution of 1.2 g (3.6 mmole) of 3-isopropoxy-N-(1-methyl-piperidin-4-yl)-4-nitro-benzamide in 25 mL of methanol was added 0.12 g of 10% palladium on carbon. The hydrogenation reaction was carried out under 50 psi of hydrogen for 2 hours. The mixture was filtered, concentrated under reduced pressure and triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to give 1.0 g of 4-amino-3-isopropoxy-N-(1-methyl-piperidin-4-yl)-benzamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.Cl[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-]>CC(=O)CC>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CN(C)CCCl
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CN(C)CCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a stirred solution of 4-amino-3-nitro-phenol (1.54 g, 10 mmol) and (2-chloro-ethyl)-dimethyl-amine hydrogen chloride (1.43 g, 10 mmol) in butanone (40 mL) was added Cs2CO3 (10 g, 30 mmol) and NaI (150 g, 1 mmol). The solution was slowly heated to 80° C. over one hour. Then the solution was stirred at 80° C. for 2 hours. The solution was filtered through Celite® and washed with acetone. The solution was evaporated with silica gel and purified by flash chromatography on silica to afford the title compound (1.0 g, yield: 45%) as a brown solid. 1H-NMR (300 MHz, DMSO-d6) δ 7.38 (d, 1H), 7.24 (s, 2H), 7.16 (dd, 2H), 6.99 (d, 1H), 3.98 (t, 214), 2.58 (t, 2H), 2.20 (s, 6H); MS (ESI) 226 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([CH2:16][CH3:17])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:22]([O:21][C:19]([NH:18][C@H:13]1[C@@H:14]([CH2:16][CH3:17])[CH2:15][NH:11][CH2:12]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: [H][H]
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C

Procedure:
A 10% palladium carbon catalyst (50 mg) was added to a solution of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-ethylpyrrolidine (514 mg, 1.48 mmol) in methanol (15 mL). The resultant mixture was stirred at room temperature for 2 hours under an ordinary pressure in a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield the title compound as a colorless oily substance (324 mg, quantitative amount).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N+:7](/[CH:10]=[CH:11]/[C:12]1[CH:16]=[N:15][N:14]2[CH2:17][CH2:18][N:19](C=O)[C:13]=12)([O-])=O.[F-].[Na+].O>O1CCCC1>[NH:19]1[C:13]2[N:14]([N:15]=[CH:16][C:12]=2[CH2:11][CH2:10][NH2:7])[CH2:17][CH2:18]1
Reactant: O=CN1CCn2ncc(/C=C/[N+](=O)[O-])c21
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NCCc1cnn2c1NCC2
Yield: 75.2 %

Procedure:
To a suspension of lithium aluminum hydride (465 mg) in tetrahydrofuran (10 ml) was added 7-[(E)-2-nitroethenyl]-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-carbaldehyde (300 mg) under ice-cooling. The mixture was refluxed for 1.5 hours. After cooling on an ice bath, sodium fluoride (2.06 g) and water (0.882 ml) were added to the reaction mixture. The insoluble materials were removed by filtration. The filtrate was concentrated in vacuo to give 2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)ethylamine (165 mg). This product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:22].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O.Cl>CN(C)C=O>[CH2:13]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[CH2:8][CH2:9][CH2:10][C:11]([OH:22])=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(CCCCO)Cc1ccccc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
A solution of benzyl-(4-hydroxy-butyl)-carbamic acid tert butyl ester (9.4 g, 33.7 mmol) in anhydrous dimethyl formamide “DMF” (40 mL) was cooled in an ice bath. Pyridinium dichromate (44 g, 117 mmol) was added in 4 portions of with 15 min intervals. The reaction mixture was allowed to stir overnight at room temperature resulting in a viscous black slurry. The slurry was poured into water (400 mL), acidified to pH 1 with concentrated HCl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with, 5% NaHSO4 (100 mL), water (4×300 mL). Subsequently, the organic layer was extracted with 1M NaOH (150, 75, and 50 mL). The combined aqueous layers were cooled with an ice bath and the pH was adjusted to 3 with concentrated HCl. The resulting white suspension was extracted three times with ethyl acetate (3×200 mL) and the combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated in vacuo to give N-benzyl-N-(t-butoxy-carbonyl)-4-amino-1-butanoic acid (4.0 g, 40%) as viscous oil. 1H NMR (CDCl3): δ 7.23-7.35 (m, 5H); 4.41 (bs, 2H); 3.29 (bs, 1H); 3.19 (bs, 1H); 2.33 (bs, 2H); 1.82 (bs, 2H); 1.46 (bs, 9H).