Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][NH2:34].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:5]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:34][CH2:33][CH2:32][C:26]2[C:25]3[C:29](=[CH:30][CH:31]=[C:23]([Cl:22])[CH:24]=3)[NH:28][CH:27]=2)=[O:18])=[CH:19][CH:20]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
Thionyl chloride (0.111 mL; 1.52 mmol) was added to a mixture of 4-benzylbenzoic acid (0.100 g; 0.508 mmol) in chloroform (10 mL). The reaction mixture was stirred at 65° C. for 18 hours and evaporated to dryness. The resulting residue was dissolved in chloroform (6 mL) and the solution is cooled to 0° C. A solution of 2-(5-Chloro-1H-indol-3-yl)ethanamine hydrochloride (0.108 g; 0.457 mmol) and triethylamine (0.357 mL; 2.54 mmol) in chloroform (6 ml) was then added and the mixture was stirred for 30 minutes at room temperature. The volatiles were removed under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) to furnish 0.155 g (78%) of 4-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:21][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: CN(C)CCN
Reactant: COC(=O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C=Cc1ccc(NCCN(C)C)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 84.2 %

Procedure:
A mixture of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (Ia, 0.658 g, 2.72 mmol), N,N-dimethylethylenediamine (0.90 mL, 8.20 mmol) and triethylamine (1.2 mL, 8.6 mmol) in dioxane (20 mL) was heated at 80° C. for 5 h. The solution was evaporated and the residue was added DCM and aqueous Na2CO3. The DCM (×3) extracts were concentrated and the residue was added EtOAc-hexane. The resulting red solid was filtered to give the titled compound (0.672 g, 84.2%). HPLC purity at 254 nm: 99.2%, tR=1.59 min. LCMS (ESI) m/z: 294 ([M+H]+). 1H NMR (CDCl3+CD3OD) δ 8.21 (1H, d, J=2.1 Hz), 7.56 (1H, dd, J=9.0, 2.1 Hz), 7.48 (1H, d, J=16.0 Hz), 6.81 (1H, d, J=9.0 Hz), 6.20 (1H, d, J=15.9 Hz), 3.70 (3H, s), 3.34 (2H, t, J=6.5 Hz), 2.56 (2H, t, J=6.4 Hz), 2.23 (6H, s); 13C NMR (CDCl3+CD3OD) δ 167.3, 145.4, 142.6, 134.0, 131.1, 127.1, 121.3, 114.8, 114.0, 56.7, 51.1, 44.6, 40.1.
Reaction SMILES: Cl.CO[C:4](=[O:13])[CH:5]1[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][NH:6]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:4]([CH:5]2[CH2:10][CH2:9][C:8]([CH3:11])([CH3:12])[CH2:7][NH:6]2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C1CCC(C)(C)CN1
Reactant: C1CCNC1
Agent: Cl
Product: CC1(C)CCC(C(=O)N2CCCC2)NC1
Reaction time: 8 h

Procedure:
4.2 g (23.5 mmoles) of 5,5-dimethyl pipecolic acid methyl ester hydrochloride were added to 40 ml of pyrrolidine kept at 0° C. After the addition, the solution was allowed to reach room temperature and stirring was continued overnight. The reaction mixture was evaporated in vacuo and the residue treated with 30 ml of 40% NaOH, extracted with diethyl ether, dried over sodium sulphate and evaporated in vacuo to dryness to give 3.3 g of the title compound.
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18]([C:25]2[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].C([SiH](CC)CC)C>ClCCl>[F:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][N:34]2[C:35](=[O:36])[C:16]3[C:15]([OH:14])=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[N:23]4)=[C:18]([C:25]4[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=4)[C:17]=3[CH2:33]2)=[CH:43][CH:42]=1.[C:47]([OH:49])([C:46]([F:51])([F:50])[F:45])=[O:48]
Reactant: COc1ncccc1-c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncccc1-c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 288 (18 mg) dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was purified by HPLC to afford 7-(4-fluoro-benzyl)-5-(2-methoxy-pyridin-3-yl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 289, TFA salt, (11.6 mg, 68%) as a yellow solid: 1H NMR (CDCl3) δ 9.0 (d, 1H), 8.3 (d, 1H), 7.9 (d, 1H), 7.5 (m, 2H), 7.2 (m, 1H+1H), 7.0 (m, 2H+1H), 4.7 (dd, 2H), 4.1(dd, 2H), 3.8 (s, 1H); MS: 416 (M+1). HPLC conditions: mobile phase A was 0.1% TFA in water, mobile phase b was 0.1% TFA in CH3CN; gradient from 5% to 60% B in 20 min; flow rate was 20 mL/min; column was Phenomenex, luna 5μ, C18(2), 150 mm×21.1 mm.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15](O)=[O:16])[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCc1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Reaction time: 1 h
Yield: 29.5 %

Procedure:
To a solution of 2-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid (435 mg, 1.60 mmol), Et3N (0.34 mL, 2.40 mmol) and THF (10 mL) was added isobutyl chloroformate (333 mg, 2.40 mmol). After 1 h, the resulting mixture was filtered through a fritted funnel and washed with THF (30 mL). The filtrate was concentrated to approximately 10 mL and MeOH (1 mL) was added followed by sodium borohydride (121 mg, 3.20 mmol). After 12 h, the mixture was partitioned between saturated aqueous NaHCO3 (30 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified directly by FCC to afford a white solid (120 mg, 27%). MS (ESI): mass calcd. for C12H9F3N2O; 254.0 m/z found, 255.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.80 (d, J=5.1, 1H), 8.57 (d, J=8.1, 2H), 7.75 (d, J=8.2, 2H), 7.30 (d, J=5.1, 1H), 4.85 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4]([CH2:7][CH:8]=1)(=[O:6])=[O:5].[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)Cl>CCOCC>[Br:9][CH2:1][C:2]1[CH2:3][S:4]([CH2:7][CH:8]=1)(=[O:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=CCS(=O)(=O)C1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=S1(=O)CC=C(CBr)C1
Temperature: 0 °C
Yield: 34.2 %

Procedure:
In a reaction vessel, 21.0 gms (0.1591 moles) 3-methyl sulfolene, 28.32 gms (0.1591 moles) N-bromo succinimide, 1.9 gms (0.0008 moles) benzoyl peroxide and 250 ml chlorform were combined. The resulting mixture was heated to reflux and then refluxed for 20 hours. The reaction mixture was cooled to 0° C. and then filtered to remove the succinimide. The filtrate was stripped until only a small amount of solvent remained. The remaining solids were removed by filtration, and the remainder of the solvent was stripped to give an orange oil. Ether was added to the oil. After a few minutes, the solids crystallized. Filtration and drying yielded 11.5 gms of the product. The NMR and IR spectra confirmed the structure.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:12]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N+:13]([O-:25])[C:14]([O:23][CH3:24])=[C:15]([CH2:17]OS(C)(=O)=O)[N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1>C1(C)C=CC=CC=1>[CH2:3]([O:10][C:11]1[C:12]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N+:13]([O-:25])[C:14]([O:23][CH3:24])=[C:15]([CH2:17][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)[N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1c(COS(C)(=O)=O)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1c(Cc2c[nH]c3ccccc23)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
300 Microliters of toluene and 3.7 mg of 60% sodium hydride were added to a mixture of 8.8 mg of 3-benzyloxy-5-mesyloxymethyl-2-isobutyl-6-methoxypyrazine 1-oxide and 8.2 mg of indole. The mixture was stirred for 16 hours at room temperature, and the reaction mixture was subjected to the same post-treatment as in Example B-1 to obtain 5.8 mg of 3-benzyloxy-5-(indol-3-yl)methyl-2-isobutyl-6-methoxypyrazine 1-oxide (Compound B-41) as colorless prismatic crystals having a melting point of 139.6°-141.9° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=2[N:10]=1)=[O:5])C.[OH-].[Na+:17]>C1COCC1>[Na+:17].[CH3:15][C:11]1[C:9]2[N:10]=[C:6]([C:4]([O-:5])=[O:3])[O:7][C:8]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1nc2c(C)cccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc2oc(C(=O)[O-])nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 4-methyl-benzooxazole-2-carboxylic acid ethyl ester (140 mg) was added 2 mL of THF, and 0.93 mL (2 eq) of NaOH solution (2N in MeOH). The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the solid was dried under vacuum to give 200 mg (100%) of 4-methyl-benzooxazole-2-carboxylic acid sodium salt as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:13])[C:5]([CH3:12])([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:3].[CH:14](O)=[O:15]>>[CH:14]([O:13][CH:4]([C:5]([CH3:11])([CH3:12])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH:2]([CH3:1])[CH3:3])=[O:15]
Reactant: O=CO
Reactant: CC(C)=CCC(C)(C)C(O)C(C)C
Product: CC(C)=CCC(C)(C)C(OC=O)C(C)C

Procedure:
52 g of 2,4,4,7-tetramethyl-oct-6-en-3-ol and 65 g of formic acid are stirred at 40° C. for 8 hours. The formic acid is then distilled off and the product is purified by cracking tube distillation.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][C@H:12]4[C:18](=O)[N:17](COCC[Si](C)(C)C)[C:16]5[CH:28]=[C:29]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]6[C:40]([O:96][CH3:97])=[CH:41][C:42]7[C:48](=[O:49])[N:47]8[CH:50]=[C:51]([C:53]#[C:54][CH2:55][NH:56][C:57](=[O:85])[C@@H:58]([NH:60][C:61](=[O:84])[C@@H:62]([NH:66][C:67](=[O:83])[O:68][CH2:69][CH:70]9[C:82]%10[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=%10[C:76]%10[C:71]9=[CH:72][CH:73]=[CH:74][CH:75]=%10)[CH:63]([CH3:65])[CH3:64])[CH3:59])[CH2:52][C@H:46]8[C:45](=O)[N:44](COCC[Si](C)(C)C)[C:43]=7[CH:95]=6)[C:30]([O:32][CH3:33])=[CH:31][C:15]=5[C:14](=[O:98])[N:13]4[CH:99]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[B-](CC)(CC)CC>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][C@H:12]4[CH:18]=[N:17][C:16]5[CH:28]=[C:29]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]6[C:40]([O:96][CH3:97])=[CH:41][C:42]7[C:48](=[O:49])[N:47]8[CH:50]=[C:51]([C:53]#[C:54][CH2:55][NH:56][C:57](=[O:85])[C@@H:58]([NH:60][C:61](=[O:84])[C@H:62]([NH:66][C:67](=[O:83])[O:68][CH2:69][CH:70]9[C:71]%10[CH:72]=[CH:73][CH:74]=[CH:75][C:76]=%10[C:77]%10[C:82]9=[CH:81][CH:80]=[CH:79][CH:78]=%10)[CH:63]([CH3:64])[CH3:65])[CH3:59])[CH2:52][C@H:46]8[CH:45]=[N:44][C:43]=7[CH:95]=6)[C:30]([O:32][CH3:33])=[CH:31][C:15]=5[C:14](=[O:98])[N:13]4[CH:99]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc5c(c4)OCO5)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(C#CCNC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)=CN1C2=O
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc5c(c4)OCO5)C[C@H]1C=N3)N=C[C@@H]1CC(C#CCNC(=O)[C@H](C)NC(=O)[C@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)=CN1C2=O
Temperature: -78 °C

Procedure:
The SEM dilactam 10d (0.063 g, 0.0455 mmol, 1.0 eq.) was solubilised in THF (2.7) and cooled to −78° C. under a nitrogen atmosphere. Super hydride solution (1M in THF, 0.093 mL, 2.04 eq.) was added dropwise over 5 minutes. After 20 minutes an aliquot was washed with water for LCMS and TLC analysis. After 30 minutes water was added and the cold bath removed. The organic layer was extracted with EtOAc (2×10 mL) and the combined organic extracts washed with brine (10 mL), dried with MgSO4, filtered and the solvent removed under reduced pressure. The crude product was dissolved in MeOH/DCM/water (6:3:1) (0.01 M) and enough silica gel to form a thick stirring suspension.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:25][C:24]2[C:12](=[CH:13][C:14]3[N+:19]([O-:20])=[N:18][C:17]([CH2:21][CH3:22])=[N:16][C:15]=3[CH:23]=2)[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH2:21]([C:17]1[N:18]=[N+:19]([O-:20])[C:14]2[CH:13]=[C:12]3[C:24]([CH2:25][CH:10]([CH2:9][OH:8])[CH2:11]3)=[CH:23][C:15]=2[N:16]=1)[CH3:22]
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CO[Si](C)(C)C(C)(C)C)C3
Agent: Cl
Solvent: CO
Product: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CO)C3
Yield: 78.4 %

Procedure:
A solution of silylether 135 (1.57 g, 4.37 mmol), and 1 N HCl (5 mL) in MeOH (40 mL) was stirred at 20° C. for 1 h. The solution was partitioned between EtOAc and water. The organic layer was dried, the solvent evaporated and the residue was purified by chromatography, eluting with a gradient (0-2%) of MeOH/DCM, to give alcohol 142 (0.84 g, 79%) as a yellow solid: mp (MeOH/EtOAc) 122-123° C.; 1H NMR [(CD3)2SO] δ 8.13 (s, 1H, H-9), 7.77 (s, 1H, H-5), 4.71 (t, J=5.2 Hz, 1H, OH), 3.42 (dd, J=6.4 Hz, 5.2 Hz, 2H, CH2O), 3.11-3.20 (m, 2H, CH2), 2.86-2.96 (m, 4H, CH2), 2.59-2.71 (m, 1H, H-7), 1.32 (t, J=7.5 Hz, 3H, CH3); 13C NMR [(CD3)2SO] δ 165.9, 153.9, 148.1, 146.8, 131.6, 122.5, 113.8, 63.5, 41.6, 35.3, 35.0, 29.6, 11.8. Anal. calcd for C13H15N3O2: C, 63.7; H, 6.2; N, 17.1. Found: C, 63.9; H, 6.2; N, 17.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH:20]=O.[CH3:22][C:23]1([CH3:31])[O:30][C:28](=[O:29])[CH2:27][C:25](=[O:26])[O:24]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH:20]=[C:27]1[C:28](=[O:29])[O:30][C:23]([CH3:31])([CH3:22])[O:24][C:25]1=[O:26]
Reactant: COCOc1cc(OC)c(OCOC)c(CC=O)c1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COCOc1cc(OC)c(OCOC)c(CC=C2C(=O)OC(C)(C)OC2=O)c1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.7 Grams (9.0 mM) of 2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]acetoaldehyde was dissolved in 80 ml of benzene, then to this solution was added 1.56 g (10.8 mM) of Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) and 2.18 g (21.6 mM) of triethylamine were added and the reaction mixture was stirred at room temperature for 12 hours. 100 Milliliters of benzene was added to the reaction mixture and washed twice with 200 ml of water and further washed twice with a saturated sodium chloride aqueous solution, then the benzene solution was dried over anhydrous magnesium sulfate. The benzene solution was concentrated under reduced pressure and the residue obtained was purified by a silica gel column chromatography (diameter 5 cm×length 15 cm, eluent: 30% ethyl acetatehexane, "Wakogel C-200") to yield 2.9 g of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethane. Light yellow indefinite form powdery substance.
Reaction SMILES: [H-].[Na+].[Cl-].[F:4][C:5]([F:35])([F:34])[C:6]1[CH:33]=[CH:32][C:9](/[CH:10]=[CH:11]/[CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1.[Cl:36][C:37]1[CH:52]=[CH:51][C:40]([CH2:41][S:42][C@H:43]2[CH2:48][CH2:47][C@H:46]([CH:49]=O)[CH2:45][CH2:44]2)=[CH:39][CH:38]=1>CCCCCC.CS(C)=O.C1(C)C=CC=CC=1>[F:35][C:5]([F:4])([F:34])[C:6]1[CH:7]=[CH:8][C:9](/[CH:10]=[CH:11]/[CH:12]=[CH:49]/[C@H:46]2[CH2:45][CH2:44][C@H:43]([S:42][CH2:41][C:40]3[CH:51]=[CH:52][C:37]([Cl:36])=[CH:38][CH:39]=3)[CH2:48][CH2:47]2)=[CH:32][CH:33]=1
Reactant: O=C[C@H]1CC[C@H](SCc2ccc(Cl)cc2)CC1
Reactant: FC(F)(F)c1ccc(/C=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(/C=C/C=C/[C@H]2CC[C@H](SCc3ccc(Cl)cc3)CC2)cc1
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
After 50 mg (1.14 mmol) of 55% sodium hydride were washed with hexane, it was suspended in 7 ml of dimethyl sulfoxide, followed by stirring of the suspension at 55° C. for 2.5 hours. The mixture was cooled to room temperature and 607 mg (1.26 mmol) of [(E)-4-(trifluoromethyl) cinnamyl]triphenylphosphonium chloride were added thereto. Further, 170 mg (0.63 mmol) of trans-4-[(4-chlorobenzyl) thio]cyclohexanecarboxaldehyde were added to the resulting mixture, followed by stirring of the mixture at room temperature for 15 minutes. The mixture was diluted with toluene and washed with water and an aqueous NaCl solution. After the mixture was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 5 g of silica gel and eluted with a mixed solvent of methylene chloride-hexane (1:2). The eluted portion was recrystallized from hexane to obtain 86 mg (yield: 31%) of the title compound having a melting point of 142 to 144° C.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:15][CH:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17]([O:19]C)=[O:18])=[O:14])[CH:5]=[N:4][C:3]1=2.[OH-].[K+].Cl>O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:15][CH:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17]([OH:19])=[O:18])=[O:14])[CH:5]=[N:4][C:3]1=2
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)CCn1cnc2c(=O)[nH]cnc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NC(Cc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 83 %

Procedure:
100 mg (0.271 mmol) of 2-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]-3-phenylpropanoic acid, methyl ester (AIT-0085) were placed into a 10 ml beaker equipped with a magnetic stirring bar. Water (5 ml) was added to the beaker and stirring was started. To the stirring heterogeneous mixture was added 100 mg (1.79 mmol) of KOH pellets. Within a few seconds the reaction mixture became a homogeneous green color. Stirring was continued for one hour. The pH of the solution was adjusted to 2.0 with concentrated hydrochloric acid. The product was collected by vacuum filtration and washed twice with 2 ml of water and then twice with 2 ml of acetone. The weight of the product, 2-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)1-oxopropyl]amino]-3-phenylpropanoic acid (AIT-0086), was 80 mg. Yield: 83%. m.p. 240°-242° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[N:16]=2)=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][C@H:11](O)[CH2:10]2)=[N:6][CH:7]=1.ClC1C(C2C=CC=C(NCC3C=CC=C(F)C=3)N=2)=CC(F)=[N:35]C=1.N[C@@H]1CC[C@H](O)C1.C(N(CC)CC)C>CN1C(=O)CCC1>[NH2:35][C@@H:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:5]2[CH:4]=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[N:16]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:10]1
Reactant: O[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Agent: N[C@@H]1CC[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: N[C@@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Preparation of (1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentanol: To 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (75 mg, 0.226 mmol), was added (1S,3R)-3-aminocyclopentanol (68.6 mg, 0.678 mmol), NMP (0.75 ml) and triethylamine (0.158 ml, 1.130 mmol). The crude reaction mixture was stirred at 100° C. for 18 hr, and the reaction progress followed by LCMS. The crude reaction mixture was cooled, filtered, and purified by prep LC. The product fractions were collected, 50 mL of 1 M NaOH and 50 mL of EtOAc were added. The aqueous layer was removed, the organic layer was washed with 50 mL of saturated salt solution, dried over sodium sulfate, and reduced to constant mass. 28 mg of the desired compound was obtained. LCMS (m/z): 413.1 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, CHLOROFORM-d, 25° C.) δ ppm 1.71 (d, J=14.09 Hz, 1 H) 1.75-1.91 (m, 2 H) 1.97-2.05 (m, 1 H) 2.10-2.16 (m, 1 H) 2.61 (br. s., 1 H) 4.03-4.18 (m, 1 H) 4.39 (tt, J= 4.84, 2.59 Hz, 1 H) 4.55 (d, J= 5.09 Hz, 2 H) 5.19 (br. s., 2 H) 6.41 (d, J= 8.22 Hz, 1 H) 6.55 (s, 1 H) 6.90-7.02 (m, 2 H) 7.05-7.18 (m, 2 H) 7.24-7.34 (m, 1 H) 7.43-7.55 (m, 1 H) 8.07 (s, 1 H).