Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH:22][CH3:23]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([N:22]([CH3:23])[CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)n2)CC1
Reactant: CNC
Solvent: CO
Product: CN(C)c1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
A solution of 2 mmol of 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 15 ml of 2M dimethylamine in methanol was stirred at room temperature for 1 hour. Concentration and purification by chromatography (SiO2; ethyl acetate/cyclohexane 1:1) yields the title compound as a colorless solid. MS (m/e): 309.1 (MH+, 100%)
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:27])[C:13]([NH:15][C@H:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([OH:26])=[CH:21][CH:22]=4)[CH2:17]3)=O)=[CH:11][C:5]=2[CH2:4][O:3]1.N(CCO)(CCO)CCO.O>O1CCCC1>[CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:27])[CH2:13][NH:15][C@H:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([OH:26])=[CH:21][CH:22]=4)[CH2:17]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H](O)C(=O)N[C@H]3CCc4ccc(O)cc4C3)ccc2O1
Solvent: OCCN(CCO)CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CN[C@H]3CCc4ccc(O)cc4C3)ccc2O1
Yield: 84.7 %

Procedure:
(-)-(2R)-2-(2,2-Dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (686 mg) was dissolved in 50 ml of tetrahydrofuran, 3.58 ml of 2 M borane-dimethylsulfide complex in tetrahydrofuran was added, and the mixture was heated under reflux for 3 hours. Then, a solution of 1.34 g of triethanolamine in 5.0 ml of tetrahydrofuran was added, and the mixture was again heated under reflux for 15 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was recrystallized from ethyl acetate to give 560 mg of (-)-(1R)-1-(2,2-dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)-2-[((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]ethanol having a melting point of 156 to 158° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.C(O)(C(F)(F)F)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH4+].[OH-]>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][CH:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(N)c1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1cccc(NC2CCN(C)CC2)c1
Reaction time: 2 h
Yield: 93.3 %

Procedure:
3-Ethynyl-phenylamine (0.1 mL, 1 mmol) and 1-methyl-piperidin-4-one (0.15 mL, 1.2 mmol) in 1,4-dioxane (4 mL) was treated first with TFA (0.2 mL, 2.6 mmol) and then with sodium triacetoxyborohydride (318 mg, 1.5 mmol). After stirring for 2 h, 10% NH4OH was added to the reaction mixture (15 mL). Extraction with DCM (3×25 mL), drying over sodium sulfate, evaporation, purification by flash chromatography over silica gel (DCM/7N NH3 in MeOH 9/1) afforded the title compound (200 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[N+:31]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O>C(O)C.O1CCCC1.C(OCC)(=O)C.[Fe]>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=3)=[CH:17][C:16]=2[NH2:31])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2N)cc1
Temperature: 25 °C
Yield: 95.6 %

Procedure:
A solution of the product of Example 49B (7.383 g, 13.97 mmol), iron powder (4.80 g, 85.94 mmol) and ammonium chloride (4.896 g, 91.53 mmol) in ethanol (60 mL), tetrahydrofuran (60 mL), and water (30 mL) was heated at 80° for 1.5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (300 mL) and washed with water (4×100 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound as a light tan solid (6.658 g, 13.36 mmol, 96%).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][OH:21])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:29]([NH:31][CH3:32])=[O:30])[N:8]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:33](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][OH:21])[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][C:10]3[C:6](=[C:7]([C:29]([NH:31][CH3:32])=[O:30])[N:8]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:33])=[CH:26][CH:27]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
To a suspension of compound (ii) (3 mg, 0.007 mmol) and potassium carbonate (3 mg, 0.022 mmol) in DMF (0.25 mL) was added iodomethane (3 μL, 0.048 mmol) and the reaction was stirred at 60° C. for 45 min. The mixture was concentrated to dryness and the residue was purified by reverse phase flash column chromatography eluting with ACN/water (5-100%) to afford Compound (55) as a white solid (2 mg, 65%). ESI-MS m/z calculated for [M+H]+: 473.2; found: 473.2; 1H NMR (400 MHz, Acetone) δ 7.86 (d, J=0.5 Hz, 1H), 7.64 (brs, 1H), 7.62-7.56 (m, 2H), 7.42 (s, 1H), 7.14-7.06 (m, 2H), 3.99-3.85 (m, 5H), 3.71-3.62 (m, 2H), 3.59 (t, J=5.2 Hz, 1H), 3.18 (s, 3H), 2.96 (d, J=4.7 Hz, 3H), 2.52-2.42 (m, 1H), 1.91-1.73 (m, 2H), 1.11-0.94 (m, 3H), 0.64-0.53 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CSc1ccc(B(O)O)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CSc1ccc(-c2cnc(N)cn2)c(C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A mixture of [2-methyl-4-(methylthio)phenyl]boronic acid (prepared as in Example 185, Step 2, 253 mg, 1.390 mmol), 5-bromo-2-pyrazinamine (242 mg, 1.390 mmol), Pd(PPh3)2Cl2 (195 mg, 0.278 mmol), DME (5 mL) and 2M Na2CO3 (8 mL) was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, charged with CH2Cl2 and water, and stirred at ambient temperature for 30 min. The mixture was filtered, the organics were separated, and the aqueous layer was washed with CH2Cl2. The organics were pooled, dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 50% EtOAc/hexane to give 190 mg (59%) of 5-[2-methyl-4-(methylthio)phenyl]-2-pyrazinamine as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 8.05 (s, 1H), 7.29 (d, 1H, J=8.5 Hz), 7.17-7.12 (m, 2H), 4.97-4.82 (m, 2H), 2.50 (s, 3H), 2.36 (s, 3H); LRMS (ESI), m/z 232 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([F:17])=[CH:12][CH:11]=3)[C:5]([CH:18]=[CH2:19])=[CH:4][CH:3]=1.[OH-].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:18][CH2:19][N:9]3[C:10]4[CH:11]=[CH:12][C:13]([F:17])=[CH:14][C:15]=4[CH:16]=[C:8]3[C:6]=2[N:7]=1
Reactant: C=Cc1ccc(Cl)nc1-c1cc2cc(F)ccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1ccc2c(c1)cc1n2CCc2ccc(Cl)nc2-1
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
A mixture of 2-(6-chloro-3-vinylpyridin-2-yl)-5-fluoro-1H-indole (100 mg, 0.36 mmol), DMSO (0.5 mL), TBAC (0.1 mL of 50% a.q. solution) and KOH (1.0 mL of 60% a.q. solution) was stirred under N2 at 100° C. for 4 h. After cooled and extracted with EtOAc, the organic layer was washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by prep-TLC (PE:EA=10:1) to give the product of 2-chloro-10-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, yield: 50.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.51 (d, J=8.0 Hz, 1H), 7.25˜7.38 (m, 3H), 7.15 (d, J=8.0 Hz, 1H), 6.98˜7.04 (m, 1H), 4.26 (d, J=6.4 Hz, 2H), 3.22 (d, J=6.4 Hz, 2H). MS (M+H)+: 273/275.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:23][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCI
Reactant: COC1(c2ccc(F)c(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN1CCC(OC)(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.6 %

Procedure:
To a solution of 3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.19 g, 0.89 mmol) in acetonitrile (5 ml), potassium carbonate (0.17 g, 1.25 mmol) and iodoethane (0.075 ml, 0.94 mmol) was added and the mixture was stirred at ambient temperature for 5 h. Aqueous sodiumcarbonate (10%, 50 ml) and ethyl acetate (50 ml) was added and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phase was washed with Brine, dried (Na2SO4) and evaporated to give the crude product. Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) followed by flash column chromatography on silica gel (EtOAc/MeOH 4:1) gave the title compound (0.10 g, 46%). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 135-136° C. MS m/z (rel. intensity, 70 eV) 241 (4), 226 (27), 211(17), 141 (26), 71 (bp).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[Br:20][C:21]1[N:22]=[C:23]([CH2:26]O)[S:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:20][C:21]1[N:22]=[C:23]([CH2:26][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[S:24][CH:25]=1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1nc(Br)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2cc(-n3ccc(OCc4nc(Br)cs4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-bromo-1,3-thiazol-2-yl)methanol (76 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (6 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallized from ethanol-hexane to give the title compound (45 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=2)=[N:19]1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:8]=3)=[O:14])[CH3:32])[N:19]=2)=[CH:24][C:25]=1[CH3:31])#[N:28]
Reactant: Cc1cc(-c2ccn(C[C@H](C)N)n2)ccc1C#N
Reactant: O=C(O)C1=NN=C(c2ccncc2)C1
Product: Cc1cc(-c2ccn(C[C@H](C)NC(=O)c3cc(-c4ccncc4)n[nH]3)n2)ccc1C#N
Yield: 39.9 %

Procedure:
The title compound was synthesized from 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (47 mg, 0.25 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (59 mg, 0.25 mmol) using the method of Example 34(d). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 41 mg (40%) of the title compound. 1H-NMR (400 MHz; MeOD): δ 1.24 (d, 3H), 2.52 (s, 3H), 4.32 (m, 2H), 4.53 (m, 1H), 6.59 (d, 1H), 7.15 (m, 1H), 7.36 (s, 2H), 7.53 (d, 1H), 7.58 (m, 2H), 7.70 (m, 2H), 8.53 (br s, 1H), 8.56 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:25]1([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]5)[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:29]=[CH:28][CH:27]=[N:26]1
Reactant: c1cn[nH]c1
Reactant: OC1CCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC1CCC(Nc2ccc3ncc(-c4ccnc(-n5cccn5)c4)n3c2)CC1
Temperature: 25 °C

Procedure:
A mixture comprising [4-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol (Example 2.1) (1 eq, 0.29 mmol, 100 mg), pyrazole (5 eq, 1.45 mmol, 99 mg) and cesium carbonate (3 eq, 0.87 mmol, 284 mg) in DMF (25 ml) is heated using microwave radiation at 145° C. for 6 hours. After cooling to room temperature, the mixture is loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The solvent is removed in vacuo and the crude product is triturated with ethyl acetate to afford the title compound; [M+H]+=375
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:13]=[C:12]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]2=[CH:10][C:9]=1[CH:19]=[O:20].[CH2:21]([NH:23][CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([N:23]([CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[C:8]1[N:13]=[C:12]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]2=[CH:10][C:9]=1[CH:19]=[O:20])[CH3:22]
Reactant: CCNC[C@@H]1CCCO1
Reactant: Cc1nn(C)c2nc(Cl)c(C=O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(C[C@@H]1CCCO1)c1nc2c(cc1C=O)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
Potassium carbonate (0.42 g, 3 mmol) was added to a solution of 6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (0.46 g, 2.2 mmol) and (S)-(+)-ethyl-(tetrahydro-furan-2-ylmethyl)-amine (4.8 mmol) in anhydrous dimethyl formamide (6 mL) under nitrogen. After stirring for 0.5 h at RT, the reaction mixture was heated for 20 h at 80-95° C. Thereafter, the reaction was cooled to RT, water (30 mL) and ethyl acetate (30 mL) were added, and the organic layer was separated from the aqueous mixture. The organic extract was washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by chromatography using silica gel (200-400 mesh) to afford the title compound as a pale yellow liquid (0.35 g, yield: 53%).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>C1COCC1>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:17][N:18]=1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(C)nc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C2(C)CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 1-(6-methylpyridin-3-yl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: C([O:5][P:6]([CH2:17][CH:18]([CH2:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:19]([O:21]C(C)(C)C)=[O:20])([CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:10]([NH:9][CH2:8][P:6]([CH2:17][CH:18]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:19]([OH:21])=[O:20])([OH:7])=[O:5])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CCC(CP(=O)(CNCc1ccccc1)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(CP(=O)(O)CNCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To a solution of di-tert-butyl 2-[((tert-butoxy){[benzylamino]methyl}phosphoryl)methyl]pentane-1,5-dioate (0.498 g, 1.0 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL) at 0° C., and the mixture was stirred at room temperature for eighteen hours. The solvent was removed under reduced pressure. The residual oil was taken up with dichloromethane (10 mL) and concentrated. This process was repeated three times to remove trifluoroacetic acid completely. The resulting oil was crystallized from methanol to give 0.174 g of white solid (53% yield): 1H NMR (D2O) δ 1.40-1.48 (m, 27H), 1.7-2.1 (m, 4H), 2.2-2.4 (m, 3H), 2.6-3.0 (m, 3H), 3.8-4.0 (m, 2H), 7.2-7.4 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[NH:20][C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Cl)cnc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cc(Cl)cnc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 1.40 g of 5-{4-(6-chloro-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-tri-phenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 65) and 20 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 0.75 g of the title compound, melting at 203°-205° C.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:3].[CH2:11]([O:13][N:14]=[CH:15][CH3:16])[CH3:12].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH2:11]([O:13][N:14]1[CH:15]([CH3:16])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:12]
Reactant: CC=NOCC
Reactant: C=C(C)C1CCCCC1=O
Agent: CCON1C(=O)CCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCON1C(=O)CCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 17, 2-(prop-1-en-2-yl)cyclohexanone (0.88 g, 6.38 mmol), acetaldehyde O-ethyl oxime (0.67 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a colorless liquid (1.14 g, 80% yield).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13]C)(=[O:12])[CH:10]=[CH2:11]>[Na]>[CH2:1]([O:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=CC(=O)OC
Agent: [Na]
Product: O=C(O)CCOCc1ccccc1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Sodium metal (249 mg, 10.8 mmol) was added to benzyl alcohol (30 g, 278 mmol) at room temperature under nitrogen and the reaction was stirred for 30 minutes. Methyl acrylate (25.9 ml, 259 mmol) was then added dropwise and the reaction was stirred at room temperature for 18 h. After quenching with saturated aqueous ammonium chloride solution (200 ml) the mixture was extracted with ethyl acetate (2×300 ml) and the combined organic extracts were washed with brine (100 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was dissolved in ethanol (300 ml) and 1M aqueous sodium hydroxide solution (300 ml) was added dropwise. After 3 hours the ethanol was removed under reduced pressure and the aqueous residue was washed with dichloromethane (200 ml). The aqueous phase was then acidified with 2N aqueous hydrochloric acid (150 ml), extracted with dichloromethane (2×250 ml) and the combined organic extracts were dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was dissolved in 10% aqueous potassium carbonate solution (300 ml), washed with diethylether (300 ml) and the aqueous phase was acidified to pH1 using concentrated hydrochloric acid. The mixture was then extracted with dichloromethane (2×300 ml) and the combined organic extracts were dried over magnesium sulphate and concentrated under reduced pressure to provide the title compound (44.4 g) as a colourless oil.