Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:36])[C:20]=3[C:24](=[O:35])[NH:25][CH2:26][CH:27]3[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.Cl.O1CCOCC1.C(=O)(O)[O-].[Na+]>>[F:34][C:30]1([F:33])[CH2:31][CH2:32][CH:27]([CH2:26][NH:25][C:24]([C:20]2[C:21]3[CH:22]=[CH:23][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[N:15][C:16]=3[CH:17]=[CH:18][C:19]=2[Cl:36])=[O:35])[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCNCC3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a stirred solution of 4-{6-chloro-5-[(4,4-difluoro-cyclohexylmethyl)-carbamoyl]-quinolin-2-yl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.09 mmol, 1.00 eq) in dichloromethane (5.00 mL, 77.14 mmol, 100 V) at 0 OC was added 4M HCl in dioxane (2 mL, 8.00 mmol, 89.05 eq) dropwise under nitrogen. The reaction mixture was stirred at RT for 2 h and the solvent was evaporated completely. The crude obtained was basified with 10% sodium bicarbonate solution and was extracted with DCM. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The crude obtained was purified by preparative HPLC to afford the title compound (10 mg, 0.02 mmol, 24.5%) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.79 (t, J=5.91 Hz, 1H), 7.99 (dd, J=9.42, 9.0 Hz, 2H), 7.76 (d, J=9.03 Hz, 1H), 7.58 (d, J=8.72 Hz, 1H), 3.43 (s, 1H), 3.25-3.29 (m, 2H), 3.03-3.06 (m, 2H), 2.91-2.98 (m, 1H), 2.58-2.67 (m, 2H), 2.02-2.04 (m, 2H), 1.64-1.84 (m, 9H), 1.23-1.30 (m, 2H). m/z: 422.0 [M+H]+
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([C:13]3[S:17][C:16]([NH2:18])=[N:15][C:14]=3[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][N:29]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:18][C:16]2[S:17][C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:12]=3)=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[N:15]=2)=[O:33])=[CH:30][N:29]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(NC3CCCC3)c2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Cc1cccc(-c2nc(NC(=O)c3ccc(Cl)nc3)sc2-c2ccnc(NC3CCCC3)c2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 43.7 %

Procedure:
To a solution of [5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.4 mmol) and 4-dimethylaminopyridine (0.052 g, 0.43 mmol) in N,N-dimethylacetamide (10 mL) was added 6-chloronicotinoyl chloride hydrochloride (0.46 g, 2.1 mmol), and the mixture was stirred at 80° C. for 14 hrs. Into the reaction mixture was poured aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 4:1) and the resulting crystals were recrystallized from ethanol to give the title compound (0.30 g, yield 42%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][C:10]([C:17](OCC)=[O:18])([C:12](OCC)=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl>CO.[Cl-].[Na+].O>[CH2:1]([N:8]1[CH2:11][C:10]([CH2:12][OH:13])([CH2:17][OH:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CN(Cc2ccccc2)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: OCC1(CO)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of diethyl 1-benzylazetidine-3,3-dicarboxylate (4.8 g, 16.5 mmol) in CH3OH (10 mL) was added NaBH4 (1.25 g, 33 mmol). The mixture was stirred at RT for 1 hr. 100 mL of brine and 200 mL of DCM were added. Organic layers were separated from aqueous layers, dried over Na2SO4, concentrated to afford 2.328 g (68%) of (1-benzylazetidine-3,3-diyl)dimethanol as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.21-7.31 (m, 5 H), 4.15-4.05 (m, 2 H), 3.48 (d, J=4.8 Hz, 2H), 3.17 (d, J=4.8 Hz, 4 H) and 2.89 (s, 2 H).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].[H-].[Na+].CN(C)C=O.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:1]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4](=[O:11])[O:3][C:2]2=[O:12])=[CH:24][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)oc(=O)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a mixture of 2H-3,1-benzoxazine-2,4(1H)-dione (18.7 g), sodium hydride (an oily, about 66%, 4.8 g) and N,N-dimethylformamide (70 ml) was added dropwise 4-methoxybenzyl chloride (17.6 ml), stirred at room temperature for 1 night. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and a saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the target compound (26.1 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>CN1C(=O)CCC1>[CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[N:15][C:2]([N:24]5[CH2:28][CH2:27][CH2:26][CH:25]5[C:29]5[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: c1cc(C2CCCN2)ccn1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCCC3c3ccncc3)cc1OCC2
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of 12-chloro-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (150 mg, 0.450 mmol), TEA (0.5 mL), and 4-(pyrrolidin-2-yl)pyridine (134 mg, 0.900 mmol) in NMP (0.5 mL) was stirred at 150° C. for 24 h under nitrogen atmosphere. The resulting mixture was purified by reverse phase combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 136, which was further purified by chiral HPLC (AD column, 30% EtOH (0.1% DEA) in n-Hexane isocratic) to separate the (R) and (S) enantiomers, 23 mg of one enantiomer and 28 mg of the other (26% total yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:12][C:13]#[N:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.OO.C(=O)([O-])[O-:18].[K+].[K+].O>CS(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:12][C:13]([NH2:14])=[O:18])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C2(CC#N)CC2)cc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(C2(CC(N)=O)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of [1-(4-methoxyphenyl)cyclopropyl]acetonitrile (60.4 mmol) in DMSO (75 mL) is treated with H2O2 (50% w/w) (434 mmol) and potassium carbonate (121 mmol) at zero degrees Celsius. The reaction mixture is stirred at room temperature over the weekend. The reaction mixture is transferred into a separatory funnel using water (100 mL) and CH2Cl2 (200 mL). The mixture is equilibrated and the CH2Cl2 layer is removed. The aqueous layer is extracted two additional times with CH2Cl2 (2×300 mL). The combined CH2Cl2 extracts are washed 5 consecutive times with water (5×200 mL) followed by a brine (500 mL) wash, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure, which affords 2-[1-(4-methoxyphenyl)-cyclopropyl]-acetamide.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:51]([OH:53])=[O:52])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:59]O>>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:51]([O:53][CH3:59])=[O:52])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)OC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 20b (1.20 g, 1.38 mmol) in methanol (30 mL) was added concentrated sulphuric acid (150 mg, 1.53 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours and then 40° C. for 6 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (3 mL) at 0° C. and concentrated in vacuo to remove most of the solvent. To the residue was added water (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/1 to give the title compound 20c as colorless semi-solid (0.48 g, 46.2%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.43 (d, 1H), 7.36 (p, 2H), 7.27 (m, 10H), 7.15 (m, 3H), 6.86 (dd, 3H), 6.78 (m, 2H), 4.82 (q, 2H), 4.75 (d, 1H), 4.60 (d, 1H), 4.50 (d, 1H), 4.26 (d, 1H), 4.17 (dd, 2H), 4.00 (m, 5H), 3.85 (d, 1H), 3.71 (d, 1H), 3.68 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>>[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: ClCc1ccc(I)cc1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(I)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl)amino]pyrimidine and 4-iodobenzyl chloride
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:31]2[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38]C)=[O:36])=[CH:33][CH:32]=2)[CH2:27]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:31]2[CH:41]=[CH:40][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:27]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(N2CC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3ccccc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(N2CC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
To a round bottom flask was added ethyl 4-((S)-3-((1R,2R)-2-(benzyloxycarbonylamino)cyclohexylamino)pyrrolidin-1-yl)benzoate trifluoroacetate (30 mg, 0.052 mmol), LiOH monohydrate (37 mg, 1.56 mmol) in water (1 ml) and MeOH (1 ml). The reaction was stirred at rt for 16 hrs. The reaction was concentrated and the residue was purified by RP prep-HPLC to afford methyl 4-((S)-3-((1R,2R)-2-(benzyloxycarbonylamino)cyclohexylamino)pyrrolidin-1-yl)benzoate trifluoroacetate (8 mg, 0.014 mmol, 26.8% yield) as a beige solid. Anal. Calcd. for C26H33N3O4 m/z 451.5, found: 452.3 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (d, J=8.8 Hz, 2H), 7.45-7.31 (m, 1H), 7.29-7.15 (m, 4H), 6.67 (d, J=8.8 Hz, 2H), 4.93 (s, 2H), 4.63 (d, J=12.2 Hz, 1H), 4.25-4.11 (m, 1H), 3.72-3.39 (m, 4H), 3.23-3.12 (m, 1H), 2.61-2.42 (m, 1H), 2.40-2.19 (m, 2H), 2.09-1.95 (m, 1H), 1.94-1.77 (m, 2H), 1.63-1.23 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[C:28](OC=C)(=O)[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]=[CH2:29])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A mixture of 1-[9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (200 mg, 0.492 mmol), vinyl acetate (182 μL, 1.97 mmol), di-μ-chlorobis[(η-cycloocta-1,5-diene)iridium (I)] (16.5 mg, 0.0246 mmol) and sodium carbonate (31.3 mg, 0.295 mmol) in o-dichlorobenzene (0.98 mL) was stirred at 100° C. for 2 hr. Vinyl acetate (100 μL, 1.08 mmol) was added to the reaction mixture and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane to give the title compound (175.2 mg, 0.405 mmol, 82%) as a white yellow amorphous.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH3:14])[NH:11][C:12]=1[CH3:13])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:14][C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[C:12]([CH3:13])[N:11]=1
Reactant: CCOC(=O)NN=Cc1nc(C)[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(C)n2c(=O)[nH]ncc12

Procedure:
A mixture of 7.37 gm. of 3-[(2,5-dimethyl-4-imidazolyl)methylene]carbazic acid ethyl ester and 50 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 263°-263.5° C.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[Na].C([O:12][C:13](=[O:18])[CH2:14][N:15]=[N+]=[N-])C>C(O)C>[Cl:1][C:2]1[O:6][C:5]2[CH:7]=[C:14]([C:13]([OH:18])=[O:12])[NH:15][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(Cl)o1
Agent: [Na]
Solvent: CCO
Product: O=C(O)c1cc2oc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-furan-2carbaldehyde (Snyder, H. R., Jr.; Seehausen, P. H., J. Heterocycl. Chem., 10: 385-6 (1973)) was annulated according to Procedure H (8 equiv sodium; aldehyde and azido-acetic acid ethyl ester added as ethanol solution (0.9 M of ester); condensation reaction mixture allowed to warm to room temperature, stirred for 1 h, quenched at −40° C., diluted with water, and extracted with ether; acrylate not purified; crude furanopyrrole filtered before concentration).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[C:20]3[C:26]([O:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:39]([O:43][C:44]([NH:46][C@H:47]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=1)[C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:58][C:55]1[CH:56]=[CH:57][C:52]([CH2:51][C@@H:47]([NH:46][C:44](=[O:45])[O:43][C:39]([CH3:41])([CH3:40])[CH3:42])[C:48]([N:36]2[CH2:35][CH2:34][N:33]([C:19]3[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[C:26]([O:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])[C:20]=34)[CH2:38][CH2:37]2)=[O:49])=[CH:53][CH:54]=1
Reactant: OC[C@H](O)COc1n[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(OC[C@@H](O)CO)c23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.055 mL, 0.32 mmol) was added to a solution of (S)-3-(5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride (0.050 g, 0.079 mmol), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.024 g, 0.079 mmol) and TBTU (0.031 g, 0.095 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, and the residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2 M) was added. The reaction was then stirred for an additional 10 minutes. Ethyl acetate (20 mL) was added, and the organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (ethyl acetate:MeOH, 20:1) to give tert-butyl(R)-3-(4-chlorophenyl)-1-(4-(3-((S)-2,3-dihydroxypropoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2 N) was added. The resulting solid was collected by filtration to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(3-((S)-2,3-dihydroxypropoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.018 g, 36%). MS APCI (+) m/z 551.2 detected.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:28].[Li+].[OH-]>>[CH2:30]([O:29][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:28])[C:3]([OH:32])=[O:2])[CH3:31]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:2]([C:3]1[C:7]2[CH:8]=[C:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1)=[O:1]
Reactant: COC(=O)c1ccc(-c2ccc3scc(CO)c3c2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc3scc(C=O)c3c2)cc1

Procedure:
A solution of Example 326B (298 mg, 1 mmol) and Dess-Martin periodinane (466 mg, 1.1 mmol) in dichloromethane at room temperature was stirred for 90 minutes and purified by flash chromatography on silica gel with 20% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 297 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].II>>[CH3:1][N:2]([CH2:15][C:14]1[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1
Reactant: CNc1cccc(F)c1
Reactant: ClCc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: II
Agent: [Na+]
Product: CN(Cc1ccc(Cl)cc1)c1cccc(F)c1

Procedure:
N-methyl-N-p-chlorobenzyl-m-fluoroaniline was prepared from 17.5 grams (0.14 mole) of N-methyl-m-fluoroaniline, 23.7 grams (0.14 mole) p-chlorobenzyl chloride (Aldrich), 11.9 grams anhydrous sodium acetate and 0.12 grams iodine according to the procedure as described in Example III. Yield 25.8 grams (74 percent), boiling point 162°-170° C. at 0.13 mmHg.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:39])=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].NC1C=CC(C(N2CCCC2)=[O:53])=CC=1>>[CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:53])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:39])=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Nc3ccc(C(=O)N4CCCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(Nc3ccc(C(=O)N4CCCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 59 %

Procedure:
According to Example 1(6), 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-{4-(pyrrolidine-1-carbonyl)phenylamino}benzonitrile was prepared using compound (6d) instead of compound (1e) and using (4-aminophenyl)(pyrrolidin-1-yl)methanone instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (34) (the second stage yield: 59%) was prepared as a white solid using 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-{4-(pyrrolidine-1-carbonyl)phenylamino}benzonitrile instead of compound (1f).