Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:19])[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=3)=[S:29])=[CH:7][CH:6]=1)[CH:18]=[CH:17]2
Reactant: Nc1ccc(Sc2ccc3cc(Cl)ccc3n2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccc4cc(Cl)ccc4n3)cc2)ccc1Cl
Yield: 51.3 %

Procedure:
2-(4-Aminophenylthio)-6-chloroquinoline (2.9 mmoles, 0.83 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (3.2 mmoles, 0.76 g) were reacted according to procedure C to yield 0.78 g, 51% of the title compound. Mass Spec (FD) 524. Calculated for C23H14ClF3N3S2 : C, 52.68; H, 2.69; N, 8.01. Found: C, 52.66; H, 2.78; N, 7.91. M Pt 138°-139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[CH:10]=[C:11]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[C:2]1([NH:1][C:13]2[CH:14]=[CH:9][CH:10]=[C:11]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(-c2ccc3ccccc3n2)c1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Nc2cccc(-c3ccc4ccccc4n3)c2)cc1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
Aniline (2.75 g, 29.6 mmol), 2-(3-chlorophenyl)quinoline (5.25 g, 21.90 mmol), sodium tert-butoxide (3.36 g, 35.0 mmol), Pd2dba3 (0.501 g, 0.548 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybephenyl (S-Phos) (0.898 g, 2.190 mmol) were charged into the reaction flask with 200 mL of toluene. This mixture was evacuated and back-filled with nitrogen then was heated at reflux for 20 h. The reaction mixture was cooled to room temperature then was diluted with 200 mL of water. The toluene layer was separated and the aqueous was extracted with 100 mL of toluene. The organic extracts were combined and removed under vacuum. The crude residue was passed through a silica gel column using 75% DCM/hexanes then was passed through a silica gel column using 1-5% ethyl acetate/DCM. The clean product fractions were combined and solvents were removed under vacuum yielding N-phenyl-3-(quinolin-2-yl)aniline (3 g, 10.12 mmol, 46.2% yield).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8](OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.O1CCOCC1.[CH3:22][O:23][CH:24]1C(=O)[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[C:1]([CH:3]=[C:4]1[CH2:5][N:6]([C@H:8]2[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:25][C@H:24]2[O:23][CH3:22])[CH2:7]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (3.0 g, 15 mmol) in tetrahydrofuran (8 mL) was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (10 mL, 40 mmol). After being stirred at room temperature for two hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), and tert-butyl 3-methoxy-4-oxopiperidine-1-carboxylate (3.58 g, 15.62 mmol) and triethylamine (3.126 g, 30.89 mmol) were added. After being stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (8.184 g, 38.61 mmol) was added. The mixture was stirred at room temperature overnight. The resulting solution was diluted with aqueous NaHCO3 and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated. Purification with combi-flash (20-100% EtOAc in hexanes) afforded 2.8 g (60% yield) of the desired product. LC/MS found: 308.1 (M−56)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1)[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[N:22]2[CH2:27][CH2:26][N:25]([C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[CH2:24][CH2:23]2)[C:13]1=[O:36])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][CH:11]([N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[N:22]2[CH2:27][CH2:26][N:25]([C@@H:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH3:29])[CH2:24][CH2:23]2)[C:13]1=[O:36])[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1
Reactant: COc1ccc(C(CCCNC(=O)OC(C)(C)C)N2C(=O)c3cccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(CCCN)N2C(=O)c3cccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.4 %

Procedure:
A 10-mL round bottom flask was charge with Compound 65 (0.15 g, 2.0 mmol) and dichloromethane (2.0 mL). Trifluoroacetic acid (0.5 mL) was added and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo to give Compound 66 (113 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.63-7.69 (m, 1 H), 7.50-7.56 (m, 5 H), 7.40-7.42 (m, 1 H), 7.26-7.29 (m, 1 H), 7.13-7.18 (m, 1 H), 7.02-7.06 (m, 1 H), 6.88-6.92 (m, 1 H), 5.25 (q, J=7.0 Hz, 1 H), 4.47 (q, J=6.8 Hz, 1 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 3.47-3.60 (m, 3 H), 3.32-3.36 (m, 4 H), 2.96-3.07 (m, 3 H), 2.54-2.67 (m, 1 H), 2.32-2.42 (m, 1 H), 1.80 (d, J=6.8 Hz, 3 H), and 1.64-1.69 (s, 2 H); MS (ES+) 543 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C]=O.O.C(OCC)(=O)C.[CH3:26][N:27]([CH3:30])[CH:28]=[O:29]>[Cl-].[Cl-].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd+2]>[CH3:26][N:27]([CH3:30])[C:28]([C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1)=[O:29]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [C]=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(=O)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Reaction time: 48 h
Yield: 32 %

Procedure:
1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (50 mg, 0.177 mmol) was dissolved in N,N-dimethylformamide and the flask was purged with carbon monoxide. Dimethylamine (0.32 ml of a 5.5M ethanol solution) was added followed by palladium bis(diphenylphosphino)ferrocene dichloride, dichloromethane complex (14 mg, 0.0177 mmol). A carbon monoxide-filled balloon was attached and the flask was stirred in a 100 C bath for 48 hrs. The reaction was worked up by addition of water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined ethyl acetate layers were washed with water and then saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated to a residue. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give 16 mg (32%) of product. MP=98-101 C, (M+H)+=275.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br.[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31]Br)[CH2:25]1)=[O:23])[CH3:20]>C1COCC1>[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][O:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:25]1)=[O:23])[CH3:20]
Reactant: OCc1ccccc1Cc1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCCN(CCOCc2ccccc2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 8.4 %

Procedure:
Sodium hydride (2.1 g, 53 mmol, 60% oil dispersion) was added portionwise to a stirred solution of 2-benzylbenzylalcohol (5.0 g, 25 mmol) in dry THF (125 ml) placed under an atmosphere of nitrogen. The mixture was heated at reflux for 1 h and then allowed to cool to ambient temperature within 30 minutes. (R)-1-(2-Bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (8.6 g, 25 mmol, EP 374801) was added and the mixture was stirred for 2 days at ambient temperature. The reaction mixture was diluted with THF (100 ml) and filtered. The solvent was evaporated in vacuo to give an oily residue which was purified by column chromatography (700 g, heptane/ethyl acetate=1/1) to give 0.8 g of (R)-1-(2-(2-benzylbenzyloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@H:6]2[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH3:10])[C@H:3]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[SH:66][CH2:67][CH2:68][NH:69][C:70](=[O:72])[CH3:71]>CN(C1C=CN=CC=1)C.C(#N)C.C(OCC)(=O)C>[C:70]([NH:69][CH2:68][CH2:67][S:66][C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@H:6]2[C:9]([CH3:10])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:13])[CH3:25])[C:3]=1[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])(=[O:72])[CH3:71]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CC(=O)NCCS
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
To a solution of 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (58 mg) and 4-(N,N-dimethylamino)pyridine (1.3 mg) in acetonitrile (3 ml) was added a solution of diisopropylethylamine (22.4 μl) in acetonitrile (0.21 ml) at 0° C. To the mixture was added a solution of diphenyl chlorophosphate (23.3 μl) in acetonitrile (0.21 ml) at 0° C. After stirring at 0° C. for 1.5 hours, the reaction mixture was cooled to -15° C., to which a solution of diisopropylethylamine (74.6 μl) in acetonitrile (0.73 ml) was added. To the mixture was added a solution of N-(2-mercaptoethyl)acetamide (13.4 mg) in acetonitrile (0.12 ml). After standing overnight at -15° C., the mixture was diluted with ethyl acetate (50 ml), washed in turn with water and saturated aqueous sodium chloride, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (2 g) eluting with a mixture of methylene chloride and acetone (20:1 to 2:1) to give 4-nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (56 mg) as an amorphous solid.
Reaction SMILES: [C:1]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH:18](O)[CH2:19][O:20]C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:3][CH:2]=1.CCCCCC.CN(C)[CH:57]=[O:58]>O1CCCC1>[C:1]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH:18]([O:58][CH3:57])[CH2:19][OH:20])=[CH:3][CH:2]=1
Reactant: COc1ccc(C(OCC(O)COCCCCCCCCOc2ccc(-c3ccccc3)cc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(CO)COCCCCCCCCOc1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A solution of 7.6 g of 1-[[8-([1,1'-biphenyl]-4-yloxy)octyl]oxy]-3-[(4-methoxyphenyl)diphenylmethoxy]-2-propanol in 20 ml of dimethylformamide and 20 ml of tetrahydrofuran was added dropwise to a solution of 849 mg of hexane washed 50% sodium hydride in 50 ml of dimethylformamide containing 5.02 g of methyl iodide over 35 minutes under argon. The mixture was stirred overnight then ice was cautiously added followed by 300 ml of iced water. This mixture was extracted three times with ether, the extracts combined, washed with water, dried and evaporated. The residue was taken up in 65 ml of chloroform and 130 ml of methanol, heated to boiling, 8 g of Amberlite® IR-4B ion exchange resin added, stirred for 2 hours, filtered and evaporated. The residue was purified by chromatography, giving 1.27 g of 3-[[8-([1,1'-biphenyl]-4-yloxy]octyl]oxy]-2-methoxy- 1-propanol.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[C:12]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:15]=[C:14]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:13]=1.O>O1CCCC1.CCCCCC>[C:1]([NH:5][C:12]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:15]=[C:14]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Nc1cc(N2CCCC2)nc(N2CCCC2)n1
Reaction time: 17 h

Procedure:
A mixture of 21.7 g of t-butylamine in 100 mL of tetrahydrofuran is cooled to about -40° and treated over about 15 min with 170 mL of 1.6M n-butyllithium in hexane. The mixture is warmed to 0° for 2 hr, then recooled to -40° and treated over 30 min with a mixture of 25 g of 4-chloro-2, 6-di-1-pyrrolidinylpyrimidine and 50 mL of tetrahydrofuran. The mixture is allowed to warm to 20°-25° and is stirred for 16-18 hr. Water (50 mL) is then added and the mixture is concentrated under reduced pressure. The residue is partitioned between methylene chloride and aqueous 10% sodium bicarbonate. The organic phase is washed with saline, dried over anhydrous sodium sulfate and concentrated. Chromatography (silica gel, 5% ethyl acetate/hexane) gives the title compound, NMR (CDCl3) 4.78, 4.25, 3.53-3.49, 3.40, 1.93-1.86 and 1.41 6.
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:36]=[CH:35][O:34][N:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].BrC1C=C(N2C3=NC=CC(C4C=NC5C(C=4)=CC=CC=5)=C3C(C(C)C)=N2)C=CC=1C#N.NC1C=C[O:71]N=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:71])=[C:25]([NH:31][C:32]3[CH:36]=[CH:35][O:34][N:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Nc3ccon3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: Nc1ccon1
Agent: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(Nc3ccon3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 40 %

Procedure:
According to Example 1(6), 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isoxazol-3-ylamino)benzonitrile was prepared using compound (6d) instead of compound (1e) and using 3-aminoisoxazole instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (32) (the second stage yield: 40%) was prepared as a white solid using 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isoxazol-3-ylamino)benzonitrile instead of compound (1f).
Reaction SMILES: [O:1]=[C:2]([O-:11])[C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[Na+]>O>[O:1]=[C:2]([OH:11])[C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C([O-])[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
One mole of sodium arabinonate (188 g) in 300 ml of water was acidified on an acid cation exchange resin, giving a solution of arabinonic acid. The arabinonic acid was transformed into the γ-lactone by concentrating in vacuum the aqueous solution to about 200 ml when 300 ml of butanol is added. After a third concentration, the solution is removed from the flask with the aid of 100 ml of butanol and seeded. Crystallization begins at once and a large crop of crystals forms. The crystalline product (115 g) is collected on a filter, washed with butanol and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:13][C@@H:14](O)[CH2:15][CH:16]=[CH2:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:16]([CH2:15][CH:14]=[CH2:13])[CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CC[C@@H](C)O
Reactant: COC(=O)c1cc(F)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(C)Oc1ccc(F)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
To a solution of methyl 5-fluoro-2-hydroxybenzoate (1.0 g, 5.88 mmol), (R)-(−)-pent-4-en-2-ol (1.210 ml, 11.76 mmol) and triphenylphosphine (2.004 g, 7.64 mmol) in THF (14 ml) was added dropwise DIAD (1.486 ml, 7.64 mmol) and the resulting solution was stirred at rt. After 20 h, the reaction was diluted with Et2O and washed with 1N NaOH, water (3×'s) and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-40% EtOAc/hexane; 20 CV) to give methyl 5-fluoro-2-(pent-4-en-2-yloxy)benzoate (1.1331 g, 4.76 mmol, 81% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J=8.7, 3.3 Hz, 1H), 7.15 (ddd, J=8.9, 7.7, 3.4 Hz, 1H), 6.96 (dd, J=9.0, 4.2 Hz, 1H), 6.02-5.79 (m, 1H), 5.20-5.06 (m, 2H), 4.50-4.34 (m, 1H), 3.90 (s, 3H), 2.60-2.32 (m, 2H), 1.34 (d, J=6.1 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15](OCC)=[O:16])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]1([C:7]23[CH2:14][CH2:13][C:10]([CH2:15][OH:16])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C12CCC(c3ccccc3)(CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC12CCC(c3ccccc3)(CC1)CC2
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 101.6 %

Procedure:
A solution of ethyl 4-phenylbicyclo[2.2.2]octane-1-carboxylate (207 g, 801 mmol) in THF (850 mL) was added to a stirred solution of lithium aluminium hydride (20 g, 527 mmol) in THF (1.25 L) under nitrogen, maintaining a temperature of 20-25° C. with an ice/water bath. The reaction mixture was stirred for 3 h, allowed to stand overnight, then quenched by addition to a mixture of water (900 mL) and ice (300 g). The mixture was acidified to pH 1-2 with concentrated hydrochloric acid then extracted with ethyl acetate (3×1 L). The combined organics were dried (MgSO4) and evaporated down to give the title compound as a brown solid (176 g; ˜100%). 1H NMR (CDCl3) 1.35 (1H, brd s), 1.40-1.52 (6H, m), 1.71-1.85 (6H, m), 3.25 (2H, s), 7.05-7.13 (1H, m), 7.17-7.30 4H, m).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
2-Fluoronitrobenzene (1.5 g) and 4-chlorophenol (1.3 g) were dissolved in dimethylformamide (20 ml) and potassium carbonate (1.4 g) was added thereto. The mixture was stirred overnight at 80° C. After the mixture was cooled, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate (50 ml×2). The mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was re-crystallized from methanol, to thereby yield the target compound (2.2 g) as pale-yellow crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:25])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].O.[OH-].[Li+]>O1CCCC1.O.CO>[C:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C:5]([CH3:25])([C:3]([OH:4])=[O:2])[N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)O)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (1.62 g, 4.52 mmol) in tetrahydrofuran/water/methanol (50 mL, 5:1:1) at 0° C. was added lithium hydroxide hydrate (2.2 g, 52.3 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The reaction mixture was heated at 40° C. for 19 h then cooled to room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and water and the mixture was acidified to pH 5 with hydrochloric acid (1 M). The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The residue was dissolved in toluene and the solvent was evaporated to give 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester as a yellow oil (1.47 g, 95%). LCMS (m/z) 343.1 [M−H], Tr=2.36 min. To a solution of 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester (1.37 g, 4.0 mmol) in dichloromethane (30 mL) at 0° C. was added (R)-1-(7-bromo-quinolin-2-yl)-ethylamine hydrochloride (1.30 g, 4.5 mmol) and N,N-diisopropylethylamine (2.8 mL, 16.0 mmol) followed by (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (1.81 g, 4.76 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with water. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were passed through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of iso-hexanes/ethyl acetate 20:1 to 0:1 to afford the title compound (929 mg, 40%) as a yellow foam and as a mixture of diastereoisomers. LCMS (m/z) 577.3, 579.2 [M+H], Tr=3.72 min.