Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12]Br)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.CCOCC>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: BrCCCc1ccc2c(c1)CCC2
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1cc2c(cc1CCCN1CCCCC1)CCC2

Procedure:
The crude 3-(5-Indanyl)-1-bromopropane (13.0 g, 0.054 M) is dissolved in 200 ml toluene and treated with 50 g of piperidine. The mixture is heated under reflux overnight, then cooled and diluted with ether to precipitate salts. The salts are removed by filtration and the solvent removed from the filtrate in vacuo. The residue is distilled collecting 8.4 g (64%) of desired product boiling at 135°-140° (0.15 mm).
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([Br:6])=[CH:8][CH:9]=2)=[O:12])[CH2:28][CH2:29]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.9 %

Procedure:
To tetrahydrofuran (120 mL) were added 4-bromobenzoyl chloride (25 g), 1-(2,4-dimethylphenyl)piperazine (22 g) and 1N aqueous sodium hydroxide solution (120 mL), and the mixture was stirred at room temperature for 6 hr. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The title compound (31 g) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[S:8](Cl)(Cl)=[O:9].O>C(Cl)Cl>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][S:8](=[O:9])[O:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CO)CO
Solvent: O
Solvent: ClCCl
Product: CC1(C)COS(=O)OC1
Temperature: 25 °C
Yield: 92 %

Procedure:
25.36 g (0.24 mol) of 2,2-dimethylpropane-1,3-diol was suspended at room temperature in 150 ml of methylene chloride in a 500 ml three-necked flask. 37.36 g (0.31 mol) of thionyl chloride was instilled over 30 minutes. After the end of the addition, the reaction solution was held at reflux for 1.5 hours and then cooled to room temperature. 100 ml of water was added to the reaction. The aqueous phase was discarded; the organic phase was extracted three times with saturated NaHCO3 solution (100 ml), then dried with Na2SO4 and concentrated by evaporation on a rotary evaporator. The residue was distilled at 24 mbars and 78° C. The product was a pure colorless liquid according to GC and weighed 23.4 g, which corresponded to a yield of 92 percent.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([C@H:16]4[CH2:20][CH2:19][O:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[CH3:21][O:22][C:23]1[C:28]([CH3:29])=[C:27](B(O)O)[C:26]([CH3:33])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>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>[CH3:21][O:22][C:23]1[C:28]([CH3:29])=[C:27]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:15]([C@H:16]5[CH2:20][CH2:19][O:18][CH2:17]5)[N:14]=[CH:13][C:7]=4[C:8](=[O:12])[NH:9][C:10]=3[CH:11]=2)[C:26]([CH3:33])=[CH:25][N:24]=1
Reactant: COc1ncc(C)c(B(O)O)c1C
Reactant: O=c1[nH]c2cc(Br)ccc2c2c1cnn2[C@H]1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn([C@H]4CCOC4)c23)c1C
Temperature: 100 °C
Reaction time: 4.5 h

Procedure:
(S)-7-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (100 mg), (2-methoxy-3,5-dimethyl-pyridin-4-yl)boronic acid (65 mg) obtained in Preparation Example 29 (4) and cesium carbonate (293 mg) were added to a mixed solution of DMF (5 mL) and water (1 mL) at room temperature. PdCl2(PPh3)2 (10.5 mg) was added to the mixture in a nitrogen gas stream. The mixture was stirred at 80° C. for one hour and at 100° C. for 4.5 hours. After cooling the reaction mixture to room temperature, water (5 mL) was added, and the mixture was extracted with isopropyl acetate. The organic layer was washed with water and brine and then concentrated under reduced pressure. A crude purified product (64.7 mg) was obtained as the title compound. The instrumental data of this compound were identical to those of the (−)-form of Example 25.
Reaction SMILES: Cl.[CH3:2][C:3](=O)CC(=O)C.[NH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[NH2:18].C(=O)([O-])O.[Na+]>C(O)C>[CH3:2][C:3]1[NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[N:18]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(C)c(N)c(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c2[nH]c(C)nc2c1
Yield: 124.2 %

Procedure:
30 ml (150 mmol) of hydrogen chloride-solution (5 M in water) and 1.5 ml (14.68 mmol) 2,4-Pentandione are added to a solution of (7.34 mmol) of 2-Amino-3,5-dimethylphenylamine (example X, Step 1) in 112 ml ethanol. The reaction mixture is refluxed for 30 minutes. The solution is neutralized with saturated sodium hydrogen carbonate solution (to pH 7) and extracted with dichlormethane. The organic phases are dried over magnesium sulfate and the solvent is evaporated under vacuum to afford 2,5,7-Trimethyl-1H-benzimidazole (1.46 g) in quantitative yield.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([CH:17]([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:18][C:19](OC)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>CCCCCC>[C:11]1([CH:17]([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:18][CH2:19][OH:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC(c1ccccc1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)c4ccccc4)c3)ncnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Diisobutylaluminum hydride in hexane (1 M, 0.69 mL) was added to a solution of methyl 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanoate (150 mg, 0.00031 mol) in DCM (3 mL, 0.05 mol) and the mixture was cooled to −78° C. under a nitrogen atmosphere. The reaction was stirred for 1 h at −78° C. and was allowed to warm to room temperature for 4 hrs. The reaction was quenched with methanol (100 μL), and saturated ammonium chloride (100 μL), and then taken up in ethyl acetate dried over MgSO4 and filtered. The filtrate was concentrated to give 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol (130 mg, 92%) as an oil. m/z=450 (M+1).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[Na].Cl.Cl[CH2:15][C:16](=[NH:21])[O:17][CH2:18][CH2:19][CH3:20]>C(O)CC>[OH:10][C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:15]=1[C:16](=[NH:21])[O:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCOC(=N)CCl
Reactant: COC(=O)c1ccccc1S
Agent: Cl
Agent: [Na]
Solvent: CCCO
Product: CCCOC(=N)c1sc2ccccc2c1O
Yield: 26.3 %

Procedure:
16.8 g (0.1 mol) of methyl thiosalicylate are added dropwise to a solution of 4.6 g (0.2 mol) of sodium in 400 ml of anhydrous n-propanol. To this mixture 17.2 g (0.1 mol) of propyl chloroacetimidate hydrochloride are slowly added and the resultant mixture is heated under reflux for 6 hours. The reaction mixture is evaporated under vacuum and the residue distributed between water and dichloromethane. The organic phase is dried, evaporated, and the residue recrystallized from ethyl acetate/diisopropylether solution to yield 6.2 g of yellow crystals with an m.p. of 185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:5]/[C:4]2[CH:3]=[C:2]([F:1])[C:9]([F:10])=[C:8]([F:11])[CH:7]=2)/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: COc1ccc(/C(C#N)=C/c2cc(F)c(F)c(F)c2)cc1OC
Yield: 18.8 %

Procedure:
3,4,5-Trifluorobenzaldehyde (160 mg) and 3,4-dimethoxybenzyl cyanide (177 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (60 mg, yield: 19%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5nnn[nH]5)cc34)cc2)cc1
Temperature: 180 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
(4-Benzyloxy-phenyl)-(6-cyanoquinazolin-4-yl)-amine (0.106 g) in dimethylformamide was treated with sodium azide (0.06 g) and ammonium chloride (0.05 g) and the mixture stirred at 180° C. for 18 hours. The mixture was cooled, poured onto water and extracted with ethyl acetate/THF (3:1). The organic extracts were dried and concentrated in vacuo. The residue was purified using solid phase extraction to yield the title compound (0.024 g); δH [2H6]DMSO 10.18(1H,s), 9.25(1H,s), 8.55(1H,s), 8.40(1H,d), 7.88(1H,d), 7.74(2H,d), 7.45(6H,m), 7.07(2H,d), 5.17(1H,s), m/z (M+1)+396.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O>[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:21][C:16]3[CH:15]=[C:14]([C:12]4[O:13][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=5)=[N:10][N:11]=4)[CH:19]=[CH:18][C:17]=3[N:20]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Reactant: Nc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCc1cc(C)c(-c2nc3ccc(-c4nnc(Nc5cccc(Cl)c5)o4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-[5-(3-chlorophenylamino)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine (210 mg, 0.7 mmol) and 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (169 mg, 0.77 mmol) (from step D) in DMSO (2.5 mL) was added Yb(OTf)3 (86 mg, 0.14 mmol) and the mixture was stirred at RT for 72 h. The mixture was poured into water and the resulting precipitate was filtered and washed with water. The solid was purified by flash chromatography using 10% MeOH/CH2Cl2 as eluent to give the title compound as a tan solid. MS: m/z 502.0 (M+1). H1-NMR (DMSO-d6): δ ppm 12.91 (m, 0.6H), 10.93 (s, 0.3 H), 10.48 (dd, 0.3H), 8.33 (s, 0.4H), 8.13 (s, 0.6H), 7.89-7.73 (M, 2.3H), 7.68 (d, 0.3 H), 7.59 (d, 0.4H), 7.52 (m, 1 H), 7.46-7.35 (m, 1H), 7.08 (s, 3H), 3.61 (s, 3H), 2.87 (t, 2H), 2.69 (t, 2H), 2.10 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][C@@H:17]([CH3:19])[N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@@H:15]([CH3:26])[CH2:14]2)=[C:9]([C:27]#[N:28])[CH:8]=1)([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][C@@H:17]([CH3:19])[N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@@H:15]([CH3:26])[CH2:14]2)=[C:9]([C:27]#[N:28])[CH:8]=1
Reactant: CCOC(=O)CN1[C@H](C)CN(c2ccc([N+](=O)[O-])cc2C#N)C[C@@H]1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CN1[C@H](C)CN(c2ccc(N)cc2C#N)C[C@@H]1C
Temperature: 65 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
Ammonium chloride (1.2 g) and iron powder (6.1 g) were added to a mixed solvent of water (90 ml) and ethanol (270 ml), and the mixture was heated to 65° C. Then, ethanol solution (20 ml) containing ethyl cis-4-(4-nitro-2-cyanophenyl)-2,6-dimethylpiperazin-1-ylacetate (10.8 g) was dropwise added in parts over 20 min and the mixture was stirred at a refluxing temperature for 1 h. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of diisopropyl ether-n-hexane to give the title compound (9.5 g), melting point: 45° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([C:32]#[C:33][CH2:34][OH:35])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]>CO.O=[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:36])=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][OH:35])=[CH:29][C:30]=3[F:31])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C#CCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=[Pt]=O
Solvent: CO
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(CCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 36 h
Yield: 77.3 %

Procedure:
A solution of 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)prop-2-yn-1-ol (714 mg, 1.28 mmol) in MeOH (75 mL) was sparged with argon, charged with PtO2 (30 wt %, 214 mg) and then pressurized to 65 psi under hydrogen atmosphere in a Parr shaker for 36 h. The reaction was monitored by LCMS and upon completion the mixture was filtered through Celite™ to remove the catalyst. The filtrate was concentrated and purified by flash chromatography (80% EtOAc/hexanes) to yield the title compound (560 mg, 0.99 mmol). MS (EI) m/z 561 (MH+).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@@H:29]1[C:41]([OH:43])=[O:42])=[O:27])([CH3:24])([CH3:23])[CH3:22].CI>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:30][C:29]1([CH3:1])[C:41]([OH:43])=[O:42])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)C[C@@H]1C(=O)O
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1(C)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To a cooled (−78° C.) solution of diisopropylamine (0.032 mol) in dry THF (15 mL), n-BuLi (0.030 mol) was added dropwise under argon atmosphere, and the reaction was stirred for 30 min at −78° C., then for one hour at −20° C. The resulting LDA solution was transferred to the solution of the known compound (R)-4-benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (CAS: 54631-81-1, e.g. Tetrahedron, 42(21), 6039-45; 1986) (3.5 g, 0.011 mol) in THF (15 mL) at −78° C., and the mixture was stirred for 30 minutes at −78° C., then at 0° C. for one hour. The reaction mixture was once again cooled to −78° C. and methyl iodide (0.82 mL, 0.013 mol) was added to it over 10 min and stirred the reaction mixture was stirred at 0° C. then at rt for one hour. After completion of the reaction by TLC, the reaction mixture was quenched with 1N HCl (20 mL) and extracted with DCM. The organic layer was concentrated under reduced pressure to give a crude material, which was purified through column chromatography (10-20% ethyl acetate:hexane, basic alumina, diameter of column—2.5 cm, height of alumina—approx. 7 inch) to afford the desired (rac)-4-benzyloxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 800 mg (22%) as a white solid.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34]O)[C:24]=1[O:25]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:24]=1[OH:25]
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Reactant: Oc1cccc2ccccc12
Product: O=C1OC(CCOc2cccc3ccccc23)C(O)=C1O
Yield: 26.2 %

Procedure:
Mitsunoble coupling of 0.17 g (1.2 mmol) of 1-naphthol with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 75 mg (26% yield) of 3,4-dihydroxy-5-[2-(1-naphthoxy)ethyl]-2(5H)-furanone as colorless cubes: mp 163-164° C. (ether/hexanes) 1H NMR (acetone-d6) δ 8.38-8.25 (m, 1H), 7.92-7.79 (m, 1H), 7.60-7.34 (m, 4H), 7.05-6.93 (m, 1H), 5.11 (dd, J=5.3, 8.7 Hz, 1H), 4.39 (dd, J=2.6, 4.7 Hz, 2H), 2.75-2.52 (m, 1H), 2.25-2.05 (m, 1H). 13C NMR (acetone-d6) δ 169.62, 154.92, 153.61, 135.13, 127.83, 126.78, 126.50, 125.92, 125.05, 122.41, 120.66, 118.53, 105.28, 72.85, 63.93, 32.58. Anal Calcd for C16H14O5 : C, 67.11; H, 4.89. Found: C, 66.70; H, 4.88.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[C:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:11])[CH:9]=[CH2:10]>>[CH2:13]([O:12][C:8]([CH2:9][CH2:10][CH:5]([NH:4][CH2:3][CH2:2][NH2:1])[CH2:6][OH:7])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: NCCNCCO
Product: NCCNC(CO)CCC(=O)OCc1ccccc1

Procedure:
A solution of 2-(2-aminoethylamino)ethanol (4.6648 g; 44.8 mmole) dissolved in 35 mL of benzyl acrylate was heated at reflux for 24 hours. The excess reagent was removed under reduced pressure and the resulting oil was purified by flash chromatography using a mixture of dichloromethane and ethyl acetate (60:40) to elute the desired material. Fractions were collected and analyzed to determine which of these contain the product. Solvents were eliminated under vacuum to give 5.8 g (21.9%) of N,N,N′-tris[2-(benzyloxycarbonylethyl]-2-(2aminoethylamino)ethanol (8).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>CCOCC>[Cl:9][CH2:10][C:11]([N:4]1[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: CC1CNCC(C)O1
Solvent: CCOCC
Product: CC1CN(C(=O)CCl)CC(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.5 %

Procedure:
2,6-Dimethylmorpholine (a mixture of trans- and cis-isomers (1.0 g, 8.7 mmol) and TEA (1.34 ml, 9.6 mmol) were dissolved in anhydrous ether (50 ml) and cooled in ice bath. To the above mixture was added dropwise a solution of chloroacetyl chloride (0.69 ml, 8.7 mmol). Then the mixture was warmed to room temperature and stirred for 3 hours. The mixture was washed with water, dried and evaporated under reduced pressure. The residue was purified by column chromatography (EA/PE=1/1) to afford the title compound (0.79 g, yield 47.5%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[C:21]1([C:27](=[N:30][OH:31])[CH2:28][CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:32]([O:39][CH2:40][CH3:41])(=[O:38])[C:33]([O:35]CC)=O>C1COCC1>[OH:31][N:30]=[C:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:28]([CH3:29])[C:33](=[O:35])[C:32]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCC(=NO)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(=O)C(C)C(=NO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 131.7 %

Procedure:
Diisopropylamine (21 mL, 148 mmol) was added to 50 mL of THF and cooled with an external ice bath. Butyllithium (56 mL, 141 mmol, 2.5 M in hexanes) was added and the mixture was stirred at 0° C. for 30 min, and brought to room temperature. The resulting LDA solution was added to a mixture of 1-phenyl-propan-1-one oxime (10 g, 67 mmol) and THF (50 mL) at 0° C. Following the addition, the reaction mixture was stirred at 0° C. for 1 hour and warmed to room temperature. The mixture was then transferred to a syringe and added dropwise to a flask containing a pre-cooled mixture of diethyl oxalate (46 mL, 336 mmol) and THF (150 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The mixture was cooled in an ice bath and quenched with 150 mL of 3M hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with EtOAc. The aqueous layer was then neutralized with solid sodium bicarbonate and extracted further with CH2Cl2. The organic layers were combined, dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-40% EtOAc/hexanes) to give 22 g of the title compound. MS: (+) m/z 250.48 (M+1).
Reaction SMILES: [Si]([O:18][C:19]1[CH:54]=[CH:53][C:22]([O:23][CH2:24][C@@H:25]([OH:52])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:51]=[CH:50][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH:45]1([CH2:44][NH:43][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:33]3[CH:50]=[CH:51][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:52])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:54][CH:53]=4)=[CH:31][CH:32]=3)[CH2:36][CH2:37]2)=[O:42])[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCC4CCCC4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCC1CCCC1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 58.1 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-(cyclopentylmethyl)-1-piperidinecarboxamide (0.24 g, 0.32 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.095 g, 0.186 mmol).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:8].[CH:10]1([NH2:14])[CH2:13][CH2:12][CH2:11]1>O>[Cl:9][C:6]1[C:7]([NH2:8])=[C:2]([NH:14][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:3]=[N:4][CH:5]=1
Reactant: Nc1c(Cl)cnnc1Cl
Reactant: NC1CCC1
Solvent: O
Product: Nc1c(Cl)cnnc1NC1CCC1
Temperature: 125 °C
Yield: 58 %

Procedure:
A mixture of 3,5-dichloro-4-aminopyridazine (Preparation 4, 200 mg, 1.22 mmol), cyclobutyl amine (0.56 mL) and water (1.12 mL) was heated under microwave irradiation at 125° C. for 4 hours. The reaction mixture was concentrated in vacuo and the crude residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 to afford the title compound as a brown solid in 58% yield, 140 mg.