Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:37]=[CH:36][C:27]([CH2:28][O:29][C:30](=[O:35])[NH:31][CH:32]([CH3:34])[CH3:33])=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.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>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:24]3[CH:37]=[CH:36][C:27]([CH2:28][O:29][C:30](=[O:35])[NH:31][CH:32]([CH3:33])[CH3:34])=[CH:26][CH:25]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Reactant: CC(C)NC(=O)OCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc(COC(=O)NC(C)C)cc3)n2n1
Temperature: 140 °C
Yield: 138 %

Procedure:
A mixture of (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-butyl-amine (50 mg, 0.19 mmol), isopropyl-carbamic acid 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (from part A, ˜0.5 mmol), K2CO3 (77 mg, 0.56 mmol) and dichlorobis(triphenylphosphine)palladium(II) (6.5 mg, 0.01 mmol) in MeCN/water (2 ml/0.5 ml) was heated in a microwave at 140° C. for 10 min. The reaction was repeated with another half of the bronic ester from Part A. The two reactions were combined for purification. The water layer was removed and the reaction mixture was diluted with MeCN (3 ml) and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (100 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (t, J=7.39 Hz, 3H) 1.19 (d, J=6.62 Hz, 6H) 1.43-1.52 (m, 2H) 1.66-1.73 (m, 2H) 3.41 (td, J=7.06, 5.73 Hz, 2H) 3.87 (d, J=6.84 Hz, 1H) 4.49 (t, J=5.29 Hz, 1H) 5.14 (m, 1H) 6.45 (d, J=9.70 Hz, 1H) 7.46 (d, J=8.16 Hz, 2H) 7.66 (d, J=9.48 Hz, 1H) 7.81 (s, 1H) 8.14 (d, J=8.38 Hz, 2H). LRMS (ESI) m/z 382.2 [(M+H)]+, calc'd for C21H27N5O2: 381.48.
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH2:13][C:14](C)(C)[CH3:15])[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:38])([F:37])[O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)[CH:25]=[CH:26][CH:27]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:6][NH:8][C@H:9]([C:10]([NH:36][C@@H:33]1[C@@H:31]2[C@@H:30]([CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:19])([F:37])[F:38])[CH:23]=3)[CH2:32]2)[CH2:35][CH2:34]1)=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(OC(F)(F)F)c3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CCC[C@H](NC)C(=O)N[C@H]1CC[C@@H]2CN(c3cccc(OC(F)(F)F)c3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norvaline for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(3-(trifluoromethoxy)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 715 Step 1 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5, temperature 90° C.) δ ppm 7.63-7.68 (bs, 1H), 7.18 (t, J=8.4 Hz, 1H), 6.60-6.64 (m, 1H), 6.51-6.54 (m, 2H), 4.27 (dt, J=13.2, 6.6 Hz, 1H), 3.47 (dd, J=9.9, 3.8 Hz, 1H), 3.35 (dd, J=9.9, 7.9 Hz, 1H), 3.22 (dd, J=9.6, 8.0 Hz, 1H), 3.10 (dd, J=6.9, 5.8 Hz, 1H), 3.01 (dd, J=9.6, 4.1 Hz, 1H), 2.63-2.80 (m, 2H), 2.39 (s, 3H), 2.05-2.13 (m, 1H), 1.92-2.01 (m, 1H), 1.74-1.83 (m, 1H), 1.58-1.69 (m, 2H), 1.37-1.54 (m, 3H), 0.88 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[CH:3]1[C:16]([O:18][CH3:19])=[O:17].[CH2:21]([SH:25])[CH2:22][CH2:23][SH:24].B(F)(F)F.CCOCC>C(O)(=O)C.CCOCC>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]([C:16]([O:18][CH3:19])=[O:17])[C:2]([CH3:20])([CH3:1])[CH2:7][C:6]3([S:25][CH2:21][CH2:22][CH2:23][S:24]3)[CH:5]=2)=[CH:9][C:10]=1[CH3:15]
Reactant: COC(=O)C1C(c2ccc(F)c(C)c2)=CCCC1(C)C
Reactant: SCCCS
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C1C(c2ccc(F)c(C)c2)=CC2(CC1(C)C)SCCCS2
Reaction time: 8 h

Procedure:
To a solution of 4a (7.75 g, 26.7 mmol) and 1,3-propanedithiol (3.03 g, 28.1 mmol) in 50 mL acetic acid was added boron trifluoride etherate (7.98 g, 56.2 mmol). The solution was stirred overnight, diluted with ether, washed with H2O, saturated NaHC3, and brine and dried (MgSO4). Removal of the volatile in vacuo provided a residue which was crystallized from hexane, wt 8.0 g, mp 100°-101° C. Anal. C20H25FO2S2 : Theory C: 63.12; H:6.62; S:16.85. Found C: 63.45; H:6.58; S: 16.44.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[CH3:23])[CH:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[C:15]([CH3:23])[CH:16]=1
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2C)ccn1
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc(N)cc2C)ccn1

Procedure:
A solution of 2-methoxy-N-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)acetamide (357 mg, estimated purity 92%, 1.04 mmol) in a mixture of MeOH (20 mL) and AcOH (2.0 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The residue was taken up into a mixture of MeOH (20 mL) and AcOH (2 mL) and re-subjected to hydrogenation under the same flow conditions, at an elevated temperature (1.0 mL min−1, 40° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode). The mixture was concentrated by evaporation in vacuo to afford the title compound, Intermediate H2, as a viscous liquid; Rt 1.05 min (Method 1); m/z 288 (M+H)+ (ES+); which was used directly in the next step (below).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[S:17]1[C:21]2[C:22]([CH:26]=O)=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.O>O1CCCC1>[S:17]1[C:21]2[C:22](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cccc2nnsc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cccc2nnsc12
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
To a suspension of 55% sodium hydride (1.81 g, 41.5 mmol) in tetrahydrofuran (30 mL) was added a solution of ethyl diethylphosphonoacetate (8.31 mL, 41.5 mmol) in tetrahydrofuran (10 mL) at 0° C. and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 1,2,3-benzothiadiazole-7-carbaldehyde (6.20 g, 37.8 mmol) in tetrahydrofuran (60 mL) at 0° C. and the mixture was stirred at room temperature for 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) and recrystallization (ethyl acetate/hexane) to give the title compound (8.70 g, yield 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:29]([O:31][C:32](=[O:34])[CH3:33])[CH3:30]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14](=[O:16])[CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:34])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
In a flask, 3-(Benzyloxycarbonylamino)-3-methylbutanoic acid (14.77 g, 58.8 mmol, prepared as described in Low, Eddy; Nair, Satheesh; Shiau, Timothy; Belisle, Barbara; Debabov, Dmitri; Celeri, Chris; Zuck, Meghan; Najafi, Ron; Georgopapadakou, Nafsika; Jain, Rakesh Bioorganic and Medicinal Chemistry Letters, 2009, 19, 196-198) was dissolved in tetrahydrofuran (200 ml). N,N-dicarbonyldiimidazole (9.54 g, 58.8 mmol) was added to the mixture, and the combined reaction mixture was stirred for about 1 hour at room temperature. In a second flask, lithium bis(trimethylsilyl)amide (1.0 M in tetrahydronfuran, 117 ml, 117 mmol) was cooled to −78° C., and ethylacetate was slowly added. The second flask was stirred for 20 minutes and then added to the first flask, which was also cooled to −78° C. The combined mixture was stirred at −78° C., for 2 hours. The reaction mixture was quenched with saturated, aqueous NaHCO3 solution, and the mixture was extracted with ethylacetate. The ethylacetate layer was concentrated, and purified by column chromatography (0 to 20% ethylacetate in hexanes) to give 10.08 g (53%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4](=[O:7])[CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>CO>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([O:8][CH:3]([C:2]([CH3:1])([CH3:21])[CH2:6][OH:5])[C:4]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:24]=2[O:23][CH3:22])=[O:7])=[CH:10][C:11]=1[C:17]([F:20])([F:19])[F:18])#[N:14]
Reactant: CC1(C)COC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CO
Product: COc1ccc(CNC(=O)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C(C)(C)CO)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A suspension comprised of (±)-4-(4,4-dimethyl-2-oxo-tetrahydro-furan-3-yloxy)-2-trifluoromethyl-benzonitrile (81.55 g; 272.5 mmol), 2,4-dimethoxybenzylamine (50.40 g; 295.4 mmol), and methanol (300 mL) was stirred at ambient temperature under a nitrogen atmosphere overnight. The suspension became a clear solution. The reaction mixture was concentrated in vacuo to afford a cloudy orange oil (145 g.) The oil was triturated with diethyl ether (500 mL) over a steam bath to gentle boiling. The flask was removed from the steam bath as a solid began to slowly form. The oil was scratched with a spatula which accelerated solid formation and the solids were collected by vacuum filtration to afford 107.25 g of an off-white amorphous solid. The mother liquor was concentrated in vacuo to give 28.35 g of a crude red-brown oil. This oil was purified by flash silica column chromatography (Isco Fraction Collector with Biotage 65i 330 g silica cartridge.) Elution with a gradient (98:2 v/v hexanes-ethyl acetate to 100% ethyl acetate over 1 hour, 12 minutes, 18×150 mm tubes, each filled to 27 mL mark in 30 seconds) afforded 20 g of a light-yellow solid. The material was recrystallized from diethyl ether to afford 9.659 g of a white crystalline solid; 1H-NMR (400 MHz; CDCl3) δ 7.61 (d, 1H, J=8.8 Hz), 7.24 (d, 1H, J=2.5 Hz), 7.07 (d, 1H, J=8.2 Hz), 6.94 (dd, 1H, J=8.8, 2.5 Hz), 6.58 (t, 1 H, J=5.6 Hz), 6.37 (dd, 1H, J=8.4, 2.5 Hz), 6.28 (d, 1H, J=2.4 Hz), 4.52 (s, 1H), 4.37-4.25 (m, 2H), 3.78 (s, 3H), 3.58 (s, 3H), 3.50 (d, 1H, J=11.7 Hz), 3.42 (d, 1H, J=11.7 Hz), 1.09 (s, 3H), 0.97 (s, 3H); 19F-NMR (376 MHz; CDCl3) δ −62.70 (s, 3F); MS (APCl+) 467.3 (M+1,100); (APCl−) 465.2 (M−1, 14), 186.0 (100).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCC1
Temperature: 25 °C

Procedure:
A room temperature solution of 5.04 gms. 4-nitro-benzoic acid in tetrahydrofuran (10 mL) is treated with 5.14 gms. 1′,1′-carbonyl-diimidizole and immediately immersed in an ice bath. The reaction mixture is stirred in the ice bath for 30 minutes, then it is allowed to warm to room temperature. Once at room temperature the reaction mixture is treated with 3 mL piperidine. The reaction mixture is allowed to stir at room temperature ovenight. The reaction is then made basic with the addition of saturated aqueous sodium bicarbonate solution, and the resulting mixture is extracted with ethyl acetate. The organics are separated, dried over anhydrous sodium sulfate, and subsequently evaporated to dryness in vacuo. The crude product residue is then chromatographed by flash silica gel chromatography using 50% ethyl acetate in hexanes as the eluant. Following evaporation of solvent, 1-(4-nitrobenzoyl)piperidine is isolated as a white solid in the amount of 5.87 gms.
Reaction SMILES: [Li][CH2:2]CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:18](=O)[CH3:19])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][O:16][CH3:17]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[C:18]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][O:16][CH3:17])=[C:8]([O:7][CH3:6])[CH:9]=1)([CH3:19])=[CH2:2]
Reactant: COCOc1ccc(C(C)=O)cc1OC
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(C)c1ccc(OCOC)c(OC)c1
Temperature: -80 °C
Reaction time: 12 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (1.1 g, 3.09 mmol, 1.3 eq.) in 5 mL dry THF cooled to −80° C. was slowly treated with BuLi (1.94 mL of a 1.6 m solution in hexane, 1.3 eq.). To this yellow suspension a solution of 1-(3-methoxy-4-methoxymethoxy-phenyl)-ethanone (500 mg, 2.38 mmol, 1 eq.) in 5 mL dry THF was added and the reaction mixture was allowed to warm to r.t. where stirring was continued for 12 h. The suspension was filtered and the solvent was evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 6:1) to yield the desired product as a color-less oil.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([O:33][C:34]([NH:36][CH2:37][C:38]1[CH:39]=[C:40]([NH:44][C:45]([O:47][CH2:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53](Br)=[CH:52][C:51]=2[Cl:57])=[O:46])[CH:41]=[CH:42][CH:43]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([NH:36][CH2:37][C:38]1[CH:39]=[C:40]([NH:44][C:45]([O:47][CH2:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([B:25]([OH:27])[OH:26])=[CH:52][C:51]=2[Cl:57])=[O:46])[CH:41]=[CH:42][CH:43]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(=O)OCCc2ccc(Br)cc2Cl)c1
Product: CC(C)(C)OC(=O)NCc1cccc(NC(=O)OCCc2ccc(B(O)O)cc2Cl)c1
Yield: 44 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 61D (1.84 g, 3.8 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 61E (750 mg, 44%) as a solid. MS (ESI) m/z 447.1 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.C([Li:16])CCC>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH:6]2[Li:16]
Reactant: Cc1ccc(C)c2c1C=CC2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: [Li]C1C=Cc2c(C)ccc(C)c21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
38.2 g (265 mmol) of 4,7-dimethylindene were dissolved in 350 ml of tetrahydrofurane and the temperature of the solution was cooled to 0° C. Then, 165 ml of n-butyllithium (1.6M in hexane, 264 mmol) were added, dropwise for 2.5 hours. After having again heated up to room temperature and stirred the whole for 4 hours, a purple-red solution of 4,7-dimethyl-indenyl-lithium was obtained. This solution was cooled to -70° C. and treated, dropwise for 35 minutes, with 25.3 g of 1,2-dibromoethane (135 mmol) in 15 ml of tetrahydrofurane. After having heated up to room temperature, a slight yellow solution was obtained to which water was added. The organic phase was collected ed dried on Na2SO4. The solvent was then evaporated under vacuum and 20 g of product were obtained (yield 48%).
Reaction SMILES: [CH3:1][CH:2]1[CH:10]2[CH:6]([N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8](=[O:11])[O:9]2)[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:3]1>CO.C(OCC)(=O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[CH:4]1[CH2:5][CH:6]2[N:7]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:8](=[O:11])[O:9][CH:10]2[CH:2]([CH3:1])[CH2:3]1
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC2C1OC(=O)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1CC(c2ccncc2N)CC2C1OC(=O)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of (+/−)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv.) in MeOH and ethyl acetate (1:1, 0.07 M) was added 10% Pd/C (0.1 equiv.) and the reaction was stirred at room temperature under an atmosphere of hydrogen. Upon completion of the reaction, the solution was filtered through a pad of Celite, washed with MeOH and ethyl acetate, the filtrate was concentrated to dryness under vacuo to give (+/−)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate as a mixture of diastereomers in >99% yield. LC/MS=348.2 (M+H), Rt=0.50 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:11][CH2:12][CH2:13][OH:14])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[F:15][C:16]([F:46])([F:45])[C:17]1[CH:18]=[C:19]([CH2:27][CH2:28][N:29]([CH3:44])[C:30](=[O:43])[CH:31](OS(C)(=O)=O)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CC(C)=O>[F:15][C:16]([F:45])([F:46])[C:17]1[CH:18]=[C:19]([CH2:27][CH2:28][N:29]([CH3:44])[C:30](=[O:43])[CH:31]([N:8]2[CH2:7][CH2:6][CH:5]([N:4]([CH2:3][CH2:2][OH:1])[CH2:11][CH2:12][CH2:13][OH:14])[CH2:10][CH2:9]2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(OS(C)(=O)=O)c1ccccc1
Reactant: OCCCN(CCO)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(c1ccccc1)N1CCC(N(CCO)CCCO)CC1

Procedure:
6.4 g of the oil of 4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidine prepared according to b) are taken up in 300 ml of acetone, combined with 13.8 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide and 33 ml of triethylamine and refluxed for 6 hours. The mixture is cooled, the solvent is eliminated in vacuo, the residue is stirred into 10% sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, the solvent is eliminated in vacuo and the residue is chromatographed over silica gel with ethyl acetate/methanol/conc. ammonia solution 20:80:1. The uniform fractions according to TLC are combined and freed from the solvents in vacuo. 8.4 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide are obtained as a yellowish-brown oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:3]=1.[NH2:20][CH:21]1[CH2:24][CH:23]([NH:25]C(=O)OC(C)(C)C)[C:22]1([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:20][C@H:21]1[CH2:24][C@H:23]([NH:25][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[N:3]=2)[C:22]1([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC1CC(N)C1(C)C
Reactant: N#Cc1cnc(NCCc2cccc(Cl)c2)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(C)[C@@H](Nc2nc(NCCc3cccc(Cl)c3)ncc2C#N)C[C@@H]1N
Temperature: 125 °C
Reaction time: 5 h
Yield: 63.7 %

Procedure:
To a mixture of 4-chloro-2-((3-chlorophenethyl)amino)pyrimidine-5-carbonitrile (600 mg, 2.04 mmol) and tert-butyl (3-amino-2,2-dimethylcyclobutyl)carbamate (490 mg, 2.29 mmol) in dioxane (20 mL) was added DIEA (738 mg, 5.73 mmol). The resulting mixture was stirred at 125° C. under microwave irradiation for 5 h. After removal of the organic solvent under reduced pressure, the residue was diluted with ethyl acetate and the organic layer ws washed with aqueous solution of ammonia chloride. The organic layer was separated and dried over sodium sulfate and concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (10% to 33% ethyl acetate in petroleum) to afford the title compound (610 mg, 1.30 mmol, 63% yield) as a pale yellow solid. The racemic product (500 mg, 1.06 mmol) was separated by chiral preparative supercritical fluid chromatography (chiral column: OJ, Column size: 0.46 cm I.D.×25 cm L, 5 um; Mobile phase: CO2:MeOH:DEA=60:40:0.1, Flow: 2.5 mL/min, 220 nm T=35° C.) to give four isomers: tert-butyl ((1S,3S)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 1, 100 mg, 0.21 mmol, 20% yield, RT=7.88 min, d.e.=100%, e.e. =100%), tert-butyl ((1R,3R)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 3, 102 mg, 0.22 mmol, 20% yield, RT=9.37 min, d.e.=100%, e.e. =100%), tert-butyl ((1R,3S)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 2, 85 mg, 0.18 mmol, 17% yield, RT=8.29 min, d.e.=100%, e.e. =100%) and tert-butyl ((1S,3R)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 4, 82 mg, 0.17 mmol, 17% yield, RT=10.96 min, d.e.=100%, e.e. =100%). MS (ESI) m/z 471.2 [M+H]+
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]([CH3:32])([CH3:31])[CH2:14][CH2:15][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]#[N:18])[CH2:9]1>CC(O)(CC)CC>[Cl:3][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]([CH3:32])([CH3:31])[CH2:14][CH2:15][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]([NH2:18])=[O:1])[CH2:9]1
Reactant: [OH-]
Reactant: COc1ccc(O[C@@H]2CCN(C(C)(C)CCC(C#N)(c3ccccc3)c3ccccc3)C2)cc1Cl
Agent: CCC(C)(O)CC
Agent: [K+]
Product: COc1ccc(O[C@@H]2CCN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1Cl
Temperature: 25 °C
Yield: 33 %

Procedure:
Potassium hydroxide (140 mg, 2.49 mmol) was added to a solution of the product of example 27 (61 mg, 0.125 mmol) in 3-methyl-3-pentanol (5 mL) and the mixture was heated under reflux for 16 hours. The solution was cooled to room temperature, concentrated in vacuo and the residue was partitioned between dichloromethane (10 mL) and water (5 mL), aqueous was extracted with dichloromethane (3×10 mL). Combined organics were concentrated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with ethyl acetate:methanol:0.88 ammonia, 90:10:1. The product containing fractions were evaporated under reduced pressure to afford the title compound as a colourless gum in 33% yield, 21 mg.