Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][C:16](=[O:22])[NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[N:10]=[C:9]1[NH2:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O.[Cl:31]CCl>>[ClH:31].[NH2:23][C:9]1[NH:8][CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][C:16]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:22])[N:10]=1
Reactant: CC(C)CNC(=O)CCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNC(=O)CCCc1c[nH]c(N)n1
Product: Cl
Reaction time: 5 h
Yield: 97 %

Procedure:
A solution of 2-amino-4-(3-isobutylcarbamoyl-propyl)-imidazole-1-carboxylic acid tert-butyl ester 23 (76 mg, 0.234 mmol) in anhydrous dichloromethane (1 mL) was cooled to 0° C. TFA (1 mL) was charged into the flask and the reaction stirred for 5 h. After that time the reaction was evaporated to dryness and toluene (2 mL) was added. Again the mixture was concentrated and the process repeated. The resulting TFA salt was dissolved in dichloromethane (1 mL) and 2M HCl in diethyl ether (0.50 mL) was added followed by cold diethyl ether (8 mL). The precipitate was collected by filtration and washed with diethyl ether (3 mL) to yield the target compound 8 (59 mg, 97%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 11.70 (s, 1H), 7.89 (m, 1H), 7.34 (br s, 2H), 6.55 (s, 1H), 2.84 (t, 2H, J=6.6 Hz), 2.38 (t, 2H, J=7.5 Hz), 2.10 (t, 2H, J=7.5 Hz), 1.60-1.79 (m, 3H), 0.82 (d, 6H, J=6.3 Hz); 13C NMR (75 MHz, DMSO-d6) δ 171.52, 146.78, 126.31, 108.68, 46.00, 34.41, 28.09, 23.94, 23.64, 20.18; HRMS (ESI) calcd for C11H21N4O (MH)+ 225.1709. Found 225.1711.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Solvent: CCO
Product: CCCN[C@@H]1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Alternatively, to a solution of 160 mg (0.72 mmol) racemic N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R═OMe) (as the free base) in 1.0 mL EtOH were added a solution of 270 mg (0.72 mmol) of (L)-(−)-O,O—(R,R)-dibenzoyltartaric acid monohydrate in 2.0 mL EtOH and stirred for 10 min at room temperature to get a fine white precipitate, which was filtered, washed with cold ethanol and suspended in 10% (v/v) aqueous KOH. After the extraction of the aqueous layer with methylenchloride for four times the organic layers were dried over Na2SO4, the solvent was evaporated in vacuo to get (R)—N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R═OMe).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19](=O)[CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:17][C:16]1[N:18]=[C:19]([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[N:12]2[C:13]=1[CH:14]=[N:15][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N:11]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)C(C)c3ccccc3)nn2)cc1
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(C(C)c4ccccc4)n3n2)cc1
Yield: 12.3 %

Procedure:
Applying the Cyclization Procedure 2, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-phenylpropanamide (Intermediate 55) (129 mg, 0.34 mmol), pyridine (3.4 mL), 1,2,4 triazole (71 mg, 1.03 mmol) and phosphorus oxychloride (0.048+0.048 mL, 1.03 mmol), to afford 5-methyl-N-[4-(methyloxy)phenyl]-7-(1-phenylethyl)imidazo[5,1-f][1,2,4]triazin-2-amine (15 mg) as a yellow solid. MS m/z 360 (M+1).
Reaction SMILES: [OH:1][C:2]1([C:52]([NH2:54])=[O:53])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:31])[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])=[CH:17][C:16]=3[C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])[CH:10]=2)[C:5]([N:32]=NC2C=CC(C(O)=O)=CC=2)=[C:4]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:3]1[CH2:49][CH2:50][CH3:51].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:1][C:2]1([C:52]([NH2:54])=[O:53])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:31])[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])=[CH:17][C:16]=3[C:26]([CH2:29][CH3:30])([CH3:27])[CH3:28])[CH:10]=2)[C:5]([NH2:32])=[C:4]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:3]1[CH2:49][CH2:50][CH3:51]
Reactant: CCCC1C(c2ccccc2)=C(N=Nc2ccc(C(=O)O)cc2)c2ccc(C(=O)COc3ccc(C(C)(C)CC)cc3C(C)(C)CC)cc2C1(O)C(N)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC1C(c2ccccc2)=C(N)c2ccc(C(=O)COc3ccc(C(C)(C)CC)cc3C(C)(C)CC)cc2C1(O)C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6.15 g of 1-Hydroxy-2-propyl-3-phenyl-4-[(4-carboxy)phenylazo]-7-[(2,4-ditertamyl)phenoxyacetyl]naphthamide prepared in step (7) in 100 ml of ethanol was refluxed under nitrogen with strong stirring. A solution of 6.93 g of sodium hydrosulfite in 36 ml of water was then added. The reaction mixture was stirred for 30 minutes at reflux temperature. After cooling, the reaction mixture was poured into 200 ml of ice water. The organic products were extracted with ethyl ether. The extracts were washed with a sodium bicarbonate saturated aqueous solution and with water. They were finally dried and evaporated to dryness under reduced pressure. After treatment with petroleum ether, the crystals formed were filtered off. The crude product was recrystallized from acetonitrile. The recrystallized product was washed with boiling methanol and with petroleum ether before being dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11](COCC[Si](C)(C)C)[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1I.[C:30]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[N:39]1[CH2:40][CH2:41][CH:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:37][CH2:38]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(N3CCC(c4ccccc4)CC3)c(Cl)cc2[nH]1
Temperature: 90 °C

Procedure:
A 2 dram vial was charged with (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (Intermediate 3, 300 mg, 0.542 mmol), 4-phenylpiperidine (96 mg, 0.596 mmol), L-proline (12.47 mg, 0.108 mmol), cuprous iodide (10.32 mg, 0.054 mmol), potassium carbonate (150 mg, 1.083 mmol), and DMSO (1354 μl). The reaction vial under nitrogen was placed in a heating block set to 70° C. and then heated to 90° C. for 16 hours. The reaction was cooled to r.t. and diluted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified via silica gel chromatography using methanol/dichloromethane to afford the title compound as an orange waxy solid. LC-MS: calculated for C29H39ClN4O5Si 586.24 observed m/e: 587.44 (M+H)+ (Rt 1.41/2 min).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Br[C:20]1[S:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:20]3[S:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][N:24]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1
Reactant: O=[N+]([O-])c1nnc(Br)s1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Temperature: -25 °C
Reaction time: 20 h
Yield: 35.7 %

Procedure:
To a stirred solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (43 g, 0.17 mol) in anhydrous acetonitrile (2000 mL) at −20° C. was added a solution of 2-bromo-5-nitro-1,3,4-thiadiazole (70 g, 0.33 mol.) in acetonitrile (1000 mL). Then Cs2CO3 (166 g, 0.51 mol, 3 eq.) as added portionwise at this temperature. The mixture was stirred at −20 to −30° C. for 20 hrs. Then, the reaction mixture was allowed to warm to r.t. and stirred at this temperature for 15 h. After filtration, the filtrate was concentrated and acidified to pH=2 at 0° C. with diluted hydrochloric acid. The mixture was extracted with EtOAc and the organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo The residue was purified by chromatography on silica gel column (petroleum ether/EtOAc/AcOH, gradient elution) to give the ethyl 2-(1-hydroxy-4-methyl-6-(5-nitro-1,3,4-thiadiazol-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate as a yellow solid (23 g, 36% yield).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1)=[N+]=[N-].O.[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1c[nH]c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: NCc1c[nH]c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 86.4 %

Procedure:
The solution of 5-(azidomethyl)-2,4(1H,3H)-pyrimidinedione (0.275 g, 1.64 mmol) in ethanol: water (25:5 ml) was degassed with nitrogen, palladium on carbon (5%) was added, reaction was charged with hydrogen (55 PSI) and shaken for 2 h. The reaction was filtered and concentrated to give the 5-(aminomethyl)-2,4(1H,3H)-pyrimidinedione (0.20 g, 85%) as a solid. MS found: (M+H)+=142.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1N.[NH2:9][C:10]([NH2:12])=[O:11].[CH2:13](O)[CH3:14]>>[N:8]1[CH:1]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:2][N:9]1[C:6]2[CH:1]=[CH:2][CH:3]=[CH:13][C:14]=2[NH:12][C:10]1=[O:11]
Reactant: CCO
Reactant: Nc1ccccc1N
Reactant: NC(N)=O
Product: O=c1[nH]c2ccccc2n1Cc1ccccn1

Procedure:
5 g of the above o-phenylenediamine derivative are heated with 2 g of urea to 160° C. for 5 hours. After the reaction mixture has cooled, ethanol is added and the crystals which are precipitated are filtered off with suction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([CH3:17])=[N:7]2.[Se](=O)=[O:19].O>O1CCOCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:8]([CH:17]=[O:19])=[N:7]2
Reactant: Cc1nc2cccc(Br)c2nc1NC(C)(C)C
Reactant: O=[Se]=O
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1C=O
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of 8-bromo-N-(tert-butyl)-3-methylquinoxalin-2-amine (174a) (137 mg, 0.47 mmol), selenium dioxide (Aldrich; 57.0 mg, 0.51 mmol), and water (0.084 mL, 4.67 mmol) in 1,4-dioxane (5.0 mL) was stirred under argon at 60° C. for 19 h. The reaction mixture was then cooled to RT, diluted with DCM (5 mL), and adsorbed onto silica gel. Chromatographic purification (silica gel, 0-10% EtOAc/hexanes) furnished 5-bromo-3-(tert-butylamino)quinoxaline-2-carbaldehyde (132. mg, 0.43 mmol, 92% yield) as a yellow-orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.14 (1H, s), 8.03 (1H, br. s.), 7.99 (1H, d, J=7.4 Hz), 7.88 (1H, d, J=8.4 Hz), 7.22-7.25 (1H, m), 1.64 (9H, s). m/z (ESI, +ve) 308.0/310.1 (M+H)+.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[N:13][CH:14]=2)[O:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[N:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: Cc1oc(-c2ccc(F)nc2)cc1C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1oc(-c2ccc(F)nc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of 5-{4-[chloro(cyclohexyl)methyl]-5-methylfuran-2-yl}-2-fluoropyridine (0.8 g), ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.7 g), sodium carbonate (0.3 g) and sodium iodide (0.5 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (3.2 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (753 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[OH:21])[CH2:33][CH2:32]2)=[O:18])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: COc1cc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1cc(C)c(C)cc1NC(=O)N1CCN(c2ccccc2O)CC1
Yield: 87 %

Procedure:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and 1-(2-hydroxyphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound.
Reaction SMILES: CS(O[C@H:6]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]1)(=O)=O.[Si]([N:37]=[N+:38]=[N-:39])(C)(C)C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:37]([C@H:6]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]1)=[N+:38]=[N-:39]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 22 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of 3β-cholest-5-en-3-yl methanesulfonate (9.30 g, 20.0 mmol) in anhydrous CH2Cl2 (100 mL), TMSN3 (2.95 mL, 22.0 mmol) was added, followed by boron trifluoride etherate (5.0 mL, 40.0 mmol). The reaction was stirred at 22° C. for 2 h. When the starting material was no longer visible by TLC analysis (hexanes), the reaction was slowly poured into saturated aqueous NaHCO3 (100 mL) and vigorously stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with diethyl ether (60 mL×2). The organic layers were combined, washed with deionized water (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product as light yellow solid. Flash column chromatography (hexanes) afforded the product (7.75 g, 94.1%) as white solid, mp 84-86° C.; 1H NMR (300 MHz, CDCl3) δ 5.38 (s, 1H), 3.26-3.15 (m, 1H), 2.28 (d, J=7.9 Hz, 2H), 2.05-0.85 (m, 38H), 0.68 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ 139.8, 122.5, 61.1, 56.7, 56.1, 50.1, 42.3, 39.7, 39.5, 38.1, 37.6, 36.6, 36.2, 35.8, 31.8, 31.7, 28.2, 28.0, 27.9, 24.2, 23.8, 22.8, 22.5, 21.0, 19.2, 18.7, 11.8; IR (film) ν max 2934, 2896, 2861, 2097, 1464, 1443, 1377, 1367,1243, 1231 cm−1; APCI m/z 411.3607 (M+, C27H45N3 requires 411.3613).
Reaction SMILES: C(C1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)C.[C:36](Cl)(=O)[CH2:37][CH:38]([CH3:40])[CH3:39]>>[CH2:37]([C:36]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)CC(=O)Cl
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(CC(C)C)nc4c(C)cc(C)nc43)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and isovaleryl chloride.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[Si:49]([O:56][C:57]1[CH:62]=[CH:61][C:60](O)=[CH:59][CH:58]=1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50].N(C(N(C)C)=O)=NC(N(C)C)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:52]([Si:49]([CH3:51])([CH3:50])[O:56][C:57]1[CH:62]=[CH:61][C:60]([O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:59][CH:58]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: OCCOCCOCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of Compound 2 (2.8 g, 5.8 mmol) in toluene (10 ml), a solution of tributylphosphine (1.17 g, 5.8 mmol) in toluene (2 ml) was added at room temperature; this was followed by stirring for 1 hour. This was gradually added to a solution of Compound 18 (1.1 g, 4.9 mmol) and 1,1′-azobis(N,N-dimethylformamide) (1.0 g, 5.8 mmol) in toluene (10 ml), and this was followed by overnight stirring at room temperature. Ethyl acetate was added; the resulting insoluble matter was removed by Celite filtration, and washing was conducted with ethyl acetate. The combined organic phases were concentrated under reduced pressure; the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (n-hexane:ethyl acetate 2:1)) to yield Compound 21 (colorless oil 2.03 g, 60%).
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH2:42]([O:44][CH2:45][C:46]1[N:47]=[C:48]([CH2:51][N:52]2[N:56]=[C:55]([NH2:57])[CH:54]=[N:53]2)[O:49][CH:50]=1)[CH3:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:42]([O:44][CH2:45][C:46]1[N:47]=[C:48]([CH2:51][N:52]2[N:56]=[C:55]([NH:57][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:54]=[N:53]2)[O:49][CH:50]=1)[CH3:43]
Reactant: CCOCc1coc(Cn2ncc(N)n2)n1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOCc1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (42 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (5.8 mg, 0.05 mmol), HOBt (31 mg, 0.23 mmol), EDC (91 mg, 0.48 mmol) and DIPEA (0.13 mL, 0.76 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(ethoxymethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (43 mg, 0.19 mmol) in CH2Cl2 (0.9 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (10 mL) and the org. phase was washed with water (10 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (3:7 hept-EA) gave the title compound as a yellow oil: TLC: rf (7:3 hept-EA)=0.34. LC-MS-conditions 07: tR=0.91 min, [M+H]+=423.14.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:12]3[N:11]=[C:10]2[CH2:20][CH3:21])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CN(C=O)C>[C:34]([CH:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:12]3[N:11]=[C:10]2[CH2:20][CH3:21])=[CH:4][CH:3]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:27]=1)([O:36][CH3:37])=[O:35]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N)cc1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC(C(=O)OC)c2ccccc2)cc1
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 0.50 g (1.79 mmol) of 3-(4-aminophenylmethyl) -5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine (Step B, Example 25) in 4.0 mL DMF, was added 143 mg (3.57 mmol, 2.0 eq) of a 60% oil dispersion of NaH. When evolution of hydrogen ceased (approximately 5 min.), 1.04 mL (5.36 mmol, 3.0 eq) of methyl 2-bromophenylacetate was added, and the mixture was stirred for 18 hours. The DMF was removed in vacuo and the resultant brown oil was flash chromatographed with 2:1 ethyl acetate/hexane to yield 0.690 g (90%) of a yellow-green powder.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C@:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[C@H:10]([C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[C:30]([CH:10]1[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]1([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:21]#[N:22])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)[C@@H]1N[C@@H](C(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-tert-Butyl-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 51b (0.3 g, 0.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-tert-Butyl-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.4 g, 100%).