Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[CH2:3][N:4]([C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][N:21]=[CH:20]3)=[N:15][N:16]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=1)[CH2:3][NH:4][C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][N:21]=[CH:20]3)=[N:15][N:16]=1
Reactant: CC(C)(C)OC(=O)N(C[C@@H](N)Cc1ccc(C(F)(F)F)cc1)c1nnc(-c2ccc3ncncc3c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1nnc(-c2ccc3ncncc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.3 %

Procedure:
tert-Butyl (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl(5-(quinazolin-6-yl)-1,3,4-thiadiazol-2-yl)carbamate was obtained as a semi-pure yellow solid from tert-butyl 5-(quinazolin-6-yl)-1,3,4-thiadiazol-2-ylcarbamate using the procedure described previously. To a stirred mixture of tert-butyl (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl(5-(quinazolin-6-yl)-1,3,4-thiadiazol-2-yl)carbamate (17 mg, 32 μmol) in DCM (2.0 mL) was added TFA (2.0 mL). The overall mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue taken up in DCM. The mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The separated aqueous layer was extracted with DCM (2×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (eluting with a gradient of DCM to 10% MeOH in DCM) to provide N—((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(quinazolin-6-yl)-1,3,4-thiadiazol-2-amine as a white solid (1.0 mg, 7% yield). LCMS (M+H) 431.1 calc. for C20H18F3N6S 431.1. 1H NMR (400 MHz, CDCl3): δ ppm 9.43 (d, J=2.74 Hz, 1H) 9.35 (d, J=3.13 Hz, 1H) 8.46 (d, J=8.22 Hz, 1H) 8.19 (s, 1H) 8.09 (d, J=5.87 Hz, 1H) 7.60 (d, J=5.87 Hz, 1H) 7.36 (d, J=6.65 Hz, 2H) 3.66 (d, J=13.89 Hz, 1H) 3.40-3.51 (m, 1H) 2.07 (s, 1H) 1.38-1.79 (m, 2H) 1.26 (s, 2H). 2H obscured.
Reaction SMILES: [CH3:1][N:2]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:25]=2[CH3:35])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].O1CCCC1.[OH-].[Li+]>C(O)C>[CH3:1][N:2]([C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH:19]([C:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:26][C:25]=2[CH3:35])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=1)=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}benzoic acid (182 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 3-{methyl[(4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}phenyl)carbonyl]amino}propanoate. Ethyl 3-{methyl[(4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}phenyl)carbonyl]amino}propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL) was added, 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 (186 mg, 83%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:11]=[CH:12][CH:13]=1.[N-:32]=[N+:33]=[N-:34].[Na+].O>CS(C)=O>[N:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:11]=[CH:12][CH:13]=1)=[N+:33]=[N-:34]
Reactant: CN1CCC(OC(c2cccc(OCCCCCCl)c2)c2nc3ccccc3s2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC(OC(c2cccc(OCCCCCN=[N+]=[N-])c2)c2nc3ccccc3s2)CC1
Temperature: 70 °C

Procedure:
A mixture of 2-[[3-(5-chloropentyloxy)phenyl](1-methyl-piperidin-4-yloxy)-methyl]benzothiazole (200 mg) and sodium azide (85 mg) in dimethylsulfoxide (3 mL) is heated overnight at 70° C., then cooled back to room temperature. Water is added and the product is extracted with ethyl acetate. Pooled extracts are washed with water, then brine, dried over magnesium sulfate and concentrated under reduced pressure to give 2-[[3-(5-azidopentyloxy)phenyl](1-methyl-piperidin-4-yloxy)methyl]benzothiazole used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.O>[OH:13][CH2:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.00 g, 14.9 mmol) in tetrahydrofuran (15 mL) was added N-methylmorpholine (1.80 mL, 16.4 mmol) and isobutyl chloroformate (2.13 mL, 16.4 mmol) at 0° C. The mixture was stirred for 20 min. The resulting precipitate was filtered off and the filter cake was washed with tetrahydrofuran (1 mL). The filtrate was cooled to 0° C. and a solution of sodium borohydride (0.846 g, 22.4 mmol) in water (2 mL) was added. The resulting mixture was stirred for 1 h. and quenched with sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (55 mL). The organic layer was washed with brine (30 mL) and dried over sodium sulfate. The resulting solution was concentrated in vacuo. The crude product (2.79 g) was used for the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][CH:34]([CH2:39][CH3:40])[CH2:35][C:36](O)=[O:37].O.ON1C2C=CC=CC=2N=N1.N=C=N>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][CH:34]([CH3:33])[CH2:39][CH3:40])[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Reactant: CCC(C)CC(=O)O
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(C)CC(=O)N1CCN(c2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
React 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(6-piperazin-1-yl-pyridin-3-yl)-urea (0.20 g, 0.46 mmol) with 3-methyl-pentanoic acid (0.059 g, 0.51 mmol), 1-hydroxybenzotriazole hydrate (0.06 g, 0.46 mmol) and polymer supported carbodiimide (0.83 g, 1.0 mmol), suspended in a mixture CH2Cl2/DMF (18/1, mL). Stir the mixture at room temperature overnight and then filter and wash the resin with CH2Cl2. Concentrate and purify the residue with a SCX cartridge eluting with NH4OH/CH3OH 2N to yield 135 mg (55%) of the title compound as a pale pink solid. MS(ES+): m/z=532 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](=S)[C:7]=3[CH:19]=[CH:20][CH:21]=2.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][N:24]=[CH:23]1.C(O)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](=[N:30][CH2:29][CH2:28][CH2:27][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)[C:7]=3[CH:19]=[CH:20][CH:21]=2
Reactant: Cc1ccc2cccc3c2c1N(Cc1ccccc1)C3=S
Reactant: NCCCn1ccnc1
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1ccc2cccc3c2c1N(Cc1ccccc1)C3=NCCCn1ccnc1

Procedure:
A mixture of 2.9 g of (8-methyl-1-(phenylmethyl)benz[cd]indole-2(1H)-thione (Cq), 1.4 g of 1H-imidazole-1-propanamine, 250 ml of ethanol, 50 ml of dimethylformamide, and 3.5 g of mercuric acetate is reacted as described in Example 3, giving I.6 g of the desired product, mp 107°-109° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:40])[C@H:10]([NH:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([O:8][C@H:9]([CH3:40])[C@H:10]([NH2:20])[CH2:11][O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)[C@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
(2R,3R)-3-(benzyloxy)-1-{[tert-butyl(dimethyl)silyl]oxy}-N-tritylbutan-2-amine (3.26 g, 5.92 mmol) was dissolved in 75 mL of anhydrous CH2Cl2 and 9.6 mL of glacial acetic acid. The reaction mixture was cooled to 0° C. under an atmosphere of N2 and boron trifluoride diethyl etherate (790 μL, 5.92 mmol) was added dropwise over several minutes. After stirring for 4 hours, the reaction mixture was treated with 90 mL of cold, aqueous 10% NaOH solution. The layers were separated and the aqueous portion was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 0-5% methanol/CHCl3) gave 1.83 g of (2R,3R)-3-(benzyloxy)-1-{[tert-butyl(dimethyl)silyl]oxy}butan-2-amine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH3:12][C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O.P(=O)(O)(O)O>O>[CH3:12][C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=1[CH:15]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:9][CH2:10][NH:11]1
Reactant: COc1cccc(CCN)c1
Reactant: Cc1ccc(C=O)c(C)c1
Agent: O=P(O)(O)O
Solvent: O
Product: COc1ccc2c(c1)CCNC2c1ccc(C)cc1C
Temperature: 37 °C
Yield: 54.6 %

Procedure:
3-Methoxyphenylethylamine (1.51 g) and 2,4-dimethylbenzaldehyde (1.34 g) were mixed together. Phosphoric acid, 85%, (20 mL) was added then the reaction was warmed to 37° C. for 60 h. The reaction was cooled, poured into water (300 mL) then washed with diethyl ether (2×50 mL). The aqueous layer was diluted to 700 mL with water, made basic (pH=10) by the slow addition of sodium hydroxide, and then extracted with diethyl ether (2×150 mL). The organic extracts were dried and evaporated. The resulting residue was purified by silica gel chromatography (eluant: ethyl acetate-hexane, gradient from 1:1 to 100% ethyl acetate) to give the title compound (1.458 g). MS: 268.2 (MH+); HPLC tR: 1.71 min (method D); TLC Rf: 0.21 (ethyl acetate); 1H NMR (DMSO-d6): 6.96 (s, 1H), 6.86 (s, 2H), 6.67 (d, 1H, J=2.3 Hz), 6.59 (dd, 1H, J=2.5, 8.5 Hz), 6.44 (d, 1H, J=8.5 Hz), 5.07 (s, 1H), 3.69 (s, 3H), 3.03-3.11 (m, 1H), 2.82-2.89 (m, 2H), 2.63-2.77 (m, 1H), 2.26 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH:10]([CH3:13])[CH2:11][OH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl>[CH3:16][S:17]([O:12][CH2:11][CH:10]([O:9][C:8]1[CH:14]=[CH:15][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH3:13])(=[O:19])=[O:18]
Reactant: CC(CO)Oc1ccc(C(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)Oc1ccc(C(C)(C)C)cc1

Procedure:
As in Example 56, 5.1 g of 2-(p-tert-butylphenoxy)-1-propanol is reacted with 2.3 ml of methanesulfonyl chloride in 150 ml of dichloromethane in the presence of 8 ml of triethylamine. The product (7.4 g) is obtained as an amber-colored liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([CH:22]([OH:30])[C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)OCC[O:9]2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH:22]([CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:17][CH2:18]2)[OH:30])=[CH:24][CH:25]=1
Reactant: OC(c1ccc(F)cc1)C1CCN(CCCC2(c3ccc(F)cc3)OCCO2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CCC(C(O)c2ccc(F)cc2)CC1)c1ccc(F)cc1

Procedure:
A solution of 3.0 g. (0.0072 mole) of 2-(p-fluorophenyl)-2-{3-[4-(p-fluoro-α-hydroxybenzyl)piperidino]propyl}-1,3-dioxolane in 5 ml. of chloroform was stirred at room temperature with 25 ml. of 6N hydrochloric acid for 2 hr. The mixture was poured onto crushed ice and an excess of 50% sodium hydroxide solution was added. The free base of the ketone crystallized upon neutralization. The solid which was obtained was recrystallized from benzene-isooctane and gave 1 g. of white solid melting at 144°-146° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[OH:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C@H:10]1[CH3:27].IC.C(O)(=O)C>C1COCC1.O>[OH:8][C@H:9]1[C@H:13]([CH3:1])[C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=2)[C@H:10]1[CH3:27]
Reactant: CC(C)NC(C)C
Reactant: C[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Solvent: O
Solvent: CC(=O)O
Solvent: CI
Product: C[C@@H]1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)[C@H]1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A solution of diisopropylamine (0.860 mL) in THF (30 mL) was cooled to −78° C., and n-butyllithium-hexane solution (3.64 mL, 1.6 mol/L) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr. Subsequently, a solution of 4-[(2S,3S)-3-hydroxy-2-methyl-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (661 mg) in THF (5.0 mL) was added dropwise, and the mixture was further stirred at −78° C. for 1 hr. Iodomethane (0.75 mL) was added dropwise at −78° C., and the mixture was further stirred at −78° C. for 1 hr. Acetic acid (3.0 mL) was added to the reaction mixture, and the mixture was warmed to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/3) to give the title compound as a colorless solid (yield: 442.9 mg, 63.7%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.CC1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH:24]([CH3:28])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC1CCNC1
Agent: Cl
Product: CC1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methylpyrrolidine hydrochloride. MS(m/e): 385.3 (MH+).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(C2CCCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2)C(C2CCCCC2)NC(C(=O)O)C1c1cccc(Cl)c1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 50b (0.69 g, 1.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.8 g, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][C:8]2N=CC=CN=2)[CH2:2]1.BrC1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1.ICC1CCCN(C(OC(C)(C)C)=O)C1>>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][C:8]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)[CH2:2]1
Reactant: c1cnc(CC2CCCNC2)nc1
Reactant: Brc1cncnc1
Agent: CC(C)(C)OC(=O)N1CCCC(CI)C1
Product: c1ncc(CC2CCCNC2)cn1

Procedure:
Made in an analogue manner to 2-(piperidin-3-ylmethyl)pyrimidine using 5-bromopyrimidine with tert-butyl 3-(iodomethyl)piperidine-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:18]([F:28])[CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43](Cl)=[O:44].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:12]([CH:11]2[CH2:14][N:15]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[C:18]([F:28])[CH:17]=2)[C:43]([C:39]2[S:38][CH:42]=[CH:41][CH:40]=2)=[O:44])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CC2C(CNc3ccc(N4CCOCC4)c(F)c3)C2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2CN(C(=O)c1cccs1)c1ccc(N2CCOCC2)c(F)c1
Reaction time: 2 h

Procedure:
To a stirring solution of 6-[(3-Fluoro-4-morpholin-4-yl-phenylamino)-methyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester prepared above (500 mg, 1.28 mmol) in 10 mL of DCE at room temperature was added DIEA (0.33 mL, 1.92 mmol) and 2-thiophenecarbonylchloride (0.21 mL, 1.92 mmol). After 2 hours, saturated NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting crude material was taken up in 50% EtOAc/hexanes and the white solids were filtered off. The remaining filtrate was concentrated under reduce pressure to yield 640 mg of the desired product. 400 MHz 1H NMR (CDCl3) δ 7.26-7.28 (m, 1H), 6.83-7.15 (m, 4H), 6.76-6.78 (m, 1H), 3.79-3.85 (m, 5H), 3.54-3.59 (m, 1H), 3.44 (d, J=11.0 Hz, 1H), 3.39 (d, J=11.0 Hz, 1H), 3.21-3.26 (m, 2H), 3.08-3.10 (m, 4H), 1.36-1.38 (m, 11H), 0.81-0.86 (m, 1H); MS M+1)
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11](I)=[C:12]([CH2:14][C:15]([NH:17][C@H:18]([CH3:22])[C:19]([NH2:21])=[O:20])=[O:16])[CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](OCC)(=[O:35])C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:13]=[C:12]3[C:11](=[CH:10][CH:9]=2)[C:33](=[O:35])[N:17]([C@H:18]([CH3:22])[C:19]([NH2:21])=[O:20])[C:15](=[O:16])[CH2:14]3)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: C[C@@H](NC(=O)Cc1cc(OCc2ccc(F)cc2)ccc1I)C(N)=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[C@H](C(N)=O)N1C(=O)Cc2cc(OCc3ccc(F)cc3)ccc2C1=O
Yield: 25 %

Procedure:
As described for example 20f, the title compound (10 mg, 25%) was prepared from a mixture of 2-(R)-{2-[5-(4-Fluoro-benzyloxy)-2-iodo-phenyl]-acetylamino}-propionamide (50 mg, 0.109 mmol), triethylamine (0.030 mL, 0.218 mmol), bis (triphenylphosphine) palladium II chloride (1.5 mg, 0.0022 mmol) in 1 mL ethyl acetate. MS: m/e=357.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][CH:21]([C:30]([O:32]CC)=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14]1=[O:35])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:37](CCC1C=CC=CC=1)C(OC(C)(C)C)=O>>[CH2:1]([O:8][C:9]([CH:11]([N:13]1[CH2:37][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][CH:21]([C:30]([OH:32])=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14]1=[O:35])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CCCCN(C(C)C(=O)OCc2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)C(=O)CCc1ccccc1
Product: CC(C(=O)OCc1ccccc1)N1CCCCCC(NC(CCc2ccccc2)C(=O)O)C1=O

Procedure:
The diastereomers of this compound may be prepared from 3-amino-1-(1-benzyloxycarbonylethyl)perhydroazocin-2-one (Example 8) and t-butyl 2-oxo-4-phenylbutyrate following the procudure in Example 7.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.[Li+].[OH-]>O1CCOCC1>[C:26]([N:23]1[CH2:22][CH2:21][CH:20]([N:10]([C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(C(C)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCC(N(C(=O)C2CCC(C)CC2)c2cc(-c3ccccc3)sc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
3-[(1-Acetyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (50 mg, 0.104 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (1 ml) and then LiOH 1N (310 ul, 0.310 mmol) was added. After 5 hours of stirring at room temperature and 4 hours at reflux, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative chromatography (100/90/16/1 CH2Cl2/CHCl3/MeOH/Et3N) to obtain 27 mg (56%) of 3-[(1-Acetyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 48).