Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30]([OH:32])=O)[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]([CH3:29])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:66]1[CH2:71][CH2:70][CH:69]([N:72]2[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]2)[CH2:68][CH2:67]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([CH3:29])[C:23]([O:27][CH3:28])=[C:24]([CH3:26])[CH:25]=3)[C:30](=[O:32])[N:75]3[CH2:74][CH2:73][N:72]([CH:69]4[CH2:70][CH2:71][O:66][CH2:67][CH2:68]4)[CH2:77][CH2:76]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: COc1c(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 40 mg (0.08 mmol) (R)-2-(4-methoxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 29 mg (0.09 mmol) TBTU and 14 μL (0.10 mmol) triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 15 mg (0.09 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added and the mixture was stirred for a further 16 h at RT. The reaction solution was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[C@H:5](OS(C)(=O)=O)[CH2:4][C@H:3]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[C-:21]#[N:22].[Na+]>CN(C=O)C.O>[C:21]([C@@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:4]1)#[N:22]
Reactant: [C-]#N
Reactant: CN1C(=O)[C@H](OS(C)(=O)=O)C[C@H]1COc1cccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C[C@@H](C#N)C[C@H]1COc1cccnc1
Temperature: 100 °C
Yield: 35.1 %

Procedure:
To a solution of 300 mg (1.05 mmol) of 3-((trans-1-methyl-4-methanesulfonyloxy-5-oxo-2(S)-pyrrolidinyl)-methoxy)pyridine, prepared as in Exanmple 88a above, dissolved in 7 mL of 6:1 DMF:H2O was added 0.51 g (10.5 mmol) of NaCN, and the reaction mixture was heated at 100° C. for 5 hours. The reaction mixture was cooled, diluted with water, and extracted with chloroform. The extract was dried over MgSO4 and concentrated. The residue was purified on a silica gel column, eluting with 100:2 chloroform:methanol, to give 80 mg of the title compound.
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH2:18][CH3:19])=[C:12]([CH:15]=1)[C:13]#[N:14])(=[O:7])C.Cl>O.O1CCOCC1>[C:13]([C:12]1[CH:15]=[C:8]([CH:9]=[CH:10][C:11]=1[O:16][CH2:17][CH2:18][CH3:19])[C:5]([OH:7])=[O:1])#[N:14]
Reactant: CCCOc1ccc(C(C)=O)cc1C#N
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCOc1ccc(C(=O)O)cc1C#N
Reaction time: 2 h
Yield: 93.2 %

Procedure:
NaOH (5.52 g, 0.138 mol) was dissolved in water (35 ml) under ice-bath, followed by slow addition of liquid bromine (3.5 ml, 0.068 mol) under cooling. After a solution of 5-acetyl-2-n-propoxybenzonitrile (7 g, 0.034 mol) in dioxane (35 ml) was slowly added dropwise thereto, the reaction continued for 2 h. The reaction mixture was adjusted slowly to a pH of about 2 with a diluted hydrochloric acid to generate a large amount of light yellow solid. After filtered, the resultant solid was washed with ethyl acetate, and filtered to obtain the title compound (6.5 g, yield: 92%). 1H NMR (CDCl3) δ: 13.21 (1H, br), 8.18 (1H, d), 8.15 (1H, dd), 7.34 (1H, d), 4.18 (2H, t), 1.79 (2H, m), 1.00 (3H, t).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:10])[CH2:4][CH2:3]1.CN.[B-][C:23]#[N:24].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:23][NH:24][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:10])[CH2:4][CH2:3]1
Reactant: [B-]C#N
Reactant: O=C1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Agent: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CNC1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Acetic acid (0.096 ml) was added to a solution of the N-(4-oxocyclohexyl)-1H-indazole-5-carboxamide (40.0 mg, 0.155 mmol) obtained in Example 160 in methanol (1.2 ml), and the resulting solution was maintained at room temperature for 30 minutes. To this solution was added a 40% aqueous methylamine solution (60.0 mg, 0.777 mmol), and the resulting mixture was maintained at room temperature for another 2 hours. Then, a solution of sodium cyanotrihydroborate (48.7 mg, 0.777 mmol) in methanol (0.6 ml) was added dropwise thereto, and the resulting mixture was stirred for 22 hours while being maintained at room temperature. A 1N aqueous sodium hydroxide solution (0.8 ml) was added to the reaction solution, and the resulting mixture was stirred while being maintained at room temperature, and was then concentrated to dryness. The resulting crude product residue was purified by a silica gel column chromatography (eluent: chloroform/methanol/aqueous ammonia=10/1/0.1) to obtain N-[4-(methylamino)cyclohexyl]-1H-indazole-5-carboxamide (an isomer having a lower polarity) (12.2 mg, 29%) and N-[4-(methylamino)cyclohexyl]-1H-indazole-5-carboxamide (an isomer having a higher polarity) (28.3 mg, 67%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[C:12](=[CH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.[H][H]>CO.[Pd]>[CH3:23][C:4]1[CH:3]=[CH:2][CH:7]=[C:6]([CH3:8])[C:5]=1[CH:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:11][C:10]1=[O:22]
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CC(=CC2CCOCC2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Yield: 49.9 %

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)-4-[1-(tetrahydropyran-4-yl)-methylidene]-cyclopentane-1,3-dione (0.3 g, 0.8 mmol) in methanol (5 ml) is added 10% palladium on carbon (0.06 g), followed by stirring under a 1 bar hydrogen atmosphere for 8 hours. The reaction mixture is then filtered through diatomaceous earth and concentrated to give a crude product which is purified by flash chromatography (hexane/ethyl acetate) to afford 2-(2,6-dimethylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione (0.12 g).
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Cl:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3](=[O:9])[CH2:2][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(CCl)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CCl)C(=O)COc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 15 h
Yield: 55.6 %

Procedure:
42.7 g (0.2 mol) of 1-bromo-4-chloro-3,3-dimethyl-butan-2-one were added dropwise to a boiling suspension of 41 g (0.2 mol) of 4-(4-chlorophenyl)-phenol and 28 g (0.2 mol) of potassium carbonate in 300 ml of absolute acetone. The mixture was stirred for 15 hours under reflux and was then allowed to cool and the inorganic residue was filtered off and rinsed with acetone. The filtrate was concentrated by distilling off the solvent in vacuo. The residue crystallized after the addition of 50 ml of diisopropyl ether. 37.5 g (55% of theory) of 4-chloro-1-[4-(4-chlorophenyl)-phenoxy]-3,3-dimethyl-butan-2-one of melting point 67°-68° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]2([CH2:14][CH2:13]2)[O:11][CH:10]1[OH:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]1[CH:49]=[CH:48][C:39]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2O)=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:8][CH:9]1[CH:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:12]2([CH2:14][CH2:13]2)[O:11][CH:10]1[O:33][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH2:40][C:39]1[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:49][CH:48]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1OC2(CC2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COc1ccc(Cc2ccccc2O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccccc2OC2OC3(CC3)C(OCc3ccccc3)C(OCc3ccccc3)C2OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
(6R,7S,8S)-6,7,8-Tris-benzyloxy-4-oxaspiro[2.5]octan-5-ol (prepared according to an analogous procedure as described in J. Org. Chem. 2002, 67, 3733; Helv. Chim, Acta 1990, 73, 1329; Tetrahedron Lett. 1998, 39, 2021) (220 mg, 0.49 mmol) 2-(4-methoxybenzyl)-phenol (105 mg, 0.49 mmol) and triphenyl phosphine (155 mg, 0.59 mmol) were mixed under argon atmosphere followed by the addition of dry THF. The contents were cooled to 0° C. and DIAD (0.12 ml, 0.59 mmol) was added drop wise. The reaction mixture was refluxed for 12 hours and quenched with 1N dil. HCl (2 mL) and extracted with ethyl acetate (10×3 mL). Organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure to give the crude product which was purified by flash column chromatography using 1:4 (Ethyl acetate:Hexane) as eluent to yield 200 mg of 5R,6R,7S,8S)-6,7,8-tris-benzyloxy-5-[2-(4-methoxy-benzyl)-phenoxy]-4-oxa-spiro[2.5]octane.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13](O)[CH2:14][CH2:15][CH3:16])[CH3:6].N1C=CC=CC=1>ClCCl>[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([Cl:3])[CH2:14][CH2:15][CH3:16])[CH3:6]
Reactant: CCCC(O)CCCCC(=S)OCC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(Cl)CCCCC(=S)OCC
Reaction time: 1 h
Yield: 89.5 %

Procedure:
89.25 grams (0.7 mole) of thionyl chloride at +5° C. were slowly dropped into a solution of 137.0 grams (0.59 mole) of 6-hydroxy-8-methylthiooctanoic acid ethyl ester (VIb) and 1 ml of pyridine in 300 ml of dichloromethane. After stirring for 1 hour at +10° C. the mixture was heated for 3 hours at reflux and subsequently concentrated in a vacuum. The residue was treated with 200 ml of water and extracted with dichloromethane. After drying the combined extracts with sodium sulfate the solvent was removed in a vacuum. By fractional distillation there were obtained 125.1 grams (84% of theory) of 6-chloro-8-methylthiooctanoic acid ethyl ester as a colorless oil having a boiling point of 135° C. to 145° C. at 1 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(Cl)CCl.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cc1cncc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 95 %

Procedure:
To a solution of (5-bromopyridin-3-yl)acetic acid (1.00 g, 4.63 mmol) and morpholine (0.50 mL, 5.73 mmol) in DCM (50 mL) was added EDC (1.78 g, 9.30 mmol) and 1-hydroxybenzotriazole (1.25 g, 9.26 mmol). The reaction mixture was allowed to stir at rt for 50 min and then diluted with DCM (50 mL) and 1N HCl (100 mL). The organic solution was separated and discarded. The aqueous solution was neutralized with sat. aq. NaHCO3 (100 mL) and was extracted with DCM (3×50 mL). The organic solutions were combined, dried over MgSO4, filtered and concentrated to give 4-[(5-bromopyridin-3-yl)acetyl]morpholine (1.26 g, 4.40 mmol, 95%) as a light brown solid. LCMS (FA): Rt=1.11 min, m/z=287.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.[CH3:26]OC(OC)OC.O>C(O)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:26]=[N:9][N:8]=2)=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: COC(OC)OC
Reactant: Cc1ccc(C(=O)NN)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2nnco2)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
A stirred mixture of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzohydrazide (preparation 53, 0.16 g, 0.24 mmol) and trimethylorthoformate (0.24 mL, 1.44 mmol) in acetic acid (3 mL) were heated to 150° C. in a sealed tube. After 3 hours, the mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (1:1 hexanes/ethyl acetate) gave the title compound (0.05 g, 60%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:11])[CH2:9][CH3:10])=[C:4]([F:12])[C:3]=1[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14].[N:21]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH:24]=[C:23]([C:26](OCC)=[O:27])[CH2:22]1.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:34]([O:33][C:31]([N:21]1[CH2:25][CH:24]=[C:23]([C:26](=[O:27])[NH:11][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[C:4]=2[F:12])[CH2:9][CH3:10])[CH2:22]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC[C@H](N)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reactant: CCOC(=O)C1=CCN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)C1=CCN(C(=O)OC(C)(C)C)C1)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To (1S)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propan-1-amine (0.1 g, 0.3 mmol) (Example 26) in DCM was added 1-tert-butyl 3-ethyl 1H-pyrrole-1,3(2H,5H)-dicarboxylate (0.065, 0.3 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.07 mg, 0.36 mmol), 1-hydroxy-7-azabenzotriazole (0.049 g, 0.36 mmol) and triethylamine (0.085 ml, 0.6 mmol), then stirred at ambient for 18 hours. The reaction was diluted with DCM washed with 5% citric acid, sat. sodium bicarbonate then brine. The organic extract was dried (Na2SO4), filtered and concentrated to give 3-{(S)-1-[4-Chloro-2-fluoro-3-(pyridine-3-carbonyl)-phenyl]-propylcarbamoyl}-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (0.125 g). MS: [M+H]+ 488.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[N:11][N:10]=[N:9]1.Cl[CH:14]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>O>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH:14]([N:9]2[N:10]=[N:11][CH:12]=[N:8]2)[CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[CH:29][CH:28]=1)#[N:31]
Reactant: c1nnn[nH]1
Reactant: N#Cc1ccc(C(Cl)CCc2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(CCc2ccc(F)cc2)n2ncnn2)cc1
Temperature: 25 °C

Procedure:
NaH (0.45 g of 55% suspension in mineral oil) is added to anhydrous DMF under nitrogen atmosphere. Tetrazole (1.1 g) is added and the mixture is gently heated for 20 minutes. The mixture is cooled to room temperature and 1-chloro-1-(4-cyanophenyl)3-(4-fluorophenyl)propane (1.53 g) is added. The reaction mixture is then heated for 6 hours. Water is added and the products are extracted into ethyl acetate. After drying and solvent evaporation the products are purified by flash chromatography. Elution, staring with pure methylene chloride with increasing methanol content, affords first 2-[1-(4-cyanophenyl)-3-(4-fluorophenyl)propyl]tetrazole which 1H NMR spectra is as follows:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.[C:9]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=O)[CH2:10][CH3:11].C([BH3-])#N.[Na+]>CO>[CH:1]1([NH:4][CH:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCC(=O)c1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(NC1CC1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a mixture of 8 g of molecular sieves and 8.4 g (148 mmol) of cyclopropylamine in 100 ml of methanol at 0° C., were successively added 11 ml of acetic acid and 10 g (74 mmol) of 4-propionyl-pyridine. The reaction mixture was stirred for 3 hrs at reflux and cooled to room temperature. A solution of 6.9 g (185 mmol) of sodium cyanoborohydride in 20 ml of methanol was added dropwise. The reaction mixture was stirred for 3 hrs at reflux, and cooled to room temperature. The reaction mixture was concentrated in vacuum to half its volume and diluted with 80 ml of dichloromethane. Heptane was added so that a solid precipitated. The solid was filtrated. The filtrate was concentrated in vacuum to give 8.7 g (66%) of N-cyclopropyl-1-pyridin-4-yl-propylamine.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[C:18](=[O:19])([O:7][C:6]1[C:5](=[O:8])[CH:4]([CH3:9])[O:3][C:2]=1[CH3:1])[O:20][CH3:21]
Reactant: COC(=O)Cl
Reactant: CC1=C(O)C(=O)C(C)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)OC1=C(C)OC(C)C1=O
Yield: 29.3 %

Procedure:
A solution of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (pineapple ketone, 44.0 g, 0.33 mole) and triethylamine (50.5 g, 0.5 mole) in methylene chloride (220 g) is cooled to 5° C. under nitrogen atmosphere. To the cooled solution is added over a period of 2.0 hours, a solution of methyl chloroformate (38.6 g, 0.41 mole) in methylene chloride (200 g), which is then stirred at 5°-8° C. for two additional hours. The reaction mixture is filtered through a Buchner funnel to remove the triethylamine hydrochloride. The salt is washed with methylene chloride (200 ml). The combined organic layers are washed twice with 100 ml portions of water and dried over sodium sulfate. The solvent is removed in vacuo and the crude product distilled (<0.1 torr) through a Goodloe column to yield 18 g of methyl 2,5-dimethyl-3-oxo-4(2H)-furyl carbonate product, b.p. 105° C.; IR (neat film) 2960(M), 1770(S), 1710(S), 1640(S), 1250(S), 1200(S) cm-1 ; 'H NMR δ 1.55(d, J=8 Hz,3), 2.28 (s,3), 3.95 (s,3), 4.70 (q, J=8 Hz,1).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[N:13][CH:12]=[CH:11][C:8]=1[CH:9]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[Br:6][C:7]1[CH:14]=[N:13][CH:12]=[CH:11][C:8]=1[CH:9]=[CH2:1]
Reactant: [Li]CCCC
Reactant: O=Cc1ccncc1Br
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccncc1Br
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide in dry tetrahydrofuran (15 mL) at 0° C. was added n-butyl lithium (3.87 mL, 3.87 mmol) with constant stirring, yellow colour was observed. The yellow colour suspension was allowed to stir at room temperature for 40 min. After 40 min, the reaction mixture was cooled to 0° C. and 3-bromoisonicotinaldehyde (0.6 g, 3.23 mmol) in tetrahydrofuran (5 mL) was added drop wise, the yellow colour was disappeared. Reaction mass was allowed to stir at 0° C. to room temperature for 3 h. The reaction mixture was diluted with water (30 mL) and extracted with ether (3×25 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ: 8.69 (s, 1H), 8.45 (d, J=4.8 Hz, 1H), 7.41 (d, J=4.8 Hz, 1H), 7.02-6.95 (m, 1H), 5.95-5.91 (d, J=17.6 Hz, 1H), 5.60-5.57 (d, J=10.8 Hz, 1H). MS (M+2): 185.8.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([N:34]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([OH:33])=[O:32])=[O:24])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:49][CH2:50][CH:51]([CH2:53]O)[OH:52].C(Cl)CCl>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([N:34]([S:39]([C:42]2[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=2)(=[O:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([O:33][CH2:53][CH:51]([OH:52])[CH2:50][OH:49])=[O:32])=[O:24])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: OCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)NCCCC[C@@H](C(=O)OCC(O)CO)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 8 h
Yield: 38.9 %

Procedure:
A solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(4-methylbenzenesulfonyl)-L-tryptophanyl]-L-lysine (product of example 2, 70 mg, 0.1 mmol) in DMF (1 mL) was treated with glycerol (100 mg) and EDC (100 mg, 0.5 mmol) and stirred overnight. The solution is then poured in 5% citric acid and extracted with EtOAc (5 mL). The solvent was evaporated and the residue was purified by preparative HPLC to yield 30 mg (40%) of the desired ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](C)=[N:7][CH:8]=1.O[C:11]1C(C)=NC=CC=1.CI>>[CH3:1][O:2][C:3]1[C:8]([CH3:11])=[N:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(C)nc1
Reactant: Cc1ncccc1O
Solvent: CI
Product: COc1cccnc1C

Procedure:
Was prepared in a similar manner to 5-methoxy-2-methylpyridine using 3-hydroxy-2-methylpyridine (purchased from Fisher Scientific) and methyl iodide (purchased from Fisher Scientific).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.O>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:29][C:27]5[S:28][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:25][CH:26]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1ccc(C(F)(F)F)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)cn12
Yield: 20.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-(trifluoromethyl)thiophen-2-yl)methanol (130 mg) and tributylphosphine (0.27 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg) at 60° C., and the mixture was heated at the same temperature for 2 h. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated, and purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (EtOAc/MeOH). The resulting solid was purified by preparative HPLC (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (32.0 mg) as a white solid.