Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=3)[N:10]=[C:4]2[CH:3]=1.[C:18](=[O:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:19]>>[C:21]([O:20][C:18](=[O:25])[NH:19][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=3)[N:10]=[C:4]2[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Fc1cccc(-c2nc3cc(Br)ccn3n2)n1
Reactant: CC(C)(C)OC(N)=O
Product: CC(C)(C)OC(=O)Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Yield: 32.5 %

Procedure:
The product was prepared in the same manner as described in example 1c using 7-bromo-2-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.44 g, 4.91 mmol) and tert-butyl carbamate (691 mg, 5.9 mmol) as starting materials. The reaction affords [2-(6-fluoro-pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (526 mg, 32.5%), as off-white crystals. MS: m/z=330.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.C(N(CC)CC)C.[C:23]([S:31][CH2:32][CH2:33][C:34](Cl)=[O:35])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CC(C)=O.CCOCC>[C:23]([S:31][CH2:32][CH2:33][C:34]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:35])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Reactant: O=C(Cl)CCSC(=O)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(SCCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O)c1ccccc1

Procedure:
11.3 g of (4R)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid and 13.2 g of triethylamine are dissolved in 200 ml of dehydrated acetone and 11.7 g of S-benzoyl-3-mercaptopropanoyl chloride is added dropwise while stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour. 4 N Hydrochloric acid in ether is added to this mixture and the precipitate is filtered. The filtrate is concentrated in vacuo and the obtained oil is dissolved in ethyl acetate, washed with 2 N hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give the titled compound, yield 12 g (58%), mp. 100.5°-101° C. (dec.) (ethyl acetatebenzene), [α]D26 +130.8° (c=1.0, methanol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[NH2:9][CH2:10][CH2:11][CH2:12][OH:13].C([O-])(O)=O.[Na+].C(O)(CC)(C)C>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[OH:13][CH2:12][CH2:11][CH2:10][NH:9][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: NCCCO
Reactant: [O-][n+]1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccccc1NCCCO
Reaction time: 21 h
Yield: 92.9 %

Procedure:
A mixture of 2-chloropyridine-N-oxide (16.6 g, 0.1 mole), 3-amino-1-propanol (15.3 mL, 0.2 mole), NaHCO3 (42 g, 0.5 mole), and tert-amyl alcohol (100 mL) was heated to reflux. After 21 hr, the reaction was cooled, diluted with CH2Cl2 (300 mL), and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene to leave a yellow oil. Silica gel chromatography ( 20% MeOH/CHCl3) gave the title compound (15.62 g, 93%) as a yellow solid: TLC (20% MeOH/CHCl3) Rf 0.48; 1H NMR (250, CDCl3) δ 8.07 (dd, J=6.6, 1.2 Hz, 1H), 7.34 (br t, 1H), 7.10-7.30 (m, 1H), 6.64 (dd, J=8.5, 1.4 Hz, 1H), 6.40-6.60 (m, 1H), 4.49 (br s, 1H), 3.65-3.90 (m, 2H), 3.35-3.60 (m, 2H), 1.75-2.00 (m, 2H); MS (ES) m/e 169 (M+H)+.
Reaction SMILES: [OH-].[Na+].F[C:4]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:7]([F:20])=[CH:6][C:5]=1[C:21]1[N:25]([C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[N:24]=[CH:23][C:22]=1[C:31]([NH2:33])=[O:32].O.C(O)(=O)C>CS(C)=O.C(OCC)(=O)C>[F:20][C:7]1[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])=[CH:9][C:4]2[NH:33][C:31](=[O:32])[C:22]3[CH:23]=[N:24][N:25]([C@H:26]4[CH2:30][CH2:29][O:28][CH2:27]4)[C:21]=3[C:5]=2[CH:6]=1
Reactant: COc1nc(C)cc(C)c1-c1cc(F)c(-c2c(C(N)=O)cnn2[C@H]2CCOC2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1nc(C)cc(C)c1-c1cc2[nH]c(=O)c3cnn([C@H]4CCOC4)c3c2cc1F
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 17.4 %

Procedure:
Sodium hydroxide (powder, 74 mg) was added to a solution of 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxamide (199 mg) in DMSO (2 mL), and the reaction mixture was stirred at 75° C. for 1.5 hours. After the reaction mixture was cooled to room temperature, water, acetic acid (0.106 mL) and ethyl acetate were added to the reaction mixture with stirring. After the precipitated solid was filtered, organic layer was washed with water, a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 55% to 90% to 96%), and the resulting crude was solidified by adding n-heptane/MTBE to give the title compound (33 mg).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:16]3[N:17]([C:31]([CH2:34][CH3:35])=[CH:32][CH:33]=3)[N:18]=[C:19]([CH3:30])[C:20]=2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:12]=[N:13][CH:14]=1)=O)(C)(C)C>C(OC(=O)C)C.Cl>[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[C:16]3[N:17]([C:31]([CH2:34][CH3:35])=[CH:32][CH:33]=3)[N:18]=[C:19]([CH3:30])[C:20]=2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:12]=[N:13][CH:14]=1
Reactant: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(N)c1
Yield: 93.1 %

Procedure:
A solution of ethyl 5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate (190 mg) in 2 N hydrogen chloride ethyl acetate solution (4 mL) was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (100:1-20:1) to give ethyl 5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (140 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]2[O:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[N:12]=2)[N:3]=1.[C:16]1([C:22]2[O:26][CH:25]=[N:24][C:23]=2[C:27](O)=[O:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:13]([C:11]1[N:12]=[C:8]([CH2:7][N:4]2[CH:5]=[CH:6][C:2]([NH:1][C:27]([C:23]3[N:24]=[CH:25][O:26][C:22]=3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:28])=[N:3]2)[O:9][CH:10]=1)(=[O:15])[CH3:14]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(=O)c1coc(Cn2ccc(N)n2)n1
Product: CC(=O)c1coc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure B, starting from 1-[2-(3-amino-pyrazol-1-ylmethyl)-oxazol-4-yl]-ethanone and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.88 min; [M+H]+=377.95.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[C:13]3[C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:6]=1.[OH-].[Na+]>C1COCC1>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:13]3[C:12]([NH:11][C:7]4[CH:6]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:10]=[CH:9][CH:8]=4)=[N:17][CH:16]=[N:15][C:14]=3[O:18][C:19]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)Cc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(CC(=O)O)c4)c23)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Dissolve 50 mg (0.107 mmol) of 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenylacetic acid methyl ester in 2 ml of THF, add 0.322 ml of 1N sodium hydroxide solution at RT and stir at 50° C. for 4 h. Cool to RT and remove the THF under reduced pressure. Add water to the residue, and then 1N hydrochloric acid. Filter off the precipitated solid, wash with water and dry at 50° C. under reduced pressure. 41.7 mg (86% of theory) of the target compound are obtained as a white solid.
Reaction SMILES: [C:1]([S:4]/[CH:5]=[CH:6]\[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH:10]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.O>ClCCl>[CH:10]1([NH:22][C:7](=[O:8])/[CH:6]=[CH:5]\[S:4][C:1](=[O:3])[CH3:2])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCCCCCCCC1
Reactant: CC(=O)S/C=C\C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)S/C=C\C(=O)NC1CCCCCCCCCCC1
Reaction time: 0.25 h
Yield: 9.9 %

Procedure:
To a stirred, cooled (0° C.) solution of 3.0 g (0.0162 mol) of cis-3-(acetylthio)propenoyl chloride in 30 ml of dichloromethane under nitrogen was added dropwise 2.98 g (0.0163 mol) of cyclododecylamine as a solution in 30 ml of dichloromethane. After 15 min, 2.27 ml (0.0163 mol) of triethylamine was added dropwise. After 12 h the reaction mixture was poured into water and extracted three times with dichloromethane. The combined organic layers were washed with water, brine, and dried over magnesium sulfate. Filtration and removal of solvents gave 4.5 g of a 2:1 mixture of cis and trans isomers as a tan solid. Purification by flash column chromatography (Merck 60® silica gel, ethyl acetate/hexane eluant) gave 0.5 g (10% yield) of N-cyclododecyl-cis-3-(acetylthio)acrylamide as a white powder where NMR is reported in Table 2.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH2:8]([SH:10])[CH3:9].[NH2:11][C:12]1[N:20]=[C:19](Cl)[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[Cl-].[Na+].O>[NH2:11][C:12]1[N:20]=[C:19]([S:10][CH2:8][CH3:9])[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 110 °C
Yield: 80.9 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added ethanethiol (2 ml, 27 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred under heating at 110° C. for 3.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (90 mg, yield 82%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC1CCNCC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
To (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]amine (3.78 grams, 9.4 mmol) was added 20% trifluoroacetic acid (50 ml) in dichloromethane. The solution was stirred at room temperature for 4 hours. The solution was concentrated under reduced pressure and the residue was partitioned between dichloromethane and 1N sodium hydroxide. The organic layer was washed with water, dried over potassium carbonate and concentrated to give (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(piperidin-4-ylmethyl)amine as an oil (2.42 grams, 85%), M+H 303.
Reaction SMILES: N[C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+].NC(N)=O>O.[OH-].[Na+]>[OH:13][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=S(=O)(O)O
Reactant: Cc1c(N)cccc1C(=O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(O)cccc1C(=O)O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 3-amino-2-methylbenzoic acid (43.1 g, 285 mmol), water (700 mL), and sulfuric acid (55 mL) was briefly heated to give a clear solution and then cooled to a temperature below 5° C. A solution of sodium nitrite (21 g, 300 mmol) in a minimal amount of water was added in portions while maintaining the internal temperature below 7° C. After stirring for about 30 minutes in an ice bath, urea (7 g) was added to discharge the excess nitrile. A chilled solution of 98% sulfuric acid (240 mL) in water (1000 mL) was added to the diazonium solution, and the combined reaction mixture was heated slowly to 90° C. Solid sodium hydroxide (410 mg) was slowly added. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and evaporated to give 3-hydroxy-2-methylbenzoic acid as a yellow solid (44.4 g,˜100%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].Cl>C(O)C.C(O)(=O)C>[CH2:15]([NH:22][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCN1CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCN1CCC(NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
Then, ethyl 3-(4-oxopiperidino)propionate (1.29 g, 6.47 mol) and benzylamine (0.85 ml, 7.78 mmol) were dissolved in ethanol (40 ml). A solution of sodium cyanoborohydride (256 mg, 4.22 mmol) dissolved in ethanol (20 ml) was added at room temperature and acetic acid (1 ml) was further added to adjust its pH to 6-7. The mixture was stirred at room temperature for 18 hours and added with concentrated hydrochloric acid (3 ml) to adjust the pH to 1-2. The resulting precipitate was collected by filtration and a saturated aqueous sodium hydrogencarbonate solution (150 ml) was added to adjust the mixture to pH 8-9. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 1.39 g of ethyl 3-(4-benzylaminopiperidino)propionate as a colorless oil (74%). This oil (1.11 g, 3.82 mmol) was dissolved in ethanol (120 ml) and 10% palladium-carbon (320 mg) was added. The mixture was refluxed under heating for 5 hours under a hydrogen atmosphere. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure to give 617 mg of ethyl 3-(4-aminopiperidino)propionate as a colorless oil (81%).
Reaction SMILES: Br[C:2]1[N:3]([CH3:25])[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:17]#[N:18])[CH2:13][CH2:12]1)[N:7]=[CH:6][N:5]=2.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][N:3]1[C:2]([C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)=[N:10][C:9]2[C:4]1=[N:5][CH:6]=[N:7][C:8]=2[N:11]1[CH2:16][CH2:15][C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:17]#[N:18])[CH2:13][CH2:12]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cn1c(Br)nc2c(N3CCC(C#N)(c4ccccc4)CC3)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2nc3c(N4CCC(C#N)(c5ccccc5)CC4)ncnc3n2C)cn1
Temperature: 150 °C
Yield: 0.5 %

Procedure:
1-(8-bromo-9-methyl-9H-purin-6-yl)-4-phenylpiperidine-4-carbonitrile (400 mg, 1.0 mmol), 1-Methylpyrazole-4-boronic acid pinacol ester (419 mg, 2.0 mmol), and potassium phosphate (427 mg, 2.0 mmol) were suspended in dioxane (5 mL). To that mixture was added Pd(dppf)Cl2 (82 mg, 0.10 mmol) and water. This suspension was heated to 150° C. in the microwave for 30 minutes. Upon cooling, the resulting mixture was filtered through Celite and a PL-thiol SPE cartridge. The filtrate was then purified by prep HPLC to afford 2 mg of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 8.42 (s, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.59-7.51 (m, 2H), 7.42 (m, 2H), 7.35 (m, 1H), 5.62 (s, 2H), 3.93 (s, 3H), 3.84 (s, 3H), 3.34 (m, 4H), 2.27 (m, 2H), 2.08 (m, 2H). EI (MS) for C22H22N8: 399.29 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].CC1C=CC(S(O[CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=O)=O)=CC=1>C(#N)C>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: NCCOCCO
Reactant: Cc1ccc(S(=O)(=O)OCCOCCNC(=O)OC(C)(C)C)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCOCCNCCOCCO
Temperature: 75 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
2-(2-Aminoethoxyl)ethanol (0.7 g, 5 eq.) was added to a solution of 2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl 4-methylbenzenesulfonate (0.5 g, 1 eq.) in dry acetonitrile (10 mL) and the reaction mixture was heated to 75° C. for 3 h and then at 85° C. for 1 h. The acetonitrile was removed in vacuo. The crude residue was redissolved in DCM (25 mL) and washed with water (25 mL) the aqueous phase was re-extracted with DCM (2×25 mL). The combined organic phases were washed with water (50 mL), dried (MgSO4), filtered and concentrated at reduced pressure to a pale yellow oil (0.4 g). The crude product was purified by silica column chromatography eluting with 10% methanolic ammonia in DCM to give 0.19 g (50%) of 18 as a colourless oil. 13C NMR (CDCl3) δ 156.1, 72.5, 70.2, 70.1, 61.9, 49.2, 49.0, 40.5, 28.4. ESMS (C13H28N2O5) [M+H]+ calc. 293.2076. found 293.2076.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH:10]([OH:30])[CH:11]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[C:25]([F:28])([F:27])[F:26])[C:12](OC)=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH3:31][NH2:32]>CO>[F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH:10]([OH:30])[CH:11]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[C:25]([F:28])([F:27])[F:26])[C:12]([NH:32][CH3:31])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)CSc1cccc(F)c1
Reactant: CN
Solvent: CO
Product: CNC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)CSc1cccc(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
760 mg (about 1.5 mmol) of crude product from step 1.5 were dissolved in methanol. With gentle cooling, gaseous methylamine was then introduced for 30 min. The mixture was stirred at RT for 15 h. The solvents were then removed, the residue was stirred with MTBE and the precipitate was filtered off with suction. This gave 416 mg (62% of theory over 2 steps) of the title compound (4:1 diastereomer mixture) as a colorless solid of m.p. 172° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[Br:16][C:17]1[C:18](O)=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(=O)([O-])O.[Na+]>O>[Cl:3][C:18]1[C:17]([Br:16])=[CH:22][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:20][N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc(C(F)(F)F)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: FC(F)(F)c1cnc(Cl)c(Br)c1
Temperature: 120 °C
Yield: 75.1 %

Procedure:
To phosphorous oxychloride (2.02 ml, 21.6 mmol) was added quinoline (1.34 ml, 11.2 mmol) followed by 3-bromo-2-hydroxy-5-trifluoromethylpyridine (5.0 g, 20.7 mmol), and the mixture formed heated at 120° C. for 3 hrs. It was then cooled to 100° C. and water (10 ml) added. After cooling to 22° C., sodium hydrogen carbonate solution (100 ml) was added and the mixture extracted with ethyl acetate (2×100 ml). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the product as an oil (4.05 g, 75% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20](O)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>COCCOC>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@H:11]([NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:20][OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of Boc-L-aspartic acid-4-benzyl ester (100 g, 309 mmol) in DME (1.8 L) at −20° C. was added NMM (34 mL, 309 mmol) then dropwise iso-butylchloroformate (40 mL, 309 mmol) and the mixture was stirred at −20° C. for 20 min. The reaction mixture was filtered and the filtrate was cooled to −20° C. NaBH4 (17.5 g, 463 mmol) was added portionwise at −20° C. The mixture was allowed to warm and stirred at rt for 1 h. The mixture was quenched with a 20% citric acid solution and then extracted with AcOEt. The organic layer was washed with NaHCO3 solution, H2O and brine, dried (MgSO4), filtered and concentrated. The product was used without further purification for the next step.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][CH:8]([S:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([S:19][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C:6]([OH:30])=[O:5])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)OC(C)(C)C)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(SC(CCCCc2ccccc2)CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.9 %

Procedure:
To a solution of t-butyl-3-(3,4-dimethoxyphenyl)sulfanyl-7-phenylheptanoate (14.9 g, 0.03 mol) in CH2Cl2 (150 mL) cooled to 0° C., is added trifluoroacetic acid (30 mL). The solution is allowed to warm to room temperature and stir overnight after which TLC analysis indicated complete reaction. The reaction mixture is concentrated in vacuo and the brown residue is chromatographed on silica gel (pet-ether/EtOAc, 1:1) to afford 11.9 g of (±) 3-(3,4-dimethoxyphenyl)sulfanyl-7-phenylheptanoic acid (91%) as a pale yellow oil. TLC analysis [pet-ether/EtOAc, 1:1, Rf (heptanoate)=0.95, Rf (acid)=0.15]. 1H NMR (300 MHz, CDCl3) δ 1.5-1.65 (m, 6H), 2.55 (m, 4H), 3.30 (t, 1H), 3.85, (d, 6H), 6.80 (d, 1H), 6.98-7.31 (m, 7H) ppm. Mass spectrum (FAB) m/z 374 M+.