Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:63][CH2:64][O:65][CH2:66][C:67]([F:70])([F:69])[F:68])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:41]=[C:42]([O:51][CH2:63][CH2:64][O:65][CH2:66][C:67]([F:70])([F:69])[F:68])[CH:43]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:45]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCOCC(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]-amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added 2-(2,2,2-trifluoroethoxy)ethyl 4-methylbenzenesulfonate (3 eq.) from the previous step, cesium carbonate (2 eq.), and sodium iodide (5 mol %). The reaction was heated to 100° C. and stirred for 2.5 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 40% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>CO.Cl.O>[Cl:6][CH2:7][CH2:8][CH2:9][C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNC(N)=S
Reactant: O=C(CCCCl)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
Thiosemicarbazide (9.11 g, 0.1 mol) was added under nitrogen to a solution of 4-chlorobutyrophenone (16 mL, 0.1 mol) in 350 mL of methanol plus 27 mL of 1 N HCl plus 25 mL of water. After approximately 30 minutes of stirring at room temperature, all of the solid had dissolved. The reaction was then stirred at room temperature for 24 hours (overnight). The solid that had formed was collected by filtration and dried under high vacuum to give 17.41 g (68%) of the title compound as a white solid, mp 128-130° C.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].N[C:28]1C=C2C(=C[CH:37]=1)C(=O)OC2.C1(C2(CC(=O)C(O)=O)CCCC2)C=CC=CC=1>>[C:18]1([C:16]2([CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]3[CH:2]=[C:3]4[C:8](=[CH:9][CH:10]=3)[C:6](=[O:7])[O:5][CH2:4]4)=[O:26])[CH2:24][CH2:37][CH2:28][CH2:17]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Reactant: Nc1ccc2c(c1)COC2=O
Agent: O=C(O)C(=O)CC1(c2ccccc2)CCCC1
Product: O=C(CC1(c2ccccc2)CCCC1)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclopentyl)-2-oxo-propionic acid, melting point 140-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:6][N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)[N:4]=1.[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH3:1][O:2][C:3]1[C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][N:5]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:4]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of ethyl 3-[3-methoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-yl]propionate (380 mg), 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 2 hours, diluted with 1 N hydrochloric acid (2 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-methoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (319 mg, yield: 89%). This was recrystallized from ethanol-hexane. Melting point: 127–128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:25][C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C:10](=[O:24])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C@@H:20]([CH3:23])[CH2:21][OH:22])[CH:12]=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:25][C:26](=[O:27])[NH:28][CH:29]([CH3:31])[CH3:30])[C:10](=[O:24])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C@@H:20]([CH3:23])[CH2:21][O:22][S:40]([CH3:39])(=[O:42])=[O:41])[CH:12]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NC(=O)Cn1c(-c2cccc(Cl)c2)cc2ccc(OC[C@@H](C)CO)cc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)Cn1c(-c2cccc(Cl)c2)cc2ccc(OC[C@@H](C)COS(C)(=O)=O)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A suspension of 2-[3-(3-chlorophenyl)-7-((S)-3-hydroxy-2-methylpropoxy)-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (319 mg, 0.720 mmol) and triethylamine (0.30 mL, 2.16 mmol) in dry DCM (7.0 mL) was cooled to 0° C. and methanesulfonyl chloride (67 μL, 0.86 mmol) was added dropwise via a syringe. The mixture was stirred for 1 h at 0° C., a second aliquot of methanesulfonyl chloride (25 μL, 0.32 mmol) was added, and stirring was continued 30 min at room temperature. The mixture was diluted with ethyl acetate (20 mL) and washed with 1 N HCl (aq.) (20 mL), sat. NaHCO3 (aq.) (20 mL) and brine (20 mL). The aqueous washes were back-extracted with ethyl acetate (20 mL), and the combined organic extracts were dried (MgSO4) and concentrated to give crude methanesulfonic acid (R)-3-[3-(3-chlorophenyl)-2-(isopropylcarbamoylmethyl)-1-oxo-1,2-dihydroisoquinolin-7-yloxy]-2-methylpropyl ester (316 mg, 0.720 mmol, 84%) as off-white solid.
Reaction SMILES: [F:1][C:2]1[C:8]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])#[N:24]>>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:38])([F:39])([F:35])([F:36])[F:37])[CH:33]=1)[C:28]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[C:2]=1[F:1])=[O:29])#[N:24]
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Nc1cccc(-n2ccn3nc(-c4cccnc4)cc23)c1F
Product: N#Cc1cc(C(=O)Nc2cccc(-n3ccn4nc(-c5cccnc5)cc34)c2F)cc(S(F)(F)(F)(F)F)c1

Procedure:
Analogously to the process described in Example 96, 100 mg (0.341 mmol) of the compound of Example 70A and 110 mg (0.341 mmol, 85% pure) of the compound from Example 23A gave 52 mg (28% of theory) of the title compound. Here, purification was by preparative HPLC according to Method 33, and final trituration of the product could be dispensed with.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH2:18][C:19]([OH:21])=O)=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][C:14]([CH2:18][C:19]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:21])=[C:15]([CH3:17])[N:16]=2)=[CH:10][CH:11]=1
Reactant: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CC(=O)O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution of {2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}acetic acid i103 (0.5 g, 1.41 mmol, 1 eq), triethylamine (0.2 ml, 1.41 mmol, 1 eq), and piperidine (0.15 ml, 1.45 mmol, 1.03 eq) in dichloromethane (30 ml) is cooled (ice bath) and treated with 1-hydroxybenzotriazole (38 mg, 0.28 mmol, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.271 g, 1.41 mmol, 1 eq). The mixture is stirred at room temperature overnight, then diluted with 70 ml of dichloromethane. The organic layer is washed with water (2×50 ml), brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure to obtain an orange solid. The solid is triturated in acetonitrile, filtered and rinsed with cold diethyl ether to give 0.18 g of 1-({2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}acetyl)piperidine i104 as a yellow solid.
Reaction SMILES: NC1C=CC(CC(O)=O)=CC=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)#[N:13]>[Pt].Cl>[NH2:13][CH2:12][CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15]1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: [Pt]
Agent: Cl
Agent: Nc1ccc(CC(=O)O)cc1
Product: NCC1CCC(CC(=O)O)CC1
Yield: 63 %

Procedure:
The p-aminophenylacetic acid described in Example 1 is converted into p-cyanophenylacetic acid by diazotisation in the manner described in J. Chem. Soc., 1941, 745, the yield being 47% of theory; m.p. 138°-141° C. It is then hydrogenated in the presence of platinum catalyst in hydrochloric acid solution to give 4-aminomethylcyclohexylacetic acid; yield 63% of theory; m.p. 120-123° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C)ccc1Cl
Yield: 96 %

Procedure:
To a solution of 2-chloro-5-methylbenzoic acid (7.62 mmol, 1.30 g) in ethanol (16 ml), H2SO4 (35 mmol, 1.82 ml) was added and the mixture was refluxed for 20 hours. The solvent was evaporated and the crude residue was dissolved in water. The solution neutralised with 6N NaOH aqueous solution and extracted with CHCl3. The organic phase was evaporated affording 1.46 g (yield 96%) of the expected product.
Reaction SMILES: Cl.[NH2:2]O.[OH:4]/[CH:5]=[C:6](\[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=1)/[CH:7]=O.C([O-])(O)=O.[Na+]>O>[O:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=2)[CH:7]=[N:2]1
Reactant: CSc1nccc(/C(C=O)=C\O)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CSc1nccc(-c2cnoc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of hydroxylamine hydrochloride (60.0 g, 0.86 mol) in water (2 L) was added (E)-3-hydroxy-2-(2-(methylthio)pyrimidin-4-yl)acrylaldehyde (3) (342 g, 0.714 mol) in portions. After the addition, the mixture was heated at 60° C. and stirred for 2 h. The reaction mixture was allowed to cool to room temperature and the solution was adjusted to pH about 4 by addition of 10% aq. NaHCO3. The resulting precipitate was filtered, washed with water (200 mL×2) and dried in vacuum to give 4-(isoxazol-4-yl)-2-(methylthio)pyrimidine (4) (112 g, 81.2%) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:14])([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[C:15](O)(=[O:17])[CH3:16]>O.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[C:15]([O:1][CH2:2][C:3]([CH3:14])([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])(=[O:17])[CH3:16]
Reactant: C=CCCCC(C)(CO)CCCC=C
Reactant: CC(=O)O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: O
Product: C=CCCCC(C)(CCCC=C)COC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
Into a 100 mL round-bottom flask equipped with a magnetic spin bar and a glass stopper was added 6-hydroxymethyl-6-methyl-1,10-undecadiene (9.41 g, 48 mmol), glacial acetic acid (60.1 g, 1.0 mol) and scandium (III) triflate (1.23 g, 2.5 mmol). The mixture was stirred at ambient temperature for approximately 10 minutes and a colorless solution was obtained. The reaction mixture was stirred for an additional 24 hours at ambient temperature. The reaction mixture was then transferred into a 500 mL separatory funnel and diluted with 100 mL of deionized water. The solution was extracted with three 50 mL portions of methylene chloride. The combined methylene chloride extracts were washed with two 100 mL portions of deionized water, 100 mL of saturated sodium bicarbonate, 100 mL of brine and finally dried over anhydrous magnesium sulfate. The excess methylene chloride was removed with a rotary evaporator to afford a light oil. The oil was distilled under vacuum to afford 9.39 g of 6-acetoxymethyl-6-methyl-1,10-undecadiene (bp=66 to 71° C./8.7 Pa). The FTIR, 13C and 1H nmr were consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[C@H:10]2[CH2:11][O:12][CH2:13][C@H:9]2[O:8][N:7]=1)=O)C.[BH4-].[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:8]1[C@@H:9]2[CH2:13][O:12][CH2:11][C@@H:10]2[C:6]([CH2:4][OH:3])=[N:7]1
Reactant: CCOC(=O)C1=NO[C@@H]2COC[C@H]12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CCO
Product: OCC1=NO[C@@H]2COC[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A solution of (3aS,6aS)-rel-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole-3-carboxylic acid ethyl ester (18.9 mmol) (intermediate IV-2) in ethanol (60 ml) was cooled to 5° C. Sodium borohydride (37.8 mmol) was added portionwise over a period of 15 minutes. During gas evolution the temperature was maintained between 5 and 10° C. Thereafter, the reaction mixture was stirred between 25 and 28° C. for 1 hour. For the workup, the reaction mixture was cooled in an ice bath and 3M hydrochloric acid (12 ml) was added dropwise. The mixture was allowed to warm to room temperature and was then treated with a solution sodium carbonate (2M; 10 ml). The suspension was concentrated at reduced pressure, the resulting solid was stirred in dichloromethane, then filtered, and the filtrate was concentrated at reduced pressure. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 0:100 as the eluent. The (3aS,6aS)-rel-1-(3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazol-3-yl)-methanol (2.06 g, 76% yield) was obtained as a light yellow oil. MS: m/z=144.0 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[C@@H:15]([C:16]=2[CH:17]=1)[CH2:14][CH2:13][CH2:12][N:11]3[C:18]([C:20]1[CH:28]=[CH:27][C:23]2[NH:24][CH:25]=[N:26][C:22]=2[CH:21]=1)=[O:19])=[O:4].COC(C1C=CC2[C@@H]3[C@@H](N(C(C4C=CC5NC=NC=5C=4)=O)CCC3)CC=2C=1)=O>>[NH:24]1[C:23]2[CH:27]=[CH:28][C:20]([C:18]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:9]4[C:8]5[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:17][C:16]=5[CH2:15][C@H:10]34)=[O:19])=[CH:21][C:22]=2[N:26]=[CH:25]1
Reactant: COC(=O)c1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Agent: COC(=O)c1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Product: O=C(O)c1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 5 %

Procedure:
The title compound is prepared from a ca. 1:1 mixture of cis-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxylic acid methyl ester and cis-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-7-carboxylic acid methyl ester following a procedure analogous to that described in Example 35 and separated from Example 98 by HPLC on reversed phase (MeCN/H2O). Yield: 5% of theory; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CN(CCCCN1C(=O)c2ccccc2C1=O)CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(CCCCN)CCCCN
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
144 mg (0.33 mmol) of 2.2′-[(methylimino)dibutane-4,1-diyl]bis(1H-isoindole-1.3(2H)-dione) is solubilized in 2 ml of ethanol and 65 μl (0.73 mmol; 2.2 equivalents) of 35% hydrazine hydrate are added to the reaction mixture which is maintained under stirring at 150° C. under microwaves for 30 minutes. The solvents are evaporated off under reduced pressure and the excess hydrazine hydrate is eliminated by co-evaporation with 4 times 15 ml of ethanol. 100 ml of ethanol is added to the reaction mixture which is acidified to pH 1 with a 1N solution of hydrochloric acid in ethyl ether. The reaction medium is concentrated under reduced pressure, then taken up in 50 ml of ethanol and the white precipitate formed is filtered, washed with 3 times 20 ml of water and eliminated. The filtrate is basified to pH 12 with a 2M solution of soda, then concentrated under reduced pressure and used in the following stage without other purification.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1.O>[NH:20]([C:21]([NH:1][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1(CC(=O)O)CCCCC1
Reactant: O=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC1(NC(=O)Nc2ccccc2)CCCCC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
To a solution of (1-aminocyclohexyl)acetic acid (0.232 mg, 1.48 mmol) in a mixture of 1,4-dioxane (9 ml) and water (3 ml) was added 30% aqueous sodium hydroxide solution to pH 9. Phenylisocyanate (0.24 ml, 2.22 mmol) was added dropwise at 35° C. and 30% aqueous sodium hydroxide solution was added to adjust the solution to pH9. The reaction mixture was stirred at 40° C. for 1.5 hrs and concentrated under reduced pressure. 5N Hydrochloric acid was added to acidify the solution (pH3) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried (over anhydrous MgSO4). After concentration under reduced pressure, the precipitated solid was collected by filtration and washed with diisopropy ether to give the title compound (0.228 g) as a colorless powder with contamination.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[CH2:17][C:18]([OH:20])=O)=[CH:11][C:10]=2[F:22])[CH:5]=[CH:4][N:3]=1.[ClH:23].[NH2:24][C@@H:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26]([NH2:28])=[O:27]>>[ClH:23].[NH2:28][C:26](=[O:27])[C@@H:25]([NH:24][C:18](=[O:20])[CH2:17][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[C:10]([F:22])[CH:11]=1)=[O:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)O)cc2F)ccn1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Agent: Cl
Product: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Yield: 52.8 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (30 mg, 0.10 mmol) was coupled with (S)-2-amino-2-phenylacetamide hydrochloride (Acros, 28 mg, 0.15 mmol) in a manner similar to that which is described in Step C of Example 1 to give (S)—N1-(2-amino-2-oxo-1-phenylethyl)-N3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)malonamide, hydrochloride salt (25 mg, 53% yield). 1H NMR (DMSO-d6) δ 10.68 (s, 1H), 8.80 (d, 1H, J=8.0 Hz), 7.96 (d, 1H, J=7.5 Hz), 7.77-7.90 (m, 4H), 7.20-7.45 (m, 8H), 6.70 (m, 1H), 6.12 (s, 1H), 5.39 (d, 1H, J=7.5 Hz), 3.48 (d, 1H, J=15.0 Hz), 3.41 (d, 1H, J=15.0 Hz); MS(ESI+) m/z 438.26 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[C:4](=[O:18])[C:3]=1[C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=2)[C:5]([CH3:16])([CH3:17])[C:4](=[O:18])[C:3]=1[C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(C(F)(F)F)ccc2C(C)(C)C1=O
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(C(F)(F)F)ccc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
A solution of 1,1-dimethylethyl N-((4-hydroxy-1,1-dimethyl-2-oxo-6-(trifluoromethyl)-naphthalen-3-yl)carbonyl)glycinate (432 mg, 1045 μmol) in toluene (5 mL), was treated with silica gel (314 mg, 5225 μmol). The reaction was heated at 110° C. After 4 hours, the reaction was cooled to 23° C. and filtered. The residue was washed with DCM (150 mL), and the filtrates were discarded. The residue was subsequently washed with a 10% MeOH/DCM solution (1000 mL). The filtrate was concentrated in vacuo, affording 312 mg of the title compound. MS m/e=358.1 (M+H)+. Calculated for C16H14F3NO5 357.08.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:17][C:18]1[C:22](B(O)O)=[C:21]([CH3:26])[O:20][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[CH3:17][C:18]1[C:22]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[C:21]([CH3:26])[O:20][N:19]=1
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Reactant: Cc1noc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1noc(C)c1-c1cnccc1N1CCC(C(N)=O)CC1
Yield: 17 %

Procedure:
General procedure E was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (100 mg, 0.35 mmol), 3,5-dimethyl-4-isoxazole boronic acid (74 mg, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 5 mol %), acetonitrile (4 mL) and 0.5 M sodium carbonate (1.1 mL, 0.53 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, EtOH, 97:3-80:20, biotage 25+S) to furnish the title compound as a white solid (18 mg, 17%), along with 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide (10 mg, 10% RSM), LC-MS (ESI, 4 min) Rt 0.76 min, m/z 301 (100%, [M+H]+); m/z (ESI, Rt 1.22 min) C16H20N4O2 requires 300.1587, found [M+H]+ 300.1591.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11]O>>[O:1]([CH3:11])[CH:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: CO
Product: COC1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
reacting D-ribose with an acidic solution of methanol to form 1-methyl D-ribofuranoside;