Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:29]([N:31]([CH2:34][CH2:35]Cl)[CH2:32][CH3:33])[CH3:30]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:30][CH2:29][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1c1ccccc1n2Cc1ccccc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 100 °C
Reaction time: 2.3 h
Yield: 91.9 %

Procedure:
A mixture of 9-benzyl-9H-Carbazol-4-ol (0.0305 g, 0.1116 mmol), potassium carbonate (0.0308 g, 0.2232 mmol), and DMF (1.0 mL) is stirred at 100° C. Diethylaminoethyl chloride hydrochloride (0.0230 g, 0.1339 mmol) is added in aliquots over 40 min. After 2.3 h, an additional 0.032 g of potassium carbonate and 0.023 g of diethylaminoethyl chloride hydrochloride are added. The mixture is stirred overnight and then the solvent is removed and the residue partitioned between CH2Cl2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate. Chromatography on silica gel (15 mL) using acetone-hexane (20/80) gave 0.0382 g of the title compound as a solid; mp 79-80.5° C.; IR (drift) 2965, 1581, 1457, 1439, 1356, 1342, 1333, 1268, 1147, 1112, 1053, 782, 750, 729, 713 cm−1; 1H NMR (CDCl3) δ1.14, 2.75, 3.13, 4.36, 5.50, 6.71, 6.98, 7.12, 7.2-7.4, 8.38. Anal. Calcd for C25H28N2O: C, 80.61; H, 7.58; N, 7.52. Found: C, 79.90; H, 7.52; N, 7.43.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[OH-:26].[Na+].[OH:28]O.CC(O)=O>CCO.CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24](=[O:28])[NH2:25])=[CH:22][CH:23]=2)[C:12]([C:15]([NH2:16])=[O:26])=[N:13][CH:14]=1
Reactant: OO
Reactant: N#Cc1ccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)cnc2C#N)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)cnc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 5-((1R,2S)-2-aminocyclohexylamino)-3-(4-cyanophenylamino)pyrazine-2-carbonitrile (40 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (41 mg). MS 370.2 (M+H); UV 204.2, 269.5, 320.0 nm; t 0.375 min.
Reaction SMILES: C([N:8]([CH2:35][C@H:36]([OH:58])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45]CC2C=CC=CC=2)=[C:41]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:40]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[OH:58][C@H:36]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([NH:53][S:54]([CH3:57])(=[O:55])=[O:56])[CH:40]=1)[CH2:35][NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)NCCc4c[nH]c5ccccc45)cc3)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(C(=O)NCCc4c[nH]c5ccccc45)cc3)CC2)ccc1O
Reaction time: 3 h

Procedure:
A suspension of 0.246 g (0.3 mmol) of trans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}-N-[2-(1H-indol-3-yl)ethyl]benzamide and of 0.332 g of palladium-on-charcoal (10% Pd, 50% in water) in a mixture of 5.4 ml of ethanol and 4 ml of tetrahydrofuran is placed under hydrogen atmosphere and is stirred for 3 h. The catalyst is subsequently filtered off and the solvents are evaporated under reduced pressure. The title compound is obtained in the form of a white solid (0.076 g, 40%) after purification on silica gel (eluent: dichloromethane/methanol/aqueous ammonia 99/1/0.1 to 85/15/1.5 gradient in 30 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[O:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[F:27])=[C:15]3[C:10]([CH:11]=[C:12]([F:35])[C:13]([F:34])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[O:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]4[NH:38][N:37]=[N:36][N:24]=4)=[CH:21][C:20]=3[F:27])=[C:15]3[C:10]([CH:11]=[C:12]([F:35])[C:13]([F:34])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(OC(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1cc2nn(-c3ccc(Cl)cc3)c(C(Oc3ccc(-c4nnn[nH]4)cc3F)C3CCCCC3)c2cc1F

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methoxy}-3-fluoro-benzonitrile (example 35) was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as yellow solid. MS: m/e=539.2 [M+H+].
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:12](OCC)=[O:13].[Na]>CCCCCC.C(O)C>[CH:12]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:10]#[N:11])=[O:13]
Reactant: CCOC=O
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCCCCC
Product: N#CC(C=O)c1ccccc1

Procedure:
A 20.0 g. amount of sodium hydride (50% in oil) is added portionwise with stirring to a solution of 20.0 g. of phenylacetonitrile and 40.0 ml. of ethyl formate in 200 ml. of sodium dried benzene. The mixture is heated on a steam bath to start the reaction and after the vigorous reaction has subsided, the mixture is heated on the steam bath for 2 hours with stirring. Ethanol is then added dropwise to decompose the excess sodium hydride. The mixture is then swamped with n-hexane and the precipitate is collected and washed with n-hexane. The precipitate is suspended in water then an excess of dilute hydrochloric acid is added and the product is extracted with ether. The ether extracts are dried and evaporated. The residue is crystallized from acetone-n-hexane to give 12.0 g. of the product of the Example m.p. 161°-163° C. Reference: D. J. Brown and T. C. Lee, J. Chem. Soc. (C), 214 (1970).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[N:22]=[C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19](Cl)[N:14]3[N:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:23])=[CH:4][N:3]=1.C[O-].[Na+].[C:27](O)(=[O:29])C>CS(C)=O.CO.ClCCl>[F:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[N:22]=[C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([O:29][CH3:27])[N:14]3[N:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:23])=[CH:4][N:3]=1
Reactant: Cc1cnc(F)c(NS(=O)(=O)c2nc3cc(C)cc(Cl)n3n2)c1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(C)cc2nc(S(=O)(=O)Nc3cc(C)cnc3F)nn12
Reaction time: 0.05 h

Procedure:
To a solution of 0.70 g (1.9 mmol) of N-(2-fluoro-5-methyl-3-pyridinyl)-5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridine-2-sulfonamide in 25 mL of dry dimethyl sulfoxide was added with stirring 1.0 mL (4.6 mmol) of sodium methoxide as a 25 percent solution in methanol. After 3 min, 3 mL of acetic acid was added and the solution was diluted with 600 mL of dichloromethane. The resulting solution was washed with water (5×100 mL), dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 0.5 g (71 percent of theory) of the title compound as a white solid melting at 262°-264° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].IC.CN(C)C=O>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=[N+]([O-])c1cc(Cl)c(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COc1cc(F)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-4-nitro-5-fluorophenol (D41) (450 mg), potassium carbonate (600 mg), iodomethane (1 ml), and dimethylformamide (5 ml) stirred overnight at room temperature then diethyl ether added and the solution washed with water then dried over MgSO4, filtered and evaporated The product was crystallised from hexane to yield the title compound, 350 mg.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])O[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.[O:17]1CCC[CH2:18]1>C(OCC)(=O)C>[C:18]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:15])(=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccccc1
Reactant: C1CCOC1
Reactant: O=C1CCCCO1
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Product: O=C(CCCCCO)c1ccccc1
Temperature: -70 °C

Procedure:
Magnesium (1.2 g, 0.05 mole) was added to tetrahydrofuran (50 ml), and a solution of bromobenzene (8 g, 0.05 mole) in tetrahydrofuran (20 ml) was added dropwise to the mixture under stirring. After refluxing for 1 hour and cooling at -70° C., a solution of δ-valerolactone (6 g, 0.05 mole) in tetrahydrofuran (20 ml) was added dropwise to the solution. The reaction solution was stirred at -60° C. for 30 minutes, and its temperature was allowed to rise up to room temperature over the period of 1 hour. 2N hydrochloric acid and then ethyl acetate were added to the reaction solution to extract the product. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was chromatographed on a silica gel column, followed by elution with isopropyl ether-ethyl acetate (1:1) to give 5-benzoylpentan -1-ol (5.5 g). This compound was dissolved in ethanol (50 ml), and after ice-cooling, sodium boron hydride (1.0 g) was added to the solution, followed by stirring for 1 hour. Water (50 ml) was added to the reaction solution, and the ethanol was removed under reduced pressure. The product was extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 ml), and pyridine (20 ml) and acetic anhydride (8 ml) were added to the solution, followed by allowing the mixture to stand at room temperature for 18 hours. Ether (100 ml) was added to the reaction solution, and the mixed solution was washed with water, 2N hydrochloric acid and water successively. The ether layer was dried and concentrated under reduced pressure to give 1-phenyl-1,6-diacetoxyhexane (6 g). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 13.
Reaction SMILES: [H-].[Na+].[CH2:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)[CH:13]=[O:14]>>[CH2:3]([O:14][CH2:13][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
This residue (non-purified) was added to a solution of 3.8 g of sodium hydride in 150 ml of dimethylformamide. The mixture was stirred at 60° C. for 30 min and the reaction mixture was cooled to room temperature. 13.7 g of benzyl chloride was added dropwise thereto and the reaction was conducted at 60° C. again for 1 h. The reaction mixture was poured into ice/water. After extraction with ethyl acetate, the extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain crude benzyl ether. After purification according to silica gel column chromatography (ethylacetate/hexane=3:97), 12.0 g of the intended compound was obtained in the form of a faint yellow oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.[P:12]([OH:15])([OH:14])[OH:13].N1C=CC=C(CC(O)=O)C=1.[OH:26][PH:27]([OH:29])=[O:28].P(Cl)(Cl)(Cl)=O>O.C1(C)C=CC=CC=1>[CH:6]1[CH:7]=[N:2][CH:3]=[C:4]([CH2:8][C:9]([P:27]([OH:29])([OH:28])=[O:26])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH:5]=1
Reactant: O=[PH](O)O
Reactant: O=C(O)Cc1cccnc1
Reactant: OP(O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A 500 ml cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was charged with 3-pyridine acetic acid hydrochloride (6.94 g, 0.04 mole), phosphorous acid (9.84 g, 0.12 mole) and toluene (50 ml). The suspension was heated to 90° C. Hyfllo Super-Cel diatomaceous silica (17.50 g, 50% w/w of all the reagents) was added in portions after the mixture of 3-pyridyl acetic acid and H3PO3 was melted, to obtain an heterogeneous suspension. Phosphorous oxychloride (11.2 ml, 0.12 mole) was then added dropwise during 12 minutes. The reaction mixture was then heated to 95° C. for 3 hours. Water (75 ml) was added after cooling the reaction mixture to 65° C. The mixture was stirred vigorously for 30 minutes and then the Hyfllo was removed by filtration. The toluene and the aqueous phases were separated and the aqueous phase was heated at 95° C. for 16 hours. The aqueous phase was cooled to 25° C. and absolute ethanol (75 ml) was added to precipitate the final product. The suspension was cooled to 5° C. for 1 hour. The white product was filtered, washed with absolute ethanol (2×20 ml) and dried in a vacuum oven at 50° C. for 24 hours to obtain 6.30 g (56%) of risedronic acid monohydrate.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([Cl:14])=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:16].[H-].[Na+].[CH3:19]I>COCCOC>[CH3:1][C:2]1([CH3:19])[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([Cl:14])=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:16]
Reactant: CI
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2C

Procedure:
By following the procedure described in Example 5, Step E, using as the reactants 2,3-dimethyl-5-methoxy-6,7-dichloro-1-indanone (13 g., 0.05 mole), sodium hydride (1.44 g., 0.06 mole), 1,2-dimethoxyethane (500 ml.) and methyl iodide (8 ml.), there is obtained 2,2,3-trimethyl-5-methoxy-6,7-dichloro-1-indanone.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Br:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Br:15][C:16]1[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:18][CH:19]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Br

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol), 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (CAS number 71701-92-3; 2.86 g, 10.98 mmol), DIPEA (1.74 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140° C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petrol), then by column chromatography (silica, 0-15% ethyl acetate/petrol) and then by column chromatography (silica, 0-10% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:23])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:30])=[CH:32][CH:33]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (200 mg, 0.42 mmol) in DCM (5 mL) solution were added ethyl 2-aminoacetate (65 mg, 0.63 mmol), HATU (238 mg, 0.63 mmol) and iPr2NEt (0.22 mL, 1.25 mmol). The mixture was stirred at room temperature for 16 hs. The solvent was removed under vacuum. The residue was purified via silica gel column (EtOAC/Hexanes 20% to 40%) to give ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetate (240 mg, 100%) as white solid. LC-MS (Condition A), MS m/z 565.1 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.[CH:9]1([CH:12]([CH:14]2[CH2:16][CH2:15]2)O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH:9]1([CH:12]([CH:14]2[CH2:16][CH2:15]2)[N:6]2[CH:5]=[C:4]([NH2:1])[CH:8]=[N:7]2)[CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: OC(C1CC1)C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1cnn(C(C2CC2)C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (500 mg), dicyclopropylmethanol (0.92 g) and triphenylphosphine (2.3 g) in THF (10 mL) was added diisopropyl azodicarboxylate toluene (1.9M, 4.6 mL) solution at room temperature. The reaction mixture was stirred at room temperature for 2 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A suspension of the obtained residue and palladium on carbon (1 g) in methanol (30 mL) was stirred at room temperature for 12 hr under a hydrogen atmosphere, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (140 mg).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)(C(C)(C)C)(C)C.[C:21](OC)(=[O:30])/[CH:22]=C/C1C=CC=CC=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:21]([N:12]1[CH2:13][CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]([CH2:9][OH:8])[CH2:11]1)(=[O:30])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCC1CNCC1c1ccccc1
Reactant: COC(=O)/C=C/c1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CC(CO)C(c2ccccc2)C1
Temperature: 25 °C

Procedure:
A pyridine solution of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenylpyrrolidine which had been synthesized from methyl trans-cinnamate, in accordance with the technique of Ling et al. (“Tetrahedron”, 2001, vol. 57,p. 6579-6588) and the method of International Patent Publication WO 2000/59502, was mixed with acetic anhydride and stirred at room temperature for 2Hours. After completion of the reaction, this was concentrated under a reduced pressure with toluene azeotropy, and THF and 1 M THF solution of TBAF were added to the thus obtained residue and stirred overnight at room temperature. Thereafter, its work-up and purification were carried out in the standard method to obtain (1-acetyl-4-phenylpyrrolidin-3-yl)methanol. EP: 220.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][C@H:12]([OH:23])[CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[C:24]1(C)[C:25]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.[CH:35](Cl)(Cl)Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:35][C:28]1[CH:29]=[CH:24][C:25]([S:30]([O:23][C@H:12]([CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:9]#[N:10])(=[O:31])=[O:32])=[CH:26][CH:27]=1
Reactant: N#CC(C[C@H](O)CCOCc1ccccc1)c1cccc(Cl)c1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: ClC(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H](CCOCc2ccccc2)CC(C#N)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
To a solution of (4S)-2-(3-chlorophenyl)-4-hydroxy-6-[(phenylmethyl)oxy]hexanenitrile (6.00 g, 18.2 mmol) in 50% CHCl3 in pyridine at 0° C. was added DMAP (2.22 g) and toluenesulfonyl chloride (10.4 g, 54.5 mmol). After warming to room temperature over several hours, the reaction mixture was stored in the freezer for 2 days. After an aqueous work up with 1N HCl the organic layer was dried over MgSO4 and evaporated to an oil. Chromatography on silica with 25% EtOAc in Hexanes afforded the title compound (5.68 g, 66%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.9 (m, 2H) 2.1 (m, 2H) 2.3 (m, 2H) 2.4 (s, 3H) 3.4 (m, 1H) 3.5 (m, 1H) 4.4 (m, 2H) 7.1 (m, 1H) 7.3 (m, 10H) 7.8 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[C:11]([N+:15]#[C-:16])([CH3:14])([CH3:13])[CH3:12].[CH:17](=O)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>Cl(O)(=O)(=O)=O>[C:11]([NH:15][C:16]1[N:6]2[C:2]([S:3][CH:4]=[C:5]2[CH2:7][C:8]([OH:10])=[O:9])=[N:1][C:17]=1[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1ccco1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nc(CC(=O)O)cs1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2ccco2)nc2scc(CC(=O)O)n12

Procedure:
Compound 3 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) (2-aminothiazol-4-yl)acetic acid solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) furfural solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH2:15]([N:14]([CH3:13])[CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.6 %

Procedure:
To a solution of 1-Boc-azetidin-3-one 1d (1.0 g, 5.85 mmol) and N-methyl-benzylamine 6a (1.02 g, 8.43 mmol) in 1,2-dichloroethane (12 mL) and acetic acid (1 mL) was added Na(OAc)3BH (1.30 g, 6.13 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction was quenched by the addition of aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 40% EtOAc/heptane) gave compound 6b (1.40 g).