Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:8]=1)#[N:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:13])=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:8]=1)#[N:2]
Reactant: COCOc1cc(C#N)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1cc(C#N)ccc1N
Yield: 58.5 %

Procedure:
A mixture of 5-cyano- 1 -methoxymethyloxy-2-nitrobenzene (0.5 g, 2.4 mmol) and 10% palladium on carbon (.05 g) in ethyl acetate (50 mL) was stirred at rt under 1 atm of hydrogen for 72 h. The mixture was filtered through Celite to remove the palladium and the residue was chromatographed on silica gel (eluting with 25% ethylacetate/hexane) to afford the title compound (250 mg, 58%). MS(ES+) m/e 179 [M+H]+
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH:27][CH:28]1[CH2:30][CH2:29]1)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24](=[O:26])(=[O:25])[NH:27][CH:28]2[CH2:29][CH2:30]2)[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1ccccc1S(=O)(=O)NC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1ccccc1S(=O)(=O)NC1CC1
Yield: 97.5 %

Procedure:
2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.49 g), 2-(aminomethyl)-N-cyclopropylbenzenesulfonamide hydrochloride (2.0 g) and potassium carbonate (2.19 g) were stirred in ethanol (30 ml) at 90° C. for 16 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (1.29 g).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[O-]CC.[Na+].[C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH:16]([C:15](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:10]
Reactant: CCCCCC(=O)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC(C(=O)C(=O)OCC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl oxalate(7.31 G, 0.05 mol) is added to freshly made sodium ethoxide(1.05 eq.) in ethanol. Hexanophenone(8.81g, 0.05 mol) is added dropwise, and the resulting mixture is stirred at room temperature overnight. After concentration the residue is partitioned between 3N HCl and ethyl acetate, extracted with ethyl acetate. Combined organic layers are washed with brine and dried with anhydrous Na2SO4. Purification by column chromatography with hexane/ethyl acetate gives the product (172).
Reaction SMILES: C(OCCO)(=O)C=C.C(C(CO)(C)C(O)=O)O.[C:18]([C:22]1[CH:27]=[C:26](C)[CH:25]=[C:24](C(C)(C)C)[C:23]=1[OH:33])(C)(C)[CH3:19].COC1C=CC(O)=CC=1.C([O-])(=O)NC(N)=O>C(O)CO>[CH2:18]([CH:22]([CH2:27][CH2:26][CH2:25][CH3:24])[CH2:23][OH:33])[CH3:19]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=CC(=O)OCCO
Agent: CC(CO)(CO)C(=O)O
Agent: COc1ccc(O)cc1
Solvent: OCCO
Product: CCCCC(CC)CO

Procedure:
In a 4 l reaction vessel equipped with a stirrer, dropping funnel, thermometer and reflux condenser, 74.7 g of polycaprolactone (Capa 212 from Solvay, molar mass=1000 g/mol, OH number=113 mg KOH/g), 26.35 g of 1,2-ethanediol, 69.66 g of hydroxyethyl acrylate, 26.8 g of dimethylolpropionic acid, 0.088 g of 2,6-di-t-butyl-4-methylphenol and 0.047 g of hydroquinone monomethyl ether were stirred at a bath temperature of 75° C. Over the course of 60 minutes, 231.8 g of allophanate-modified polyisocyanate formed from hexamethylene 1,6-diisocyanate and 2-ethylhexanol (NCO content=17.2%, viscosity approximately 300 mPas) and 131 g of bis(4,4′-isocyanatocyclohexyl)methane were added dropwise. When the feed was at an end, 100 g of acetone were metered in. After 90 minutes 0.29 g of dibutyltin dilaurate was added dropwise. At an NCO content of 1.21% the batch was diluted with 201.97 g of acetone and neutralized with 76 g of 10% strength aqueous sodium hydroxide solution. Over the course of 20 minutes, 784.24 g of water were introduced dropwise into the polymer solution with stirring. Thereafter the acetone was distilled off under reduced pressure and the batch was diluted with 157.89 g of water.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1(C(=CC=CC=1)O)O.C(=O)([O-])[O-].[K+].[K+]>>[C:3]1([CH3:12])[C:4]([S:7]([Cl:10])(=[O:8])=[O:9])=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: Oc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1S(=O)(=O)Cl
Yield: 42.6 %

Procedure:
p-Toluenesulfonyl chloride (2.88 g, 15.08 mmol) was added in two portions, 30 minutes apart, to a stirring solution of pyrocatechol (1.49 g, 13.53 mmol) and potassium carbonate (2.05 g, 14.85 mmol). The solution was heated to reflux for 4 hours. The cooled solution was evaporated under reduced pressure, and the residue was taken up in ethyl acetate (100 cm3) and water (100 cm3). The aqueous layer was extracted with ethyl acetate (2×100 cm3), and the combined extracts were washed with brine (2×200 cm3), dried (MgSO4), and evaporated under reduced pressure. The residue was triturated with diethyl ether (2×20 cm3), and the precipitate was removed by filtration to give unreacted toluenesulfonyl chloride (1.10 g). The filtrate was evaporated under reduced pressure. The yellow crystals were recrystallized from ethyl acetate and heptane to give mono protected pyrocatechol, (1.65 g, 53%) as clear crystalline squares, mp 80-84° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]1[CH:12]=[O:13].O.C([O-])([O-])=O.[K+].[K+]>CO>[OH:13][CH2:12][C:5]1[N:4]([CH3:3])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=1
Reactant: Cn1c(C=O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cn1c(CO)ccc1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
Solid NaBH4 (0.19 g, 5.03 mmol) was added portionwise to a stirred solution of 1-methyl-5-nitro-2-pyrrolealdehyde (42) [for preparation see Fournari, P. Bull. Soc. Chim. Fr., 88, 488-491, 1963] (0.78 g, 5.07 mmol) in MeOH (40 mL) at room temperature under N2. After addition was complete, the reaction mixture was stirred for a further 20 min, then water (40 mL) was added and the mixture was saturated with solid K2CO3. Extraction with EtOAc gave 2-hydroxymethyl-1-methyl-5-nitropyrrole (43) (0.77 g, 97%), mp (EtOAc/petroleum ether) 76-77° C. 1H NMR (CDCl3) δ 7.16 (d, J=4.3 Hz, 1 H, H-4), 6.17 (d, J=4.3 Hz, 1 H, H-3), 4.68 (s, 2 H, CH2), 4.02 (s, 3 H, CH3). Anal. Calculated for C6H8N2O3 : C, 45.1; H, 5.2; N, 17.9. Found: C, 46.1; H, 5.1; N, 17.6%.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:12]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[CH:15]([OH:23])[C:14]2([CH3:25])[CH3:24])[CH:11]=[N:10][CH:9]=1)(C)(C)C.Cl>O1CCOCC1.C([O-])(O)=O.[Na+].[O-2].[Mn+4].[O-2]>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([CH:13]([N:12]3[C:8]([CH2:7][OH:6])=[CH:9][N:10]=[CH:11]3)[C:14]([CH3:25])([CH3:24])[C:15]2=[O:23])=[CH:20][CH:19]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncn1C1c2ccc(Cl)cc2C(O)C1(C)C
Agent: [Mn+4]
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CC1(C)C(=O)c2cc(Cl)ccc2C1n1cncc1CO
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-6-chloro-2,2-dimethyl-indan-1-ol (400 mg, 0.98 mmol) in 1,4-dioxane (15 mL) is added manganese(IV) oxide (2.0 g, 20 mmol). The resulting heterogeneous solution is heated at 80° C. for 60 minutes, cooled to room temperature, filtered and concentrated. The resulting residue is then dissolved in methanol, cooled to 0° C. and treated with 4 N hydrochloric acid in 1,4-dioxane (1 mL, 4.0 mmol). The reaction is placed at room temperature and permitted to stir for 3 hours, at which time the reaction is cooled to 0° C. and diluted with saturated aqueous NaHCO3. The reaction mixture is then concentrated in vacuo to ca. one fourth of the original volume and diluted with ethyl acetate. The layers are separated and the aqueous layer is extracted two times with ethyl acetate. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (ethanol-ethyl acetate, 0:1 to 1:10) to furnish 6-chloro-3-(5-hydroxymethyl-imidazol-1-yl)-2,2-dimethyl-indan-1-one; HRMS: (ESI) m/z 291.0891 [(M+H)+: Calcd for C15H16N2O2Cl: 291.0900]; 1H NMR (400 MHz, CDCl3) δ ppm 0.87 (s, 3 H), 1.44 (s, 3 H), 1.89 (br. s., 1 H), 4.70-4.92 (m, 2 H), 5.75 (s, 1 H), 6.92 (s, 1 H), 7.07 (s, 1 H), 7.41 (d, J=8.1 Hz, 1 H), 7.69 (dd, J=8.3, 2.0 Hz, 1 H), 7.87 (d, J=2.0 Hz, 1 H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[O:12][C:11]([OH:13])=[N:10][N:9]=2)[CH2:4][CH2:3]1.Cl[C:15]1[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=1>>[OH:13][C:11]1[O:12][C:8]([CH:5]2[CH2:4][CH2:3][N:2]([C:15]3[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=3)[CH2:7][CH2:6]2)=[N:9][N:10]=1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: Oc1nnc(C2CCNCC2)o1
Agent: Cl
Product: OB(O)c1cnc(N2CCC(c3nnc(O)o3)CC2)nc1

Procedure:
Prepared from 5-(piperidin-4-yl)-1,3,4-oxadiazol-2-ol hydrochloride (1.30 g, 6.32 mmol) and (2-chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol) in accordance with General Method C to give the title compound as an off-white semi-solid. HPLC-MS: m/z (M−H)+ 290.2, RT 0.17 minutes.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:30]2=[C:31]([C:35](O)=[O:36])[CH:32]=[CH:33][CH:34]=[C:29]2[O:28][CH2:27][CH2:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]3[O:28][CH2:27][CH2:26][N:25]([CH3:24])[C:30]=23)=[O:36])=[O:10])[N:12]=1
Reactant: CN1CCOc2cccc(C(=O)O)c21
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2N(C)CCO3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-5-carboxylic acid. LC-MS (basic): tR=0.89 min; [M+H]+=503.1.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]2.[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH4+].[Cl-]>C1COCC1.[Cu]I>[C:10]([O:9][C:7]([N:3]1[CH2:2][C@@H:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:5]([OH:6])[CH2:4]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](c2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 7 g (37.8 mmol) tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (prepared according to the procedure of Okada, T.; Sato, S.; Tsuji. T.; Tsushima, T.; Nakai, H.; Yoshida, T.; Matsuura, S.; Chem. Pharm. Bull. 1993, 41 (1), p. 132-133) was suspended 0.36 g (1.89 mmol; 0.05 equiv.) copper(I) iodide in 100 mL dry THF under nitrogen atmosphere. The mixture was cooled in an ice/water bath. To this mixture was added dropwise 41.6 mL (41.6 mmol; 1.1 equiv.) of a 1.0M solution of phenylmagnesium bromide in THF. The reaction mixture was stirred at 0° C. for 3 hr then warmed to room temperature. The reaction mixture was poured into 150 mL sat. aq. NH4Cl and stirred until a blue colored solution resulted. The mixture was transferred to a separatory funnel and extracted with diethyl ether (2×150 mL). The combined ether extracts were dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The resulting thick yellow oil was purified by silica gel chromatography eluting with hexanes/EtOAc (9/1) then hexanes/EtOAc (1/1). The product fractions (Rf˜0.5 in hexanes/EtOAc (1:1) were combined and evaporated under vacuum to give the product as a clear thick oil which solidified on standing. On larger scale this product could be further purified by crystallization from hexanes. 1H-NMR (CDCl3): δ: 1.45 (s, 9H), 3.2-3.4 (m, 3H), 3.65-3.95 (m, 3H), 4.37 (q, 1H, 5 Hz), 7.25 (t, 3H), 7.37 (t, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (200 mg, 0.90 mmol) [Prepared according to the procedure of Example 151], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (288 mg, 0.86 mmol) [Prepared according to Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (512 mg, 1.09 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (162 mg, 32%): LC-MS (ES) m/z=503 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[H-].[Na+].[CH3:29][O:30][CH2:31]Cl.O>CN(C)C=O>[CH3:29][O:30][CH2:31][O:1][C:2]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6]
Reactant: COCCl
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)=C(OCOC)C(=O)OCc1ccccc1
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
992 mg of 1-benzyl 3-tert-butyl 2-ethyl 1-oxo-1,2,3-propanetricarboxylate in 10 ml of dimethylformamide was stirred together with 131 mg of 60% oily sodium hydride at room temperature for 1 hour. After addition of 273 mg of chloromethyl methyl ether, the reaction solution was stirred for another 45 minutes, then poured into water and extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1] to give 962 mg of the title compound as a colorless oily substance.
Reaction SMILES: [C:1](#[N:7])[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH2:9][OH:10].[OH-].[Na+]>CCO.O.ClCCl>[OH:10][NH:9][C:1](=[NH:7])[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: NO
Reactant: CC(C)CCC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(C)CCC(=N)NO
Temperature: 25 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
A mixture of isocapronitrile (1.00 g, 10.30 mmol), hydroxylamine hydrochloride (0.786 g, 11.32 mmol), and sodium hydroxide (0.453 g, 11.32 mmol) in EtOH (21 mL) and water (5 mL) was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo to yield a white solid which was re-dissolved in dichloromethane (100 mL). The insoluble salt was removed by filtration. The organic layer was concentrated in vacuo to dryness. The title compound was obtained as a white solid in 55% yield (0.730 g). 1H NMR (300 MHz, CDCl3) δ 6.6 (br., s, 1H), 4.5 (br., s, 2H), 2.2 (m, 2H), 1.50 (m, 1H), 1.4 (m, 2H), 0.85 (m, 6H).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][C:18]([F:27])([F:26])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:12]1)C1C=CC=CC=1>[Pd].C(O)C>[F:26][C:18]([F:27])([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)[CH2:17][O:16][C@H:13]1[CH2:14][CH2:15][C@H:11]([NH2:10])[CH2:12]1
Reactant: Cc1ccc(C(F)(F)CO[C@H]2CC[C@H](NC(=O)OCc3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(F)(F)CO[C@H]2CC[C@H](N)C2)cc1
Reaction time: 2 h
Yield: 101.7 %

Procedure:
A mixture of 600 mg of trans [3-(2,2-Difluoro-2-p-tolyl-ethoxy)-cyclopentyl]-carbamic acid benzyl ester and 500 mg of 10% palladium on carbon in 25 mL of ethanol was stirred under an atmosphere of hydrogen for 2 h. Removal of the catalyst by filtration and concentration under reduced pressure gave 400 mg of product as an oil: MS (m+1)=256.3; 1H NMR (400 MHz, CDCl3) 7.4 (dd, 2H), 7.22 (dd, 2H), 4.05 (m, 1H), 3.75 (t, J=14 Hz, 2H), 3.5 (m, 1H), 2.4 (s, 3H), 2.2 (m, 2H), 2.0 (m, 2H), 1.62 (m, 1H), 1.5 (m, 1H), 1.24 (m, 1H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C-:12]#[N:13].[K+].C1OCCOCCOCCOCCOCCOC1.Cl>CS(C)=O>[C:12]([C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1)#[N:13]
Reactant: Oc1ccc2nc(Cl)sc2c1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1nc2ccc(O)cc2s1
Temperature: 120 °C

Procedure:
4 g. of the mixture of 2-chloro-6-hyroxybenzothiazole and 2-iodo-6-hydroxybenzothiazole obtained in Example 2 are added to a suspension of 3 g. potassium cyanide and 100 mg. 18-crown-6 in 150 ml. dimethyl sulphoxide heated to 120° C. and stirred at a bath temperature of 120° C. After a reaction time of 3 hours, the reaction mixture is poured in 1 liter of ice water and the solution obtained is acidified with dilute hydrochloric acid. Subsequently, it is extracted twice with 500 ml. amounts of diethyl ether and the extracts are washed with water, dried over anhydrous sodium sulphate, mixed with charcoal, filtered and the filtrate evaporated in a vacuum. 2.5 g. Crude 2-cyano-6-hydroxybenzothiazole are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[C:5]([NH2:8])=[N:6][CH:7]=1.I[C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]([CH3:25])[CH:13]=1>C(N(CC)CC)C.CN(C)C=O.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH3:25])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C#Cc1cc(Cl)cnc1N
Reactant: COc1cc2c(I)cn(C)c2cc1OC
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2c(C#Cc3cc(Cl)cnc3N)cn(C)c2cc1OC
Temperature: 20 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A suspension of 0.43 g of 5-chloro-3-ethynylpyridin-2-ylamine, 0.6 g of 3-iodo-5,6-dimethoxy-1-methyl-1H-indole (example 103-f), and 0.072 g of copper iodide, in a mixture of 60 ml of triethylamine and 30 ml of dimethylformamide, is degassed with argon for 15 minutes. 0.066 g of bis(triphenylphosphine)palladium(II) chloride is added to the above suspension. The mixture is agitated at around 20° C. for approximately 6 hours; 0.075 g of 5-chloro-3-ethynylpyridin-2-ylamine is added and the mixture is agitated at this same temperature for 2 days. The mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 100 ml of water and extracted with three times 100 ml of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (50/50 by volume)]. 0.44 g of 5-chloro-3-(5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl)pyridin-2-ylamine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH2:27][CH:28]=O)=[CH:21][C:20]=2[Cl:30])=[O:17])[CH3:13])[CH2:8][CH2:7]1)=[O:4].C([O-])(=O)C.[Si:45]([O:52][C@H:53]([C:56]1[CH:65]=[CH:64][C:63]([OH:66])=[C:62]2[C:57]=1[CH:58]=[CH:59][C:60](=[O:67])[NH:61]2)[CH2:54][NH3+:55])([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46].C(NCCNC(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-]>CO>[OH:1][C:2]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([CH2:27][CH2:28][NH:55][CH2:54][C@H:53]([O:52][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[C:56]3[CH:65]=[CH:64][C:63]([OH:66])=[C:62]4[C:57]=3[CH:58]=[CH:59][C:60](=[O:67])[NH:61]4)=[CH:21][C:20]=2[Cl:30])=[O:17])[CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](C[NH3+])c1ccc(O)c2[nH]c(=O)ccc12
Reactant: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: CC(C)NCCNC(C)C
Solvent: CO
Product: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CCNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of trans-4-[(3-{[2-chloro-5-methoxy-4-(2-oxoethyl)phenyl]amino}-3-oxopropyl)(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 123; 173 mg, 0.16 mmol) in methanol (1.73 mL) was added (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethanaminium acetate (prepared according to preparation 8 from US20060035931) (78 mg, 0.2 mmol), diisopropylethylendiamine (0.03 mL, 0.2 mmol) and sodium triacetoxyborohydride (108 mg, 0.51 mmol). The reaction mixture was stirred for 2.5 hours at room temperature. At 0° C. the mixture was added into a 20 mL of bicarbonate 4%, then the crude was extracted with ethyl acetate, washed with water and brine, dried and the solvent was removed under reduced pressure. The crude obtained was purified by column chromatography with silica gel, eluting with methylen chloride/methanol (9:1) to give the title compound as a yellow solid (52%).