Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[C@H:6]([OH:8])[CH3:7].[C:15]([O-])(=[O:19])[CH2:16]CC.C(OC(=O)C)(=O)C.N1C=CC=CC=1>>[C:15]([O:8][C@@H:6](/[CH:5]=[CH:4]/[CH2:3][C@H:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:7])(=[O:19])[CH3:16]
Reactant: CCCC(=O)[O-]
Reactant: CC(C)=CCC[C@@H](C)C/C=C/[C@@H](C)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H](C)/C=C/C[C@H](C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99 %

Procedure:
A flame-dried 100 mL, three-necked flask with magnetic stirring bar was charged under argon with 2.0 g (10.2 mmol) of (2R,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol [(2R,6R)/(2S,6R)=90;10 by GC diastereomer analysis of butyrate derivative]. Then, after cooling in an ice-bath, 1.5 g (1.4 mL, 15 mmol) of acetic anhydride, 1.58 g (1.6 mL, 20 mmol) of dry pyridine and 12.3 mg (0.1 mmol) of 4-N,N-dimethylaminopyridine were added, and the reaction was stirred for 75 minutes at ambient temperature. Work-up as described in Example 9 followed by Kugelrohr distillation at ca. 110°/0.25 mm afforded 2.35 g (99%) of (2R,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol acetate as colorless liquid; GC purity 90%; [α]D25 =+47.17° (5.3% in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[C:21]([C:22]4[CH:23]=[C:24]([C:30]5[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][C:31]=5[CH3:40])[CH:25]=[CH:26][C:27]=4[O:28][CH3:29])=[CH:20][N:19]=[C:18](SC)[N:17]=3)[C@H:10]2[CH3:43])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:45]1C=CC=C(C(OO)=O)C=1.[S:55]([O-:59])([O-])(=[O:57])=S.[Na+].[Na+]>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[C:21]([C:22]4[CH:23]=[C:24]([C:30]5[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][C:31]=5[CH3:40])[CH:25]=[CH:26][C:27]=4[O:28][CH3:29])=[CH:20][N:19]=[C:18]([S:55]([CH3:45])(=[O:59])=[O:57])[N:17]=3)[C@H:10]2[CH3:43])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=S([O-])([O-])=S
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Temperature: 25 °C

Procedure:
To methyl 3′-[4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-(methylsulfanyl)pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (294 mg, 0.46 mmol) in DCM (5 mL) at 0° C. was added m-chloroperbenzoic acid (319 mg, 1.381 mmol). The reaction was allowed to warm to room temperature and was diluted with DCM and sat'd sodium thiosulfate solution. The organic was washed with sat'd NaHCO3, brine, dried (Na2SO4) concentrate before purification by column chromatography to yield methyl 3′-[4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-(methylsulfonyl)pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (292 mg, 0.435 mmol). LCMS calc.=670.2. found=670.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.N1C=CC=CC=1>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: ClCC1CO1
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(OCC2CO2)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
A mixture of methyl 4-hydroxyphenylacetate (4.98 g, 0.030 mol), epichlorohydrin (23.5 ml, 0.30 mol) and pyridine (121 μl, 1.5 mmol) was stirred at 85° C. for 2 hours. The reaction mixture was cooled and excess epichlorohydrin was distilled off (rotavapor). The residue was taken up in ethyl acetate, washed with brine and dried (Na2SO4). The solution was filtered and concentrated. The dark residue was chromatographed (silica, hexane/ethyl acetate 7:3) to give 2.25 g (34%) of a colourless oil. 1H (300 MHz) and 13C NMR (75 MHz) spectra were in accordance with the structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].N[C:16](N)=[O:17].N.[CH2:20]([OH:22])[CH3:21]>>[CH2:10]([O:9][Si:5]([CH2:4][CH2:3][CH2:2][NH:1][C:16](=[O:17])[O:22][CH2:20][CH3:21])([O:12][CH2:13][CH3:14])[O:6][CH2:7][CH3:8])[CH3:11]
Reactant: NC(N)=O
Reactant: CCO
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: N
Product: CCOC(=O)NCCC[Si](OCC)(OCC)OCC

Procedure:
In a 10 L distillation autoclave, 3-aminopropyltriethoxysilane (3321 g, 15 mol) are brought to reaction with urea (928 g, 15.45 mol) and ethanol (3458 g, 75 mol) at 230° C. and pressure between 35 and 23 bar. The resultant ammonia is continuously stripped out by the ethanol vapors.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])#[N:3]>C1COCC1>[C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:1])=[O:8])#[N:3]
Reactant: N
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(C(N)=O)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of 28% aqueous ammonia (20 ml) and THF (30 ml) was cooled to 5° C. and 3-cyanobenzoyl chloride (1.45 g) was slowly added. The mixture was stirred for one hr. and the reaction mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was recrystallized from ethyl acetate to give the title compound (802 mg) as colorless needle crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](#[N:13])[CH:11]=[CH2:12].C(N(CC)C(C)C)(C)C>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:12][CH2:11][C:10]#[N:13])=[CH:5][CH:4]=1
Reactant: C=CC#N
Reactant: COc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(OCCC#N)cc1

Procedure:
That is, 4-methoxyphenol (a) is reacted with acrylonitrile (b) in the presence of a base such as Triton B, triethylamine, N,N-diisopropylethylamine or the like, at 25 to 120° C. for 1 to 72 hours to obtain 3-(4-methoxyphenoxy)propionitrile (c), and the resultant is either reduced in a solvent such as tetrahydrofuran, dioxane or the like at 25 to 100° C. using a borane-tetrahydrofuran complex, a borane-dimethylsulfide complex, lithium aluminum hydride or the like, or reduced in a hydrogen atmosphere or in the presence of ammonia, using a catalyst such as Raney nickel or the like, thus to obtain 3-(4-methoxyphenoxy)propylamine (d). Subsequently, the resultant is reacted with 3-hydroxybenzaldehyde (e) in a solvent such as methanol, ethanol, isopropyl alcohol, tetrahydrofuran, toluene, acetonitrile or the like, and then the resultant is reduced using a reducing agent such as sodium borohydride, sodium triacetoxy borohydride or the like to obtain N-(3-(4-methoxyphenoxy)propyl)-3-hydroxybenzylamine (f). This is reacted with 2-chlorobenzoxazole (g) in a solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate or the like, in the presence of an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate or the like, or an organic base such as triethylamine, N,N-diisopropylethylamine, pyridine or the like, thus to obtain N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydrox ybenzylamine (compound (2)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17](=[O:19])[NH2:18])[CH:12]=1)[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]>CO.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17](=[O:19])[NH2:18])[CH2:12]1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1ccnc(C(N)=O)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](NC(=O)OC(C)(C)C)C1CCNC(C(N)=O)C1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of [(S)-1-(2-carbamoyl-pyridin-4-yl)-propyl]-carbamic acid tert-butyl ester (1 g, 3.58 mmol) in MeOH (16.6 mL) and glacial acetic acid (3.3 mL) was added to a flask containing 10% palladium on carbon (0.38 g, 0.36 mmol) under nitrogen. The reaction was stirred at 60° C. under hydrogen at 400 psi using a Biotage Endeavour Argonaut instrument. After 20 hours, the reaction was filtered and concentrated. The crude material was diluted with EtOAc (100 mL), washed with saturated sodium carbonate solution (20 mL), brine, dried over sodium sulfate, filtered and concentrated to afford [(S)-1-(2-carbamoyl-piperidin-4-yl)-propyl]-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1.[Cl:17][Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].C(OCC)C>C1COCC1>[Cl:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1
Reactant: COCOc1ccc(Br)cc1
Reactant: CC(C)[Si](Cl)(Cl)C(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCOc1ccc([Si](Cl)(C(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 71.2 %

Procedure:
A solution of n-butyllithium (1.6M, 72.50 mL, 0.116 mol) was added slowly dropwise to a solution of bromo-4-methoxymethoxybenzene (25.23 g, 0.116 mol) in dry THF (110 mL) at −78° C. After stirring for 50 min at −78° C., dichlorodiisopropylsilane (21.00 mL, 0.116 mol) was charged into the flask. The reaction mixture was slowly allowed to warm to room temperature with stirring. Diethyl ether (100 mL) was added, the mixture was then stirred for 15 min and filtered. The filtrate was concentrated in vacuo to an oil. The oil was purified by short path distillation (116-128° C./0.18 mm Hg) to afford the compound (23.7 g, 71%) as a slightly cloudy pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1CCO[CH:9]1[CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[CH:17]=[CH:16][C:15]1=[O:26].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18]([CH:17]=[CH:16][C:15](=[O:26])[N:14]2[CH2:13][CH:9]=[O:8])=[N:19][CH:20]=1
Reactant: COc1cnc2ccc(=O)n(CC3OCCO3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CC=O)c2c1

Procedure:
To 184 mL of 80% trifluoroacetic acid, 4.60 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one was dissolved, and the resultant solution was stirred at room temperature for 11 hours and at 60° C. for 3.5 hours. The reaction mixture was charged with chloroform and alkalified with a 10% aqueous sodium hydroxide solution under cooling with ice. The organic layer was separated, and washed with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH3:23])[NH:8][C:7]=1[NH2:24])=[O:5])[CH3:2].[CH3:25]C[O-].[Na+].CI>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH3:25])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH3:23])[N:8]=[C:7]1[NH2:24])=[O:5])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1ccccc1
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)C1=C(C)N=C(N)C(C)(C(=O)OCC)C1c1ccccc1
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A solution of 33.0 g of 2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol is brought to the boil and treated with 15 g of methyl iodide. After boiling for a further 60 minutes under reflux, the mixture is concentrated by distillation and the residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water. Concentration of the organic phase and recrystallization from ethanol gives 18.6 g (54% of theory) of 2-amino-3,6-dimethyl-4-phenyl-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 139° C.
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H:18]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[CH:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:42])=[N:40][CH:41]=1>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[N:6](/[CH:34]=[C:35](/[C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][CH:37]=3)\[CH3:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc(C=CBr)cn1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)C(C)C2)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,3,8-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (107 mg, 0.5 mmol) was dissolved in DMF. Copper (I) iodide (9.5 mg, 0.05 mmol), L-proline (11.5 mg, 0.1 mmol) and potassium phosphate (414 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 5-(2-bromovinyl)-2-methylpyridine (116 mg, 0.55 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 100° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-7% MeOH-DCM. Yield: 125 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.78 (s, 1H), 8.22 (d, 1H), 7.90 (s, 1H), 7.58 (d, 1H), 7.30 (s, 1H), 7.18 (d, 1H), 7.10 (d, 1H), 4.60 (m, 2H), 4.0 (m, 1H), 3.30 (m, 1H), 3.05 (m, 3H), 2.95 (m, 1H), 2.65 (s, 3H), 2.42 (s, 3H), 2.0 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.Cl.[F:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:25][C:26](O)=[O:27].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:26](=[O:27])[CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[N:17]=[CH:16][C:15]([F:14])=[CH:24]3)[S:5][CH:6]=1
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Reactant: O=C(O)Cc1cccc2cc(F)cnc12
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc2cc(F)cnc12)Nc1scc(Br)c1-c1nc[nH]n1
Reaction time: 1 h

Procedure:
4-Bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (17 mg, 69.4 umol), 2-(3-fluoroquinolin-8-yl)acetic acid hydrogen chloride (22 mg, 91.0 umol), 2-chloro-1-methylpyridinium iodide (101 mg, 395 umol) and triethylamine (0.2 ml) in methylene chloride (1 ml) was heated to reflux. After stirring for 1 h, the solution was concentrated and the residue was purified by HPLC to yield N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3-fluoroquinolin-8-yl)acetamide. Method [7] retention time 5.67 min by HPLC (M+432 and 434) and (M+Na 454 and 456). 1H NMR (300 MHz, CDCl3) δ 12.25 (s, 1H), 8.83 (d, J=3.3 Hz, 1H), 7.87 (m, 2H), 7.80 (d, J=6.0 Hz, 1H), 7.73 (s, 1H), 7.66 (t, J=7.8 Hz, 1H), 6.90 (s, 1H), 6.70 (broad s, 2H), 4.56 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[C:8]([CH3:13])([CH3:12])[C:7]=2[CH:14]=1)#[N:2].[CH3:15][NH:16][CH3:17]>C(OCC)C.C(O)C>[OH:10][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:14][C:7]=1[C:8]([CH3:13])([CH3:12])[C:9]([N:16]([CH3:17])[CH3:15])=[O:11]
Reactant: CC1(C)C(=O)Oc2ccc(C#N)cc21
Reactant: CNC
Solvent: CCOCC
Solvent: CCO
Product: CN(C)C(=O)C(C)(C)c1cc(C#N)ccc1O
Temperature: 25 °C

Procedure:
A suspension of 5-cyano-2,3-dihydro-3,3-dimethylbenzofuran-2-one (3.7 g), prepared as in Example 3, in diethyl ether (50 ml) was treated with a solution of dimethylamine in ethanol (8.6 ml of a 20.8% solution) portionwise with stirring at room temperature. The mixture was stirred for two hours, and the product was isolated by filtration, yield 4 g, mp 146°-148° C.
Reaction SMILES: [NH:1]([C:5]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C(C)=O.[OH-].[Na+].C([OH:23])C>O>[NH2:1][C:5]1[CH:16]=[CH:15][C:14]([C:17](=[O:23])[NH2:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: CCN(CC)Cc1cc(C#N)ccc1NC(C)=O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)Cc1cc(C(N)=O)ccc1N
Reaction time: 4 h

Procedure:
A mixture of 10 gm of 2-acetamino-5-cyano-N,N-diethyl-benzylamine, 100 ml of 5 N sodium hydroxide and 70 ml of ethanol was boiled for 4 hours. Thereafter, the reaction solution was cooled, diluted with 200 ml of water and extracted three times with 250 ml of chloroform each. The combined chloroform extracts were dried over sodium sulfate and evaporated in vacuo, and the residue was recrystallized from ethanol. The 2-amino-5-carbamoyl-N,N-diethyl-benzylamine of m.p. 129°-131°C was obtained.
Reaction SMILES: [C:1]([C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([C:9]2[C:19]([CH2:20][CH:21](O)[CH3:22])=[CH:18][CH:17]=[C:11]3[C:12]([NH:14][C:15](=[O:16])[C:10]=23)=[O:13])[CH2:5][CH2:4]1)#[N:2].C(N(S(F)(F)[F:36])CC)C>C1C=CC=CC=1>[C:1]([C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([C:9]2[C:19]([CH2:20][CH:21]([F:36])[CH3:22])=[CH:18][CH:17]=[C:11]3[C:12]([NH:14][C:15](=[O:16])[C:10]=23)=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(O)Cc1ccc2c(c1N1CCC(C#N)(c3ccccc3)CC1)C(=O)NC2=O
Reactant: CCN(CC)S(F)(F)F
Solvent: c1ccccc1
Product: CC(F)Cc1ccc2c(c1N1CCC(C#N)(c3ccccc3)CC1)C(=O)NC2=O
Temperature: 70 °C
Yield: 54.4 %

Procedure:
A mixture of 3-(4-cyano-4-phenylpiperidin-1-yl)-(2-hydroxypropyl)phthalimide (2.60 g, 6.1 mmol) and diethylaminosulfur trifluoride (DAST, 1.96 g, 12.2 mmol) in benzene (100 mL) was stirred and heated at 70° C. under argon atmosphere for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (1000/28/14) as the eluent, to obtain the desired product as a viscous oil (1.30 g, 50%).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[C:9]([C:22]1[C:26]([CH3:27])=[CH:25][N:24]([CH2:28][C:29]2[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=2)/[CH:32]=[CH:33]/[C:34]([O-:36])=[O:35])[C:23]=1[CH3:40])(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:41]1(C)C=CC=C[CH:42]=1>[Cu]>[C:9]([C:22]1[C:26]([CH3:27])=[C:25]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:24]([CH2:28][C:29]2[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=2)/[CH:32]=[CH:33]/[C:34]([O:36][CH2:41][CH3:42])=[O:35])[C:23]=1[CH3:40])(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCC(=O)c1c(C)cn(Cc2cccc(/C=C/C(=O)[O-])c2)c1C
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Product: CCCCCCCCCCCC(=O)c1c(C)c(CC(=O)OCC)n(Cc2cccc(/C=C/C(=O)OCC)c2)c1C

Procedure:
0.24 ml of ethyl diazoacetate is added in portions each of 0.08 ml over the course of 15 min to a stirred solution of 233 mg (0.5 mmol) of (E)-3-[(3-dodecanoyl-2,4-dimethylpyrrol-1-yl)methyl]cinnamate in 3 ml of absol. Toluene at a bath temperature of 115-120° C. After each of these additions of ethyl diazoacetate a spatula tip of copper powder is added. The mixture is then heated for a further 5 min. After cooling and after addition of a little petroleum ether, the complete mixture is loaded onto a silica gel column; elution takes place with petroleum ether/ethyl acetate 9+1. The product fractions are concentrated, leaving a waxy substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][S:25](Cl)(=[O:27])=[O:26])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:25]([CH2:24][C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)(=[O:26])=[O:27])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=S(=O)(Cl)Cc1ccc(F)cc1
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)Cc3ccc(F)cc3)c2)cc1Cl
Yield: 23.5 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added (4-fluoro-phenyl)-methanesulfonyl chloride (20 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-1-(4-fluoro-phenyl)-methanesulfonamide (8.2 mg, >95% purity, yield: 23.4%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 2): ESI-MS m/z: 402 [M+H]+, retention time=2.24 min, 1H NMR (400 MHz, DMSO-d6) δ ppm 4.67 (s, 2H) 7.09-7.16 (m, 2H) 7.29-7.37 (m, 2H) 7.66 (t, J=2.27 Hz, 1H) 7.78 (dd, J=8.15, 1.71 Hz, 1H) 8.02 (d, J=1.64 Hz, 1H) 8.09 (d, J=8.08 Hz, 1H) 8.34 (d, J=2.40 Hz, 1H) 8.61 (d, J=2.02 Hz, 1H) 10.24 (br. s., 1H).
Reaction SMILES: C[NH2:2].[O:3]([CH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[CH2:15]C1C=CC=C2C(NC(=O)C=12)=O)[Si:4]([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>C(O)C>[O:3]([CH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[CH2:15][NH2:2])[Si:4]([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Cc2cccc3c2C(=O)NC3=O)c1
Reactant: CN
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
Methylamine (a 30% ethanol solution, 400 mL) was added to a solution of 3-(tert-butyldimethylsiloxymethyl)benzylphthalimide (11.93 g, 31.3 mmol) in ethanol (200 mL) at room temperature, and the resulting mixture was stirred at room temperature for 5 minutes and then at 90° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diethyl ether and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure at 20° C. and the residue was diluted with diethyl ether (300 mL), and ultrasonic waves were applied thereto for 1 hour. The resulting cloudy liquid was filtered and the filtrate was concentrated under reduced pressure at 20° C. to obtain the title compound (6.23 g, 79%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][C:26](=[O:28])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[BH4-].[Na+]>O1CCCC1.C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:25][C@H:26]([OH:28])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@@H](O)C1

Procedure:
A solution of 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanone (0.208 g, 0.00056 mol) in tetrahydrofuran (10 mL) and absolute ethanol (5 mL) was reacted with sodium borohydride (0.021 g, 0.00056 mol) at room temperature for four hours. Added water (5 mL) and extracted with ethyl acetate (3×15 mL). The combined organics were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (98:2). The solvent was removed in vacuo to give cis 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanol (0.090 g, 0.00024 mol) as a white solid.