Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)CCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 88.6 %

Procedure:
A mixture consisting of 35 g of 4-nitrophenol, 35 g of chloroacetone, 35 g of potassium carbonate, 1 g of potassium iodide and 500 ml of acetone was heated at reflux with stirring for 3 hr. Reaction mixture was concentrated underd reduced pressure; the concentrate was extracted with ethyl acetate; the ethyl acetate layer was washed consecutively with 5% aqueous solution of sodium hydroxide, water and saturated saline; and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; the residue was dissolved in 300 ml of ethanol, added with 100 ml of n-hexane; and subsequently left standing overnight at room temperature. Yellow crystals thus isolated were filtered off, dried and yielded 43.5 g of 4-nitrophenoxyacetone.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=4)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:36]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH3:36][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH:19]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:21]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: N#Cc1ccc(-c2cc(COCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)c2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3′-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (18.3 mg, 0.04 mmol) and formaldehyde (37 wt. % solution in water, 86.4 μL, 3.22 mmol) were combined in acetonitrile (1.0 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (12.6 mg, 0.2 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 12.1 mg (65%). 1H-NMR (CDCl3, 500 MHz) δ 7.74-7.76 (m, 2H), 7.66 (s, 1H), 7.58-7.60 (m, 2H), 7.44 (s, 1H), 7.41 (s, 1H), 7.36-7.38 (m, 2H), 7.30-7.33 (m, 2H), 7.18-7.21 (m, 1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.58-2.60 (m, 2H), 2.17-2.28 (m, 4H), 2.21 (s, 3H), 1.98-2.08 (m, 2H). Mass spec.: 465.11 (MH)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[N:24][CH:25]=1.C[Si](C)(C)[C:31]([F:34])([F:33])[F:32]>C1COCC1.O>[Br:19][C:20]1[CH:21]=[C:22]([C:26]([OH:28])([CH3:27])[C:31]([F:34])([F:33])[F:32])[CH:23]=[N:24][CH:25]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(c1cncc(Br)c1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 33 μl, 0.033 mmol) was added to a solution of 1-(5-bromopyridin-3-yl)ethanone (65 mg, 0.33 mmol) and trimethyl(trifluoromethyl)silane (92 mg, 0.65 mmol) in THF (1.1 mL) at ambient temperature. After 30 minutes, the reaction mixture was diluted with water and extracted with DCM, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate/hexanes, linear gradient) to afford 2-(5-bromopyridin-3-yl)-1,1,1-trifluoropropan-2-ol. MS ESI calc'd. for C8H8BrF3NO [M+H]+ 270 and 272. found 270 and 272. 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 8.69 (d, J=2.5 Hz, 1H), 8.10-8.08 (m, 1H), 2.58 (s, 1H), 1.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:31]([OH:33])=O)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][C@@H:35]([CH2:44][CH2:45][CH3:46])[C@H:36]([OH:43])[C:37]([NH:39][CH:40]1[CH2:42][CH2:41]1)=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:28])([F:29])[F:30])(=[O:19])=[O:20])[CH2:15][C@H:14]3[C:31]([NH:34][C@@H:35]([CH2:44][CH2:45][CH3:46])[C:36](=[O:43])[C:37]([NH:39][CH:40]3[CH2:42][CH2:41]3)=[O:38])=[O:33])=[O:12])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide in step 1. MS (m/e)=668.18 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22].CO>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:24](=[O:25])[NH:23][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1cc(-c2ccc(O)cc2)cc2ccc(=O)[nH]c12
Reactant: CCCN=C=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCNC(=O)Oc1ccc(-c2cc(C)c3[nH]c(=O)ccc3c2)cc1

Procedure:
A solution of 8-methyl-6-[4-hydroxyphenyl]-2-(1H)-quinolone (0.30 g) and n-propylisocyanate (0.5 cm3) was heated under reflux in THF (10 cm3) under nitrogen for 50 hours. Methanol (10 cm3) was then added to dissolve solid material, followed by silica (Merck "MK 60.9385" [Trade Mark]) (10 g), and the volatile material was removed in vacuo. The residue was placed on top of a silica column (Merck "MK 60.9385") and eluted with chloroform:methanol, 19:1. Combination and evaporation of appropriate fractions in vacuo gave a solid which was recrystallised from propan-2-ol to afford the title compound, m.p. 224°-228°, (0.28 g).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1.O.C(OCC)(=O)C>C(O)(=O)C.O1CCCC1>[Br:1][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([OH:3])=[N:5][CH:6]=1
Reactant: Oc1nccc2ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Oc1ncc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Bromine (1.78 ml, 34.5 mmol) was added to an ice-cooled solution of 1-hydroxyisoquinoline (5.01 g, 34.5 mmol) in acetic acid (50 ml), and this reaction mixture was stirred at room temperature for 2 hours. Water, ethyl acetate, and tetrahydrofuran were added, and the resulting reaction mixture was filtered through filter paper. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to give the title compound (6.19 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:40]CC1.O>O=[Os](=O)(=O)=O>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OCC1Cc1ccccc1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
Dissolve 4-Benzyl-3-[2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (3.09 g, 5.89 mmol) in 3/1 mix of THF/water (100 ml). Add OsO4 (5.99 g, 0.59 mmol) and NaIO4 (3.82 g, 17.86 mmol). Stir the resulting suspension for 3 hr at room temperature. Quench with 1M solution of sodium thiosulfate (300 ml). Extract in ethyl acetate. Column separation affords 0.885 g (28.5%) of 4-(4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=2)=[CH:15][CH:14]=1.CCCCC.C(OCC)(=O)C>C(OCC)C.ClCCl.[O-2].[Mn+4].[O-2]>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([O:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:18][CH:17]=2)=[N:23][CH:24]=1
Reactant: COC(=O)CCCc1ccc(CCOc2ncnc3ccccc23)cc1
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCC
Product: OCCCCc1ccc(CCOc2ncnc3ccccc23)cc1
Reaction time: 0.25 h
Yield: 45.3 %

Procedure:
To a dry 15 mL flask was added lithium aluminum hydride (233 mg, 6.0 mmol) and anhydrous diethyl ether (3 mL). The mixture was cooled with an ice bath. A solution of Example 1C (538 mg, 1.54 mmol) in anhydrous diethyl ether (3 mL) was slowly added with vigorous stirring. The bath was removed and the slurry was stirred for 15 minutes. The reaction was quenched with water (0.233 mL), aqueous 15% sodium hydroxide (0.233 mL) and water (0.699 mL). The white solid was filtered and the filtrate was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a clear oil. The oil was then dissolved in anhydrous dichloromethane (10 mL) and manganese(IV) oxide (500 mg, 5.8 mmol) was added to the solution. The mixture was stirred for 12 hours. Filtration through diatomaceous earth (Celite®) followed by concentration of the filtrate under reduced pressure afforded 395 mg of crude product. Column chromatography [silica gel; eluent pentane-ethyl acetate (2:3)] provided the desired product (225 mg, 49%). 1H (CDCl3) δ(ppm): 1.55-1.61 (m, 2H); 1.65-1.68 (m, 2H); 2.61 (t, 2H); 3.17 (t, 2H); 3.64 (t, 2H); 4.79 (t, 2H); 7.12 (d, 2H); 7.23 (d, 2H); 7.56 (t, 1H); 7.82 (t, 1H); 7.93 (d, 1H); 8.14 (d, 1H); 8.77 (s, 1H). 13C (CDCl3) δ(ppm): 27.52, 32.31, 34.89, 35.21, 62.81, 67.74, 116.67, 123.54, 127.08, 127.49, 128.63, 128.98, 133.61, 135.23, 140.64, 150.68, 154.29, 166.79.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1)[CH3:2].[Cl-].[NH4+].O>C(O)C>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([S:3][CH2:1][CH3:2])=[N:5][CH:6]=1
Reactant: CCSc1ccc([N+](=O)[O-])cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCSc1ccc(N)cn1
Yield: 88.4 %

Procedure:
A mixture of 5.0 g of 2-ethylthio-5-nitropyridine, 27 g of ammonium chloride, 54 ml of water, and 108 ml of ethanol is heated to 70°-80° C., and 16.2 g of reduced iron is added slowly with stirring. The mixture is stirred at the same temperature for 45 minutes. The hot reaction mixture is filtered, and the filtrate is concentrated. To the residue is added 50 ml of water, and the mixture is extracted with three 50-ml portions of chloroform. The combined extracts are washed with water, dried over magnesium sulfate and concentrated to give 3.7 g of crude 5-amino-2-ethylthiopyridine.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]>C(O)C.[Pd]>[C:1]([CH2:3][CH2:4][C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: CCOC(=O)C=CC(CCC#N)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(CCC#N)(c1ccccc1)c1ccccc1
Yield: 87.8 %

Procedure:
A solution of ethyl 6-cyano-4,4-diphenyl-hex-2-enoate (22.06 g) in ethanol (500 mL) was hydrogenated in the presence of 10% Pd/C (2.2 g) under 4 atmospheric pressure for 17 hr. The catalyst was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography eluting with (95:5) hexane/ethyl acetate. The desired product (19.49 g) was obtained as colorless oil: MS showed (M+NH4)+ @ 339; 1H-NMR (CDCl3, δ): 1.20-1.25 (t, 3H), 1.95-2.06 (m, 4H), 2.38-2.52 (m, 4H), 4.03-4.12 (m, 2H), 7.10-7.36 (m, 1OH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39]>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([O:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[I:32])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccccc3I)n2)cc1Cl
Temperature: 80 °C
Yield: 94.7 %

Procedure:
A mixture of compound 133 (1.75 g, 4.57 mmol), potassium carbonate (3.15 g, 22.85 mmol) in dimethylformamide (8 mL) was added 2-iodophenol (1.20 g, 5.48 mmol). It is heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound as white solid (2.45 g, 95%). mp 206-208° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 5/60, 15/80, 30/80, 35/60, 40/60; 230 nm, Rt 26.65 min, 98.30% purity; MS (CI): m/z 566 (M+H, 100).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][C:25]1[N:26]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]=2)[CH:27]=[CH:28][N:29]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:33]5[CH:32]=[N:31][C:30]([N:26]6[CH:27]=[CH:28][N:29]=[C:25]6[CH3:24])=[CH:35][CH:34]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: Cc1nccn1-c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(-n5ccnc5C)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-(2-methyl-imidazol-1-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 78.1.1) to give the title compound as a white solid. (HPLC: tR 2.10 min (Method A); M+H=451 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.68-8.66 (m, 1H), 8.18-8.13 (m, 2H), 8.09-8.00 (m, 2H), 7.78-7.74 (m, 1H), 7.63-7.59 (m, 2H), 6.94-6.93 (m, 1H), 3.93 (s, 3H), 3.59 (s, 3H), 2.54 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: CN(C)CCN
Product: Cc1cc(C)c(C#N)c(NCCN(C)C)n1
Temperature: 105 °C

Procedure:
A mixture of 2-chloro-3-cyano-4,6-dimethylpyridine (10.0 g, 60 mmol) and N,N-dimethyl-1,2-diaminoethane (10.6 g, 120 mmol) is heated at 105° C. for 20 hours. Added benzene, evaporated to dryness, dissolved residue in water, made basic with sodium carbonate and extract product into methylene chloride, dried and evaporated to give 13.4 g of oily title A product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(=O)[O:11][CH2:10][CH2:9][O:8]1.[C:13]1([C:23]2[N:28]=[N:27][N:26]=[C:25]([C:29]3[CH:34]=[CH:33]C(O)=[CH:31][C:30]=3[OH:36])[C:24]=2[C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([C:23]2[N:28]=[N:27][N:26]=[C:25]([C:29]3[CH:34]=[CH:33][C:7]([O:11][CH2:10][CH2:9][OH:8])=[CH:31][C:30]=3[OH:36])[C:24]=2[C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Temperature: 140 °C

Procedure:
9.39 g of potassium carbonate and 4.39 g of ethylene carbonate are added to 20 g of the product from Example A6 in 200 ml of anhydrous DMF. The reaction mixture is heated at 140° C. for 18 h. The salts which precipitate are filtered off and washed with toluene. The combined organic phase is freed of solvent in vac. and used directly for the further reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[C-:9]#[N:10]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Br)c1
Reactant: [C-]#N
Solvent: c1ccncc1
Product: N#Cc1ncccc1Br

Procedure:
In Scheme I is described the preparation of pyridine intermediates (5) and (6). In Scheme I, Step 1,3-bromopyridine (1) is oxidized to 3-bromo-pyridine-N-oxide (2). In Scheme I, Step 2, cyanide addition gives 3-bromo-pyridine-2-carbonitrile (3). The nitrile of formula (3) is hydrolyzed to the carboxylic acid and esterified with acid catalysis to the ester of formula (4). In Scheme I, Step 4, the ester is reduced to the pyridylmethanol of formula (5a) using sodium borohydride.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: OCCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 21.1, 4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol and methanesulfonic acid chloride were converted to yield Methanesulfonic acid 4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester, MS: 430 (MH+).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].Br[CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.C(OCC)(=O)C>CN(C)C=O>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11]
Reactant: O=c1ccc2ccncc2[nH]1
Reactant: BrCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccc2ccncc2n1CC1OCCO1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a suspension of 6.0 g of 1,7-naphthyridin-2(1H)-one in 60 mL of N,N-dimethylformamide, 2.5 g of 60% sodium hydride was added at room temperature, and the mixture was stirred at 50 to 60° C. for 1 hour. Thereto was added 6.4 mL of 2-bromomethyl-1,3-dioxolan, the temperature was increased to 90 to 95° C., and the reaction mixture was stirred for 2 hours 30 minutes. The temperature was further increased to 95 to 100° C., and the mixture was stirred for 4 hours. Thereto were added 0.82 g of 60% sodium hydride and 2.1 mL of 2-bromomethyl-1,3-dioxolan and the mixture was further stirred at the same temperature for 2 hours. Thereto were added 0.49 g of 60% sodium hydride and 1.3 mL of 2-bromomethyl-1,3-dioxolan and the mixture was stirred at 90 to 100° C. for 2 hours. Thereto were further added 0.49 g of 60% sodium hydride and 1.3 mL of 2-bromomethyl-1,3-dioxolan and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was cooled to 5° C., and ethyl acetate and ice water were then added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=100:0 to 0:100 and then, using gradient elution with chloroform:methanol=100:0 to 90:10 to obtain 3.1 g of 1-(1,3-dioxolan-2-ylmethyl)-1,7-naphthyridin-2(1H)-one as a brown solid.
Reaction SMILES: [OH:1][C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.O[C@H]1O[C@H]([C@@H](CO)O)[C@H](O)[C@H]1O.O[C@@H]1O[C@H]([C@@H](CO)O)[C@H](O)[C@H]1O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: OC[C@@H](O)[C@H]1O[C@@H](O)[C@H](O)[C@H]1O
Agent: OC[C@@H](O)[C@H]1O[C@H](O)[C@H](O)[C@H]1O
Agent: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
α-D-glucopyranose; β-D-glucopyranose; α-D-glucofuranose; β-D-glucofuranose
Reaction SMILES: CN(C)CCN.[CH:7]1([CH2:13][O:14][N:15]2C(=O)C3=CC=CC=C3C2=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])=[C:33]([C:45](=O)[CH2:46][CH3:47])[CH:32]=1>CCO>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])=[C:33]([C:45](=[N:15][O:14][CH2:13][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:46][CH3:47])[CH:32]=1
Reactant: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(=NOCC1CCCCC1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
N,N-Dimethylethylenediamine (1.53 mL, 13.18 mmol) was added to a solution of N-(cyclohexylmethoxy)phthalimide (2.33 g, 8.99 mmol) in EtOH (30 mL), and the reaction allowed to stir at RT for 2 hours. Glacial acetic acid (5 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (1.89 g, 5.99 mmol) in EtOH (10 mL), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl2/PE, 3:4 to 1:3) to afford N-[4-chloro-2-(1-cyclohexylmethoxyiminopropyl)phenyl]trifluoromethanesulfonamide 104 (2.34 g, 91%), as colorless crystals. 1H n.m.r. (400 MHz, CDCl3) δ 12.01, br s, 1H; 7.67, d, J=8.8 Hz, 1H; 7.48, d, J=2.4 Hz, 1H; 7.32, dd, J=2.4 and 8.8 Hz, 1H; 4.02, d, J=6 Hz, 2H; 2.81, q, J=7.6Hz, 2H; 1.74, m, 6H; 1.27, m, 3H; 1.19, t, J=7.6Hz, 3H; 1.01, m, 2H. HRMS (M+) 426.0971.