Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:10][CH2:9][CH2:8][C@H:7]([OH:11])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: OCC[C@H](O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H](O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of (S)-1-phenylpropane-1,3-diol (500 mg, 3.28 mmol) and triethylamine (399 mg, 3.94 mmol) in CH2Cl2 (5 mL) was added 4-methylbenzene-1-sulfonyl chloride (626 mg, 3.28 mol) slowly at 0° C., and the reaction mixture was stirred at rt for 2 h. The reaction solution was dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC (3:1 Petroleum ether/EtOAc) to give (S)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (576 mg, 57%). 1H NMR (400 MHz, CDCl3): δ=1.91-2.00 (m, 3H), 2.48 (s, 2H), 4.00 (m; 1H), 4.22 (m, 1H), 4.75 (m, 2H), 7.25-7.30 (m, 7H), 7.75 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])C.[OH-].[K+].[Mn]([O-])(=O)(=O)=O.[K+].S(=O)(O)[O-].[Na+].C(N(CC)CC)C.Cl[C:32]([O:34][CH3:35])=[O:33]>O.ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[C:32]([O:34][CH3:35])=[O:33]
Reactant: CC(=O)c1ccccc1C
Reactant: COC(=O)Cl
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)c1ccccc1C
Reaction time: 2 h

Procedure:
1.4 g (10 millimoles) of ortho-methylacetophenone, 2.0 g of potassium hydroxide, 200 ml of pyridine and 100 ml of water are initially taken at +10° C. 5 g of potassium permanganate in 250 ml of water are added dropwise and the mixture is stirred for 2 hours at this temperature. Thereafter, sodium bisulfite solution is added dropwise until the red coloration of the mixture vanishes. The mixture is filtered, the filtrate is acidified with concentrated hydrochloric acid and filtered again and this filtrate is extracted with 5×50 ml of methyl tert-butyl ether. The organic phase is dried over sodium sulfate and evaporated down and the residue is then directly reacted further (ratio of ketoacid to benzoic acid 8-9:1 according to 1H-NMR). 2.0 g of the above mixture in 20 ml of dichloromethane are initially taken and 1.6 g (16 millimoles) of triethylamine are added. 1.5 g (16 millimoles) of methyl chloroformate are added dropwise at room temperature. After 1 hour at this temperature, the mixture is extracted with phosphate buffer (pH 7) and evaporation and distillation are carried out.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>CN(C=O)C>[N:1]1([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1
Reaction time: 0.17 h

Procedure:
To imidazole (7 gm, 103 mmol) suspended in degassed DMF (250 mL) under argon was added NaH 60% dispersion in mineral oil (4.53 gm, 113 mmol) with stirring for 10 minutes. A solution of 4-bromomethyl benzonitrile in 50 mL of DMF was added and the reaction was stirred for 16 hrs. The reaction was quenched with the addition of 20 mL of water and the solvent was removed in vacuo. The residue was suspended in methylene chloride (500 mL) and extracted 3 times with water (200 mL) and the organic layer was dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. The residue was chromatographed on silica gel with methylene chloride to remove the oil followed by 95:5 methylene chloride: methanol. The resulting fractions where reduced to a small volume in vacuo and the product spontaneously crystallized. The crystals were filtered to give the desired product.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.[C:15]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH:23][C:24]1[N:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1)=[O:22]>>[S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][N:5]([C:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:16]4[C:15]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:22])=[N:29][CH:28]=3)=[O:31])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Reactant: c1ccc2c(c1)CNc1ccsc1C2
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3sccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 12, 5,10-dihydro-4H-thieno[3,2-c][2]benzazepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1.N1C=CC=CC=1>ClCCl.CN(C)C=O>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:6]([C:5]2[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[C:4]=2[N+:16]([O-:18])=[O:17])=[O:8])=[N:27][CH:28]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(C(=O)Nc2ccc(Br)cn2)c([N+](=O)[O-])c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4,5-trimethoxy-2-nitrobenzoic acid (0.5 g, 1.95 mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.34 ml, 3.9 mmol) and a few drops of dimethylformamide. The mixture was stirred at r.t. for 2 hrs. After the evaporation of the solvent, the residue was dissolved in dichloromethane (5 ml). 2-amino-5-bromopyridine (0.81 g, 4.7 mmol) and pyridine (0.94 ml, 11.7 mmol) were added to the solution. The mixture was stirred at r.t. overnight. After the evaporation of the solvent, the crude residue was purified by silica gel column chromatography using solvent system 25% ethyl acetate in hexane as eluent to give N-(5-bromo(2-pyridyl))(3,4,5-trimethoxy-2-nitrophenyl)carboxamide as a solid (790 mg; 98%). MS found for C15H14BrN3O6 M+=412, (M+2)+=414.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[OH:11][CH:12]([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=2)[N:36]=[CH:35][CH:34]=1)[CH2:13][CH2:14][C@@H:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]#[C:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][C@@H:16]1[C:29](OC)=[O:30].[Cl-].[NH4+]>C1(C)C=CC=CC=1.ClCCl>[OH:30][CH2:29][C@@H:16]1[C@H:15]([CH2:14][CH2:13][CH:12]([OH:11])[C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:43][CH3:44])[CH:41]=3)[N:36]=[CH:35][CH:34]=2)[CH2:20][CH2:19][N:18]([CH2:21][C:22]#[C:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:17]1
Reactant: COC(=O)[C@H]1CN(CC#Cc2cccs2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4cccs4)C[C@@H]3CO)c2c1
Temperature: -20 °C
Yield: 36.1 %

Procedure:
4.2 cm3 of a 20% solution of diisobutylaluminum hydride in toluene were added to a mixture, cooled to −20° C., with stirring, of 0.5 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-carboxylate in 10 cm3 of toluene. Stirring was maintained for 3 hours at this temperature and then 15 cm3 of a saturated ammonium chloride solution were added, stirring was maintained for 15 minutes and the temperature was allowed to rise to a temperature in the region of 20° C. The aqueous phase was separated by settling, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2 kPa). The residue obtained was purified by chromatography on a column of silica gel (particle size 20-45 μm; diameter 2 cm; height 20 cm), elution was carried out, under a pressure of 50 kPa of nitrogen, with dichloromethane and then a mixture of dichloromethane and methanol (95/5 by volume), and 30-cm3 fractions were collected. Fractions 14 to 16 were combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 5 cm3 of dichloromethane and filtered. The filtrate was concentrated to dryness under reduced pressure (2 kPa). 0.17 g of (3R,4R)-3-hydroxymethyl-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine was obtained in the form of a gum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2OS(C(F)(F)F)(=O)=O)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)CCC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.CCOC(C)=O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:18][CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=2)[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccn2)c(-c2ccc(Cl)c(OCc3ccccc3)c2)n1
Temperature: 90 °C
Yield: 55.7 %

Procedure:
Stir a suspension of 0.5 g (1 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate, 0.44 g (1.2 mmol) of 2-tri-n-butylstannylpyridine and 42 mg (1 mmol) of anhydrous lithium chloride in 2 mL of anhydrous DMF for 10 min while bubbling with argon, then add 9.5 mg (0.05 mmol) of CuI, 45 mg (0.05 mmol) of Pd2(dba)3 and 27 mg (0.05 mmol) of PdCl2 (dppf) and then heat the reaction mixture to 90° C. After stirring for 5 h at 90° C., cool the mixture to RT, take up in 30 ml of EtOAc, treat and stir for 15 minutes with 30 mL of a 5 wt. % aqueous solution of potassium fluoride. Then filter the two-phase mixture on a bed of celite, and rinse the celite with 30 mL of EtOAc. Wash the organic phase with 4×60 mL of water, dry over Na2SO4 and concentrate at reduced pressure. Purify the residue obtained by chromatography on a silica column, eluting with a toluene/EtOAc gradient from 0 to 15% of EtOAc. After concentration under reduced pressure, we obtain 240 mg of methyl 2′-[3-(benzyloxy)-4-chlorophenyl]-2,3′-bipyridine-6′-carboxylate in the form of oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17]>CC(C)=O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:16][CH3:17])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCI
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1ncc(Cl)c(Cl)c1=O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a suspension of 4.00 g (24.2 mmol) of 4,5-dichloro-2H-pyridazin-3-one (CAS: [932-22-9]) and 6.70 g (48.5 mmol) of potassium carbonate in 40 ml of acetone were added 3.92 ml (7.56 g, 48.5 mmol, 2 eq.) of ethyl iodide. The suspension was stirred for 8 h at 55° C. and allowed to cool to room temperature. The reaction was filtered and the solids were washed twice with acetone. The filtrate was concentrated in vaccuo, taken up in ethyl acetate and the precipitated salts were filtered off. The filtrate was concentrated in vaccuo, taken up in methylene chloride and purified by flash chromatography (SiO2, heptane:ethyl acetate 80:20 v/v) to yield the title compound as a light yellow crystalline solid.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]([CH2:18][OH:19])([OH:17])[CH2:4]1)[CH3:2]>C(O)C.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH2:6][C:5]([CH2:18][OH:19])([OH:17])[CH2:4][N:3]([CH2:1][CH3:2])[C:9]=2[CH:10]=1
Reactant: CCN1CC(O)(CO)COc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CCN1CC(O)(CO)COc2ccc(N)cc21

Procedure:
Hydrogenation of 9-Ethyl-7-hydroxymethyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ol (0.225 g, 0.839 mmol) in Ethanol (15 mL) with 10% Palladium on Carbon (50% Wet) (89 mg) under an atmosphere of Hydrogen (40 psi) for 6 h followed by filtration gave 2-Amino-9-ethyl-7-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ol in quantitative yield as an oil (199 mg). 1H-NMR (DMSO): 9.7 (br s, 3H), 6.80 (d, 1H, J=8.2 Hz), 6.64 (s, 1H), 6.51 (d, 1H, J=8.2 Hz), 3.96 (d, 1H, J=12 Hz), 3.81 (d, 1H, J=12 Hz), 3.22 (m, 6H), 1.05 (m, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:14](=[O:23])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C@@H:26]1[C:30]2[NH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][C:29]=2[C:28](=[O:43])[NH:27]1>>[C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:14](=[O:23])[C:13]2[C:8](=[C:9]([C:32]3[NH:31][C:30]4[C@@H:26]([CH3:25])[NH:27][C:28](=[O:43])[C:29]=4[CH:33]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOCCn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Product: COCCOCCn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](C)NC4=O)cccc2c1=O
Yield: 40.2 %

Procedure:
This compound (102 mg, 40% yield) as a tan amorphous solid was prepared according to the procedure described for Example 448, using 2-(tert-butylamino)-8-iodo-3-(2-(2-methoxyethoxyl)ethyl)quinazolin-4(3H)-one (716) (250 mg, 0.56 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (178 mg, 0.68 mmol) as the starting materials. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.99 (2H, dd, J=7.6, 1.8 Hz), 7.23 (1H, t, J=7.7 Hz), 6.75 (1H, s), 4.69 (1H, q, J=6.8 Hz), 4.27-4.38 (2H, m), 3.90 (2H, t, J=4.3 Hz), 3.67-3.74 (2H, m), 3.55-3.63 (2H, m), 1.60 (9H, s), 1.52 (3H, d, J=6.8 Hz), 1.22 (6H, s). m/z (ESI, +ve) 454.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[F:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25](O)=[O:26])[CH2:20][CH2:19]2)=[CH:15][CH:14]=1>O>[F:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8](=[O:10])[NH:7][C:6]=4[CH:11]=3)=[O:26])[CH2:22][CH2:23]2)=[CH:15][CH:14]=1
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: O
Product: O=C(Nc1ccc2oc(=O)[nH]c2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 5-amino-3H-benzoxazol-2-one [J. Med. Chem., 10, 408. (1967)] and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) according to the method described in Example 2. Melting Point: 226-231° C. (water)
Reaction SMILES: [CH2:1]([CH:3]([C:24]([OH:26])=[O:25])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2].[N+]([O-])(O)=O.C[C:32]1C=C(C)[N:34](C(N)=N)[N:33]=1>N1C=CC=CC=1>[CH2:1]([CH:3]([C:24]([OH:26])=[O:25])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][CH:32]=[N:33][NH2:34])=[CH:21][CH:22]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CCC(C(=O)O)N(CCCCc1ccc(N)cc1)c1cccc(C#N)c1
Solvent: c1ccncc1
Solvent: O=[N+]([O-])O
Product: CCC(C(=O)O)N(CCCCc1ccc(NC=NN)cc1)c1cccc(C#N)c1
Yield: 58.3 %

Procedure:
Part E. A solution of ethyl N-[4-[4-aminophenyl]butyl]-N-[3-cyanophenyl]glycine (0.12 gm, 0.34 mmol) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (0.103 gm, 0.51 mmol) in 10 mL pyridine was heated to 100° C. under a nitrogen atmosphere for 3 hrs. The reaction mixture was allowed to cool and was partitioned between ethyl acetate and water. The combined organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product. The product was purified by flash chromatography on silica gel eluting chloroform:methanol (v:v, 80:20) to give ethyl N-[4-[4-[(aminoiminomethyl)amino]phenyl]butyl]-N-[3-cyanophenyl]glycine 0.078 gm (58%) MS 394(M+H)+ 1 H NMR (CDCl3): 7.0(m, 10H), 6.8(m, 2H), 4.2(q, 2H), 4.0(s, 2H), 3.4(m, 2H), 2.7(m, 2H), 1.2(t, 3H).
Reaction SMILES: [C-:1]#[N:2].[K+].C(O)(=O)C.[NH:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(O)C>[NH:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]([OH:19])[C:1]#[N:2])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1cccc(Nc2ccccc2)c1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: N#CC(O)c1cccc(Nc2ccccc2)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
1.5 g of KCN and 1.8 ml of acetic acid were added to 2.5 g of the aldehyde thus obtained dissolved 40 ml of ethanol and then left overnight under stirring. Then, the reaction mixture was poured into 100 ml of 2N-HCl and the extraction was effected with benzene. After washing with NaCl aqueous solution, the benzene layer was condensed to yield 2.7 g of 3-anilino-α-cyanobenzylalcohol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][CH2:13][C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1[C:26]2[C:21](=[N:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13](=[CH:27][C:23]3[CH:24]=[CH:25][C:26]4[C:21](=[CH:20][CH:19]=[CH:18][N:17]=4)[N:22]=3)[C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(NCCc2cccc(F)c2)=N1
Reactant: O=Cc1ccc2ncccc2n1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1N=C(NCCc2cccc(F)c2)SC1=Cc1ccc2ncccc2n1
Temperature: 130 °C
Yield: 36.8 %

Procedure:
To a suspension of 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one (38.1 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 10 min., then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 2-[2-(3-fluoro-phenyl)-ethylamino]-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a brown solid (22.3 mg, 36.9%). HR-ES (+) m/e calcd. for C20H15FN4OS: (M+H)+ 379.1024. Found: 379.1024.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9](=[O:22])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])C(OC)=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[Cl-].[Na+].O>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[C:3]([C:9](=[O:22])[CH2:10][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)C(C(=O)c1ncc(F)cc1F)c1ccccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=C(Cc1ccccc1F)c1ncc(F)cc1F
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
11.65 g (37.67 mmol) of the compound from Example 13A were initially charged in DMSO (37 ml). Subsequently, 2.42 g (41.44 mmol) of sodium chloride and water (7 ml) were added, and the mixture was stirred in a microwave at 150° C. for 30 min. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed three times with water and once with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. This gave 9.07 g (89%, 85% of theory) of the desired compound in solid form, which was converted without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([N:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[CH2:28]=[C:29]([CH3:31])[CH3:30]>C(#N)C>[CH3:28][C:29]1([CH3:31])[C:4]2[C:5](=[CH:17][CH:18]=[C:2]([CH3:1])[CH:3]=2)[NH:6][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:30]1
Reactant: Cc1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Reactant: C=C(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1[N+](=O)[O-])N2
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a suspension of 4-methyl-N-(2-nitrobenzylidene)aniline (10 g) and boron trifluoride etherate (3 mL) in anhydrous acetonitrile was added isobutene (70 mL, pre-cooled to −78° C.) at ice-bath. After addition, the resulting mixture was stirred at 90° C. in sealed tube overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 4,4,6-trimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (10.5 g, yield 85.4%). LC/MS m/e obsd. (ESI+) [(M+H)+] 297.2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7](=[O:18])[CH:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH3:23]C(C)([O-])C.[Na+].IC>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCOCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC12COCCN1c1nc(Cl)ncc1N(C1CCOCC1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
To a 20 mL vial containing 2-chloro-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (0.0907 g, 0.279 mmol) was added DMSO (0.5 mL); placed in a dry ice-acetone bath and then added sodium tert-butoxide (0.030 g, 0.307 mmol) followed by DMSO (0.5 mL) and iodomethane (0.019 ml, 0.307 mmol). The dry ice-acetone bath was removed and the mixture was allowed to warm up to room temperature and stirred for 16 h. The reaction was diluted with 10 mL of water and vigorously stirred at room temperature. Collected rust/orange solids by vacuum filtration, washed with additional water and dried under high vacuum affording 2-chloro-6a-methyl-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (46.0 mg, 48.4% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (d, J=0.76 Hz, 3H) 2.48-2.72 (m, 2H) 3.17-3.34 (m, 1H) 3.41-3.77 (m, 5H) 3.94-4.19 (m, 6H) 4.61 (tt, J=12.38, 4.29 Hz, 1 H) 7.98-8.14 (m, 1H). MS [M+H] found 339.3.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=1.O>C1COCC1.CCCCCC>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[C:21]2=[N:26][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:22]2[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ncccc1-c1ccc2ccccc2c1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=S1(=O)CCN2C=CC=C(c3ccc4ccccc4c3)C2=N1
Yield: 71.8 %

Procedure:
To a suspension of 60% sodium hydride (0.79 g) in THF (20 mL) was added 2-chloroethanesulfonyl chloride (1.93 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 5 min. Then, a solution of 3-(naphthalen-2-yl)pyridin-2-amine (0.87 g) in THF (20 mL) was added. The reaction mixture was stirred at room temperature overnight and at 50° C. for 1 hr, and water and hexane were added under ice-cooling. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the title compound (0.88 g).