Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.C(O)(=O)C.[C:16]([CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[Cl:27])[NH2:23])#[N:17]>O>[C:16]([CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([N:23]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])[CH:24]=[CH:25][C:26]=1[Cl:27])#[N:17]
Reactant: N#CCCc1cc(N)ccc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: N#CCCc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Temperature: 25 °C
Yield: 86 %

Procedure:
To a stirred slurry of 5.0 g of 3,4,5,6-tetrahydrophthalic anhydride in 5 ml. of glacial acetic acid under N2 is added 7.5 g of 3-(2-cyanoethyl)-4-chloroaniline and the mixture heated to reflux for 2 hours. The reaction mixture is cooled to room temperature, water is added together with several mls. of conc. HCl and the mixture extracted with ether. The combined ether extracts are washed with saturated brine and then dried over MgSO4. Filtration and removal of the solvent yielded 8.9 g of a brown oil. The oil is dissolved in CH2Cl2, passed through a plug of alumina, the solvent removed, and then further purified by MPLC eluting with 25% EtOAc/hexanes to yield the product as a yellow solid, m.p. 87°-97° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>ClCCl.[Cl-].[Na+].O>[Br:1][C:2]1[S:6][C:5]([S:7]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccc(Br)s1)N1CCCC1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
5-Bromo-2-thiophenesulfonyl chloride (523 mg, 2 mmol) was dissolved in dichloromethane (20 mL). Pyrrolidine (213 mg, 3 mmol) and potassium carbonate (829 mg, 6 mmol,) are added, and the mixture was stirred at 23° C. for 1 h. After tlc (30% ethyl acetate in hexanes) indicated that the reaction had gone to completion, brine was added and the mixture was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by isco combiflash, eluting with 0-50% ethyl acetate in hexanes (40 g column), giving the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH3:2]>[Pd].C1(C)C=C(C)C=C(C)C=1>[CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:10])[CH3:2]
Reactant: CCC1C(=O)CCCC1=O
Agent: [Pd]
Solvent: Cc1cc(C)cc(C)c1
Product: CCc1c(O)cccc1O
Temperature: 160 °C
Reaction time: 48 h
Yield: 14.9 %

Procedure:
2-Ethyl-1,3-cyclohexanedione (15 g, 107 mmol), mesitylene (240 mL), and 5% Pd/C (7.8 g) were placed in a flask. The reaction mixture was stirred at 160° C. for two days. Filtration gave a crude product, which was purified by chromatography (EtOAc/Hexane) to give 2-ethyl-3-hydroxy phenol (2.2 g, 15%).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([CH:6]1[CH2:9][CH2:8][N:7]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O)[CH3:2].B.C1COCC1>C1COCC1>[CH2:1]([N:3]([CH2:4][CH:6]1[CH2:9][CH2:8][N:7]1[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:17][CH3:18])[CH3:2]
Reactant: CCN(CC)C(=O)C1CCN1C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Product: CCN(CC)CC1CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
A solution of t-butyl 2-diethylcarbamoylazetidine-1-carboxylate (0.614 g) in THF (15 ml) was cooled in an ice/water bath and borane/THF complex (1M in THF, 7.68 ml) was added dropwise over 15 minutes. The mixture was then warmed to room temperature and stirred for a further 18 hours. The mixture was evaporated to dryness and ethanol and water (9:1, 20 ml) was added. The reaction mixture was then heated to reflux for 3 hours. After cooling, it was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM:methanol:acetic acid:water with a gradient of 350:20:3:2 to 120:15:3:2 to give t-butyl 2-diethylaminomethylazetidine-1-carboxylate (0.47 g) as a yellow oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([NH:30][C:31]([C:33]2([CH3:41])[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]2)=[O:32])[CH3:29])[CH:9]=1.[Br:52]N1C(=O)CCC1=O>C(O)(=O)C>[CH3:51][Si:2]([CH3:1])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:47])([CH3:48])[CH3:49])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([NH:30][C:31]([C:33]2([CH3:41])[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]2)=[O:32])[CH3:29])[C:9]=1[Br:52]
Reactant: CC(NC(=O)C1(C)COC(C)(C)OC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CC(NC(=O)C1(C)COC(C)(C)OC1)c1nc2c(-c3cnc4ccc(F)cc4c3)cnn2c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br
Reaction time: 0.17 h

Procedure:
N-{1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl]ethyl}-2,2,5-trimethyl-1,3-dioxane-5-carboxamide (370 mg, 0.501 mmol) was dissolved in acetic acid (13 mL). and N-bromosuccinimide (104 mg, 0.585 mmol) was added in a single portion, and the reaction was stirred for 10 min before being quenched with 20% aq. Na2S2O3 (20 mL) and saturated aq. NaHCO3 (60 mL) and EtOAc (50 mL). Solid NaHCO3 was added until the pH was above 5. The layers were separated, and the aqueous was extracted with EtOAc (2×50 mL). The combined organics were washed with brine (50 mL), dried with MgSO4, filtered, and concentrated in vacuo to give N-{1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-6-bromo-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl]ethyl}-2,2,5-trimethyl-1,3-dioxane-5-carboxamide, which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1.CO>O>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[O:4]1
Reactant: OCc1ccc(CO)o1
Solvent: O
Solvent: CO
Product: OCC1CCC(CO)O1
Temperature: 30 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a 2 gal. stainless steel stirred autoclave was charged 1420.5 g. of 2,5-dihydroxymethylfuran and 113.68 g. of the cationic ruthenium zeolite and 1 gal. of methanol. The system was pressurized with H2 to 3500 psig and heated to 30° C. An exothermic gas uptake was seen and the temperature rose within a minute to 82° C. Cooling water was started to control the exothermic reaction. After 5 hours, gas uptake had essentially ceased and gas chromatographic analysis indicated no starting material was present. Distillation gave 92 percent yield of 2,5-dihydroxymethyl tetrahydrofuran and about 8 percent of a product identified as 5-methyl tetrahydrofuran-2-methanol (hydrogenolysis product).
Reaction SMILES: O[CH2:2][C:3]1([CH2:8][O:9][CH3:10])[CH2:7][S:6][S:5][CH2:4]1.[H-].[Na+].S1([O:19][CH2:18][CH2:17][O:16]1)(=O)=O.Cl>C1COCC1>[OH:16][CH2:17][CH2:18][O:19][CH2:2][C:3]1([CH2:8][O:9][CH3:10])[CH2:7][S:6][S:5][CH2:4]1
Reactant: COCC1(CO)CSSC1
Reactant: O=S1(=O)OCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(COCCO)CSSC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A solution of 4-Hydroxymethyl-4-methoxymethyl-1,2-dithiacyclopentane (0.1 g) in THF (20 ml) was added to a suspension of sodium hydride (0.03 g) in THF (20 ml) and the mixture was stirred at room temperature for 30 min. Ethylene sulfate (0.14 g) was added and the resulting mixture stirred at room temperature for 48 h. Hydrochloric acid (3M, 5 ml) was added, and the aqueous layer extracted with ethyl acetate (5×20 ml). The organic layers were combined and washed with water (50 ml) and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting oil purified by flash chromatography (ethyl acetate-light petroleum, 1:1 as eluant) to give 4-(2-hydroxyethoxy)methyl-4-methoxymethyl-1,2-dithiacyclopentane (66.8 mg, 54%). 1H-n.m.r. (CDCl3) δ2.93 (AB quartet, 4H), 3.34 (s, 3H), 3.36 (s, 2H), 3.46 (s, 2H), 3.56 (m, 2H). 3.70 (m, 2H); 13C-n.m.r. (CDCl3) δ44.7, 56.2, 59.3, 61.6, 72.2, 72.3, 74.2; m/z 224 (M+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[CH3:24][C@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@@H:25]([CH3:24])[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Product: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-chloro-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:16][CH2:15][N:14]([C:17]([C:19]4[S:27][C:26]5[CH2:25][CH2:24][NH:23][CH2:22][C:21]=5[CH:20]=4)=[O:18])[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>ClCCl.CN(C)C=O>[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([N:23]1[CH2:24][CH2:25][C:26]2[S:27][C:19]([C:17]([N:14]3[CH2:15][CH2:16][C:11]4([CH2:28][CH2:29][N:8]([C:5]5[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=5)[CH2:9][CH2:10]4)[CH2:12][CH2:13]3)=[O:18])=[CH:20][C:21]=2[CH2:22]1)=[O:41]
Reactant: O=C(c1cc2c(s1)CCNC2)N1CCC2(CC1)CCN(c1ccncc1)CC2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc2c(s1)CCN(C(=O)c1ccccc1Cl)C2)N1CCC2(CC1)CCN(c1ccncc1)CC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(9-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)(4,5,6,7-tetrahydrothieno[3,2-c]-pyridin-2-yl)methanone hydrochloride (0.089 g, 0.208 mmol) was dissolved in dichloromethane (4 ml) and N,N-dimethylformamide (1 ml), and triethylamine (0.072 ml, 0.52 mmol) was added. The mixture was cooled with an ice bath, and 2-chlorobenzoyl chloride (0.036 g, 0.208 mmol), dissolved in dichloromethane (4 ml), was added slowly at 0° C. The cooling bath was removed and the reaction mixture was stirred for 15 h at RT. Saturated sodium hydrogen carbonate solution (15 ml) was then added and the phases were separated. The aqueous phase was extracted with dichloromethane (25 ml) and the combined organic phases were washed with saturated NaCl solution (10 ml) and saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol/ammonia (25% aq.), 500:100:1). Yield: 80 mg (72%). MS, Rt=3.0 min; m/z=535.2 [MH]+
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=2)[CH2:7]1>C(O)(C(F)(F)F)=O>[CH3:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:1]([O-:4])=[O:2])=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=2)[CH2:7]1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)CC(C)C2
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CC(C)C2
Temperature: 20 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of nitric acid (70%, 3.2 mL, 50.3 mmol) in TFA (5 mL) was added dropwise to a stirred solution of acetamide 91 (3.93 g, 16.8 mmol) in TFA (40 mL) and the solution stirred at 20° C. for 2 h. The solution was poured into ice/water (400 mL) and stirred for 30 min. The precipitate was filtered, washed with water (3×30 mL), and dried. The solid was purified by chromatography, eluting with 10% EtOAc/pet. ether, to give nitroacetamide 92 (3.79 g, 96%) as a red solid: mp (EtOAc/pet. ether) 99-100° C.; 1H NMR δ 10.41 (br s, 1H, NH), 8.50 (s, 1H, H-7), 8.00 (s, 1H, H-4), 3.03-3.13 (m, 2H, CH2), 2.51-2.67 (m, 3H, H-2, CH2), 2.29 (s, 3H, COCH3), 1.14 (d, J=6.4 Hz, 3H, CH3); 13C NMR δ 169.0, 153.9, 139.4, 135.3, 133.7, 121.1, 117.7, 41.6, 40.2, 34.7, 25.6, 20.4. Anal. calcd for C12H14N2O3: C, 61.5; H, 6.0; N, 12.0. Found: C, 61.6; H, 6.2; N, 11.5%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14]Cl>CN(C=O)C>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CN(C)CCCl
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.44 g, 44.55 mmol), K2 CO3 (13.6 g) and DMF (50 ml) was added in portions 2-dimethylaminoethylchloride hydrochloride (7.1 g). The reaction mixture was stirred at room temperature overnight, filtered and the filtrate was stripped. The residue was diluted with 1N HCl (300 ml), and extracted with ether, and the ether layer was dried over MgSO4 and stripped. The acidic aqueous layer was cooled and then treated with 8N NaOH till basic, then it was extracted with ether (3×150 ml). The ether layers were combined, dried over MgSO4, filtered and stripped to afford, as an oily liquid, 1.43 g of 3-[2-(dimethylamino)ethoxy]benzaldehyde.
Reaction SMILES: [C:1]([CH:5]=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2].[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH2:21][NH2:22].O>C1C=CC=CC=1>[C:1]([CH:5]=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:22][CH2:21][CH:20]([OH:19])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1ccc(Cl)cc1
Reactant: COC(=O)C=CCOc1ccc(CC(C)=O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C=CCOc1ccc(CC(C)NCC(O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A mixture of 1-(4-(3-carbomethoxyprop-2-eneoxy) phenyl) propan-2-one (2.27 g) and 2-hydroxy-2-(4-chlorophenyl) ethanamine (1.57 g) in benzene (100 ml) was boiled under reflux with azeotropic removal of water using a Dean and Stark trap. The solution was evaporated, the residue dissolved in methanol (50 ml), cooled in ice and sodium borohydride added. The solution was stirred for 1 hour at 0° C., the methanol evaporated, and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was dried (MgSO4) and evaporated to give a cream solid (3.1 g) which was crystallised from ethyl acetate m.p. 120°-122°. as a 0:100 mixture of diastereoisomers. Recrystallisation of the mother liquors from hexane gave a 70:30 mixture of diastereoisomers, m.p. 55°-65°.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[C:14]([F:25])[CH:13]=2)[CH2:7]1)=O)C.[CH3:26][NH2:27]>CO>[CH3:26][NH:27][C:4]([C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[C:14]([F:25])[CH:13]=2)[CH2:7]1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)C1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a stirred solution of 3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxylic acid ethyl ester (EXAMPLE 69, within Step 6, 120 mg, 0.34 mmol) in MeOH (1 mL) is added MeNH2 (2 mL, 4.0 mmol, 2.0 M solution in MeOH). The reaction mixture is stirred for 1 h at room temperature. Solvent is removed and the residue purified by column chromatography (10% MeOH/CH2Cl2) to give the title compound as a pale yellow solid (60 mg, 52%), 1H NMR (300 MHz, DMSO) δ 8.39 (m, 1H), 7.65-7.38 (m, 4H), 5.06 (dd, 1H), 4.98 (d, 1H), 4.27 (t, 1H), 4.02 (dd, 1H), 3.87 (t, 2H), 2.65 (d, 3H); MS for C16H16FN3O4 m/z 334.5 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11](N2CCOCC2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH:10]=[CH:11][CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(N2CCOCC2)CCN(Cc2ccccc2)C1
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: C1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.7 %

Procedure:
A solution of 5.16 g (20 mmoles) of 1-benzyl-4-morpholino-1,2,3,6-tetrahydropyridine in 10 ml of tetrahydrofuran (THF) is added to 2.44 g (20 mmoles) of solid 9-BBN. A suspension results which becomes clear after stirring for 6 hours at 25° C. The THF is removed under reduced pressure (20 Torr) and 2 ml of methanol is added to the remaining solid. An exothermic reaction is initiated by gentle warming and results in a clear solution which is stirred. The stirring is stopped and the mixture is cooled slowly to crystallize the by-product, B-(morpholino)-9-BBN methanol complex. The solid is triturated with n-pentane (3×30 ml) and the combined pentane layers are washed successively with water (3×10 ml), 3N sodium hydroxide (3×6 ml) and water (2×10 ml). The pentane layer is evaporated. The residue is purified by distillation to give 2.90 g (85 percent yield based on 1-benzyl-4-morpholino-1,2,3,6-tetrahydropyridine) of 1 -benzyl-1,2,3,6-tetrahydropyridine, boiling point 98° C.-100° C. at 1 Torr.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1COCC1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26](F)[CH:25]=1>CS(C)=O.O>[F:23][C:24]1[CH:25]=[C:26]([CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[CH:29]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(Oc2cc(F)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-hydroxyphenyl)acetamide (1.00 g, 6.5 mmol) in DMSO (12 ml) was added 1M t-BuOK/THF solution (7.13 ml, 7.13 mmol) dropwise at room temperature and the mixture was stirred at room temperature for 30 minutes under N2 flow. 1,3-Difluoro-5-nitrobenzene (0.89 ml, 7.8 mmol) was added at room temperature, and then the mixture was stirred at room temperature for 2 hours and at 50° C. for 2 hours under a N2 flow. The reaction mixture was cooled to room temperature, diluted with H2O, and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the title compound as a pale brown solid, which was purified by washing with i-Pr2O to give the desired product as slightly brown crystal (1.73 g, 92%).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:16][CH2:17][CH3:18].[Na+].O>C(O)C>[CH2:17]([O:16][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:18]
Reactant: CC[O-]
Reactant: CCc1c(Cl)nn2c(N)nnc2c1CC
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nn2c(N)nnc2c(CC)c1CC
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
6-Chloro-7,8-diethyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-ylamine (W2.014, 0.1 g) was dissolved in ethanol (13 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (61 mg) and stirred at RT for 1 h, then at 55° C. for 30 min. Subsequently, a further 2 equivalents of sodium ethoxide were added and the mixture was stirred at 55° C. for 4.5 h. After another 1 equivalent of sodium ethoxide had been added, the mixture was stirred at 55° C. for 2.5 h and left to stand over the weekend. The solvent was then drawn off, and the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 92 mg of the title compound were obtained. LC-MS rt: 0.80 min [M+H]+: 236.2 (met. b)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[N:12]S(C(C)(C)C)=O.Cl>O1CCOCC1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[NH:12]
Reactant: CC(C)(C)S(=O)N=C1CCOc2ccc(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N=C1CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
N-(6-Bromochroman-4-ylidene)-2-methylpropane-2-sulfinamide (2.0 g, 6.0 mmol, Intermediate 1) was dissolved in dry dioxane (2 mL), and 4M HCl in dioxane (15 mL, 60.00 mmol) was added. A white precipitate started to form. The mixture was stirred at r.t. for 12 h. The mixture was diluted with dry Et2O (50 mL) and vacuum filtered. The filter cake was washed with dry Et2O (50 mL), then immediately dissolved by shaking in NaHCO3 (aq) and CH2Cl2. The organic phase was dried (K2CO3) and evaporated to give 6-bromochroman-4-imine (1.3 g, 5.7 mmol). The solid was dissolved together with 2-oxopropanethioamide (Intermediate 2, 1.7 g, 17 mmol, Intermediate 2) in dry methanol (5 mL) and the resulting solution was heated at 60° C. for 12 h. Evaporation onto silica and purification by flash chromatography (EtOAc in heptane) gave the title compound (0.39 g, 21% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.18 (m, 1 H), 2.35 (m, 1 H), 2.42 (s, 3 H), 4.35-4.40 (m, 1 H), 4.60 (m, 1 H), 6.81 (d, 1 H), 6.88 (d, 1 H), 7.33 (dd, 1 H); MS (ES+) m/z 311 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C.O>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([N:20]([O:21][CH3:22])[CH3:19])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 0.67 h
Yield: 81 %

Procedure:
To a suspension of 136.8 g (0.60 mol) 3-benzyloxybenzoic acid in 1200 ml dichloromethane 60.6 g (0.6 mol) triethylamine was added at 10° C. A solution of 64.8 g (0.60 mol) ethyl chloroformiate in 100 ml dichloromethane was added over a period of 15 minutes keeping the temperature between 10° C. and 15° C. After stirring for 40 minutes and addition of 58.2 g (0.60 mol) N,O-dimethylhydroxylamine hydrochloride a solution of 60.6 g (0.60 mol) triethylamine was added over a period of 20 minutes at 10–15° C. After additional strirring for 30 minutes water was added and the organic layer dried over sodium sulphate. Fractionated distillation in vacuo yielded 131.9 g (81%) B1.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[N:13]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH2:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>CC#N>[Cl:12][C:4]1[N:3]=[C:2]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:13]=[CH:14][CH:15]=[CH:16]3)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: NCc1ccc2ncccc2c1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a mixture of 2,6-dichloro-3-nitropyridin-4-amine (624 mg, 3 mmol) and quinolin-6-ylmethanamine (316 mg, 2 mmol) in CH3CN (10 mL) was added Et3N (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. After cooled to room temperature, the mixture was concentrated to afford the title compound (658 mg). MS (m/z): 330 (M+1)+.