Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[CH:20](Br)[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].C(OCC)(=O)C>C(Cl)Cl>[Cl:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[CH:20]([N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:21](=[O:26])[C:22]([F:24])([F:25])[F:23]
Reactant: O=C(C(Br)c1ccccc1Cl)C(F)(F)F
Reactant: c1cc2c(s1)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(C(c1ccccc1Cl)N1CCc2sccc2C1)C(F)(F)F
Temperature: 25 °C
Yield: 39.2 %

Procedure:
10 ml of methylene chloride were added to 0.39 g (2.6 mmole) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and 0.28 g (2.6 mmole) of sodium carbonate, and then a solution of 0.67 g (2.2 mmole) of 2-chloro-α-trifluoroacetylbenzyl bromide in 10 ml of methylene chloride was slowly added to the resulting mixture, whilst stirring at room temperature. The mixture was then stirred at room temperature for 3 hours. At the end of this time, 200 ml of ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, using a 100:4 by volume mixture of toluene and ethyl acetate as the eluent, to give 0.31 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH:16][NH2:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:20][N:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:22]=2[C:23]([F:26])([F:25])[F:24])[O:11][N:10]=1.[C:34](Cl)(=[O:36])[CH3:35]>O1CCOCC1>[C:34]([NH:17][NH:16][C:14]([C:13]1[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:10][O:11][C:12]=1[C:18]1[CH:19]=[N:20][N:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:22]=1[C:23]([F:25])([F:26])[F:24])=[O:15])(=[O:36])[CH3:35]
Reactant: NNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Product: CC(=O)NNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Yield: 84.7 %

Procedure:
To a solution of 190 mg (0.393 mmol) 3-(2-chloro-6-fluorophenyl)-5-(1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carbohydrazide (which was synthesized in analogy to the procedure described for example I-133) in 5.8 ml absolute dioxane, 148 mg (1.885 mmol) acetyl chloride were added. The conversion is complete within minutes. Volatiles were evaporated, residue was re-evaporated with ethanol. Residue was crystallized from EtOAc-heptane to give 175 mg (85%) of compound I-142 as a pale yellow powder. Result of LC/MS MH+: 526.06; 1H-NMR (400 MHz, methanol-d4) δ ppm: 1.98 (3H, s, CH3), 7.25-7.32 (1H, m, CH-arom.), 7.41-7.48 (3H, m, CH-arom.), 7.54-7.61 (1H, m, CH-arom), 7.64-7.74 (1H, m, CH-arom.), 8.63 (1H, s, CH-pyraz.)
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:3][NH:4][C:5]1[CH:6]=[N:7][C:8]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)Nc1cnc(N2CCOCC2)cc1-c1ccccc1C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CNc1cnc(N2CCOCC2)cc1-c1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of 3.0 g (9.1 mMol) (6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-carbamic acid methyl ester in 15 ml toluene was added at room temperature over 15 minutes to a solution of 13 ml (46 mMol) Red-Al® (70% in toluene) and 15 ml toluene. After 2 hours at 50° C., the reaction mixture was cooled to 0° C. and 25.5 ml aqueous NaOH 1N were added over 10 minutes (very exothermic). The phases were separated and the aqueous phase extracted with toluene. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated. The residue was crystallized from n-heptane at −10° C. to yield 2.3 g (88%) methyl-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-amine as a light beige powder of m.p.=73.5-76° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:11][C:4]1[N:3]=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: Cc1nc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 2-fluoro-5-nitro-6-picoline (3.0 g, 19.2 mmol) in DMSO (26 mL) were added morpholine (3.35 mL, 38.4 mmol) and potassium carbonate (6.64 g, 48.0 mmol). The reaction mixture was allowed to stir overnight, at 70° C. The reaction mixture was then partitioned between EtOAc (40 mL) and water (40 mL). The organic solution was separated and the aqueous solution was extracted with EtOAc (2×40 mL). The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated to give 4-(6-methyl-5-nitropyridin-2-yl)morpholine (4.0 g, 99%), as a muddy green solid. LCMS (FA): Rt=1.59 min, m/z=224.0 (M+H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:33]1([CH2:39][CH2:40][C:41]2[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)CC>C1COCC1.C(OCC)(=O)C.O.CN1C(=O)N(C)CCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:45][C:44]2[CH:47]=[CH:48][C:41]([CH2:40][CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:42][CH:43]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: BrCc1ccc(CCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(CCc3ccccc3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4.4 g (14.53 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [preparation, see Example 2b)] in 21.4 ml of abs. THF and 2.4 ml of DMPU is treated, at -75° C. and under an N2 atmosphere, with 28 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich, Steinheim, FRG), and the mixture is subsequently stirred at this temperature for 15 min. A solution of 6.0 g (approximately 80%, 17.5 mmol) of p-(2-phenylethyl)benzyl bromide in 5.4 ml of abs. THF is then added dropwise, and this mixture is thoroughly stirred at -70° C. for 30 min. 5.4 ml of propionic acid are then added at -75° C., followed by 5.4 ml of water. The mixture is warmed to 0° C. and diluted with 150 ml of ethyl acetate; this mixture is then washed with 80 ml of a 10% solution of citric acid, with sat. sodium bicarbonate solution and with saline. The aqueous phases are reextracted 2× with ethyl acetate, and the organic phases are dried over sodium sulfate and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 3:1) yields the pure title compound: TLC Rf (E)=0.27; tRet (II)=20.8 min; FAB-MS (M-Buten+H)+ =444.
Reaction SMILES: BrC(Br)C.[CH:5]1[C:10]([CH2:11]Br)=[CH:9][CH:8]=[C:7]([C:13]#[N:14])[CH:6]=1.I[C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1>C1COCC1.[Zn].[Ni].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:21]([N:19]1[CH:20]=[C:16]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:13]#[N:14])=[CH:6][CH:5]=2)[N:17]=[CH:18]1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Ni]
Agent: CC(Br)Br
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
To a suspension of activated zinc dust (3.57 g, 54.98 mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60 mmol) and the reaction stirred under argon for 45 minutes, at 20° C. The suspension was cooled to 0° C. and a-bromo-p-tolunitrile (9.33 g, 47.6 mmol) in THF (100 mL) was added dropwise over a period of 10 minutes. The reaction was then allowed to stir at 20° C. for 6 hours and bis(triphenylphosphine) Nickel II chloride (2.40 g, 3.64 mmol) and 4-iodo-1-tritylimidazole (15.95 g, 36.6 mmol, S. V. Ley, et al., J. Org. Chem. 56, 5739(1991)) were added in one portion. The resulting mixture was stirred 16 hours at 20° C. and then quenched by addition of saturated NH4Cl solution (100 mL) and the mixture stirred for 2 hours. Saturated aq. NaHCO3 solution was added to give a pH of 8 and the solution was extracted with EtOAc (2×250 mL), dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 0-20% EtOAc in CH2Cl2) to afford the title compound as a white solid.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]2[NH:28][C:27]([O:29][C@@H:30]3[CH2:34][O:33][C@@H:32]4[C@:35]([CH:39]=C)([OH:38])[CH2:36][O:37][C@H:31]34)=[N:26][C:11]2=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C[OH:42].C(Cl)Cl>C(#N)C.O.CCOC(C)=O.CO.O.[Ru](Cl)(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]2[NH:28][C:27]([O:29][C@@H:30]3[CH2:34][O:33][C@@H:32]4[C@@:35]([OH:38])([CH:39]=[O:42])[CH2:36][O:37][C@H:31]34)=[N:26][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: C=C[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Reactant: CO
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium periodate (21.9 mg, 0.102 mmol) was added to a stirred suspension of (3R,3aR,6R,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-6-vinyl-3,3a,5,6a-tetrahydro-2H-furo[3,2-b]furan-6-ol (23.4 mg, 0.049 mmol) and ruthenium(III) chloride hydrate (1.0 mg, 4.44 μmol) in acetonitrile (0.42 ml) and water (0.07 ml). The reaction mixture was stirred at room temperature for 4 h, then partitioned between EtOAc (20 ml) and saturated aqueous sodium thiosulfate (20 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine (1×10 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a colorless residue. The residue was dissolved in EtOAc/MeOH and loaded onto a 500 micron 20 cm×20 cm silica gel plate, which was developed twice using 5% MeOH/DCM. The silica containing the product band was collected and eluted with 10% MeOH/DCM (80 ml). The solvent was evaporated under reduced pressure to give the title compound as a colorless residue. LC-MS: calculated for C25H20ClN3O5 477.11 observed m/e: 478.05 (M+H)+ (Rt 1.15/2 min)
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH2:13]([O:15][P:16]([CH2:21][CH2:22][NH2:23])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]>C(O)C>[CH2:18]([O:17][P:16]([CH2:21][CH2:22][NH:23][C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])(=[O:20])[O:15][CH2:13][CH3:14])[CH3:19]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCOP(=O)(CCN)OCC
Solvent: CCO
Product: CCOc1c(NCCP(=O)(OCC)OCC)c(=O)c1=O

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (4.00 g, 23.5 mmol) in ethanol (100 mL) was added 2-aminoethylphosphonic acid diethyl ester (5.43 g, 30.0 mmol) in ethanol (100 mL) over a 1 hour period. After leaving overnight the reaction mixture was preadsorbed onto silica gel and purified by flash chromatography (5.5 cm diameter, gradient elution with 2.5-10% isopropanol in dichloromethane) to yield [2-[(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]ethyl]phosphonic acid diethyl ester as an oil which solidifies on standing (3.98 g, 55%, mp 66°-68° C.); IR (KBr, cm-1): 3400, 3180, 1800, 1700, 1600; MS (+FAB): 306 (MH+, 100), 278 (14), 137 (14), 109 (35); 1H NMR (CDCl3, 400 MHz): δ6.58, 6.46 (br s, NH), 4.75 (br m, 2H), 4.21-4.07 (m, 4H), 4.00, 3.75 (br m, 2H), 2.08 (d of t, J=17.5 and 6.5 Hz, 2H), 1.46 (br m, 3H), 1.35 (t, J=7 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:8]([C@H:9]4[C@@:13]([CH2:16][CH2:17]3)([CH2:14][CH3:15])[C:12](=[O:22])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[CH3:23][N:24]([CH:26](N(C)C)OC(C)(C)C)[CH3:25]>C(O)C>[CH3:23][N:24]([CH:26]=[C:11]1[CH2:10][C@H:9]2[C@H:8]3[C@H:18]([CH2:17][CH2:16][C@:13]2([CH2:14][CH3:15])[C:12]1=[O:22])[C:19]1[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7]3)[CH3:25]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CCO
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC(=CN(C)C)C2=O
Temperature: 160 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
A mixture of 10 g of 3-methoxy-18-methyl-1,3,5(10)-estratrien-17-one and 15 g of bis(dimethylamino)tert.-butoxymethane is stirred for 3 hours at 160° C. After cooling the mixture is combined with 50 ml of ethanol and left at -5° C. for crystallizing purposes. After filtering off and drying, 10.6 g of 16-dimethylaminomethylene-3-methoxy-18-methyl-1,3,5(10)-estratrien-17-one is obtained, m.p. 157°-159° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH:13]([CH3:27])[CH2:14][C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH2:18][CH:17]=[CH:16]1)[C:10](=O)[CH3:11])[CH3:8]>O1CCCC1>[CH3:27][CH:13]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])[CH2:14][C:15]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[CH:17][CH2:18][CH:19]=[CH:20]1
Reactant: CCN(C(C)=O)C(C)CC1(c2ccccc2)C=CCC=C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)C(C)CC1(c2ccccc2)C=CCC=C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
0.266 g. of lithium aluminum hydride is placed in 10 ml. of tetrahydrofuran. After the addition of 1 g. of N-ethyl-N-[1-methyl-2-(1-phenyl-2,5-cyclohexadien-1-yl)ethyl]-acetamide in 10 ml. of tetrahydrofuan, the mixture is stirred at room temperature for 7 hours. Subsequently, excess lithium aluminum hydride is destroyed by the addition of ethyl aceate and of water. The mixture is filtered and the filter is rinsed with ether. After separation of the phases, the organic phase is dried with sodium sulfate, filtered and concentrated completely. The crude product is chromatographed on 60 g. of Alox neutral with ethyl acetate. There is obtained α-methyl-N,N-diethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine in the form of an oily product. This is converted as usual into the hydrochloride which, after crystallization from methylene chloride/ether, has a melting point of 172°-174° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C:13]#[N:14])([CH3:12])[CH2:9]1)=O)(C)(C)C.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[C:13]([C:10]1([CH3:12])[CH2:11][NH:8][CH2:9]1)#[N:14]
Reactant: CC1(C#N)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C#N)CNC1
Temperature: 25 °C

Procedure:
3-Cyano-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.23 g, 1.17 mmol) was dissolved in 12 mL of dichloromethane and the reaction was then stirred in an ice bath. Trifluoroacetic acid (3.6 mL) was added slowly and the solution was warmed to room temperature. After 3 h the reaction mixture was evaporated to afford 3-cyano-3-methyl-azetidine trifluoroacetate which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1>[CH2:24]([NH:31][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: Nc1nc(NCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1
Yield: 77.8 %

Procedure:
To a stirred solution of 335 mg (0.95 mmol) trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester in 20 ml dioxane was added 1.03 ml (9.46 mmol) benzylamine and the mixture heated at reflux for 1 hour. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate) followed by recrystallisation from ether/hexane afforded 230 mg (78%) N4-benzyl-6-furan-2-yl-5-nitro-pyrimidine-2,4-diamine as a yellow crystalline solid. ES-MS m/e (%): 312 (M+H+, 100).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)(=O)=O>CN(C=O)C.CCOC(C)=O>[N:1]([CH2:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCCc1nc(-c2ccccc2)cs1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCCc1nc(-c2ccccc2)cs1
Temperature: 100 °C
Yield: 91 %

Procedure:
Sodium azide (263 mg, 4.05 mmol) was added to a solution of 3-(4-phenylthiazol-2-yl)propyl methanesulfonate (0.4 g, 1.35 mmol) in dry DMF (8 mL), and the reaction mixture was heated to 100° C. for 2 h. The mixture was allowed to cool down to room temperature and diluted with EtOAc. The organic product was extracted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 2-(3-azidopropyl)-4-phenylthiazole (0.3 g, yield 91%) as a pale orange liquid, which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 7.91-7.89 (m, 2H), 7.46-7.41 (m, 2H), 7.36-7.31 (m, 2H), 3.49-3.44 (t, J=6.7 Hz, 2H), 3.20-3.15 (t, J=7.5 Hz, 2H), 2.21-2.12 (m, 2H). MS (ESI) m/z: Calculated for C12H12N4S: 244.08. found: 245.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[NH:17][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]C(C)([O-])C.[K+].CI.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[N:17]([CH3:22])[N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCN(c3n[nH]c4ccsc34)CC2)cc1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(N2CCN(Cc3ccccc3)CC2)c2sccc21
Temperature: -30 °C

Procedure:
To a stirred solution of 3-(4-benzyl-piperazin-1-yl)-1H-thieno[3,2-c]pyrazole (318.0 g, 1.07 mol) in THF (2.5 L) was added a mixture of potassium t-butoxide (134.4 g, 1.2 mol) in THF (1.5 L) dropwise over a period of 1 hour while keeping the reaction temperature below 25° C. After complete addition, the mixture was cooled to −30° C. and MeI (65.4 mL, 1.05 mol) was added dropwise over a period of 30 minutes. The mixture is then slowly warmed to room temperature overnight. To the reaction mixture is slowly added saturated NaHCO3 (1 L). The solution is then evaporated to remove the THF and the resulting aqueous mixture is taken up in EtOAc and washed with water and brine. The EtOAc extract is dried (Na2SO4), filtered and evaporated. The viscous concentrate is filtered through a silica gel plug with 1:1 EtOAc/heptane and evaporated yielding a viscous oil that is then dried under vacuum where it solidifies and yields 326.03 g (98%) as a 12:1 ratio of regioisomers in favor of the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12]C(O)=O)(=O)[CH3:2].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][CH:12]=[C:1]([CH3:2])[C:4]=2[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1coc2ccc(Br)cc12
Temperature: 140 °C
Reaction time: 3.5 h

Procedure:
A solution of [(2-acetyl-4-bromophenyl)oxy]acetic acid (1.648 mmol) in acetic acid (2.075 mL) was treated with sodium acetate (9.89 mmol) and acetic anhydride (21.42 mmol). The reaction solution was heated with stirring to 140° C. for 3.5 h. Analysis by LCMS showed a major product that did not ionize, and consumption of starting material. The mixture was diluted with water and ethyl acetate and was washed with 1N aq NaOH until the aqueous phase was basic (pH˜12). The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to an oil in vacuo. No further purification was carried out. 1H NMR (400 MHz, chloroform-d) δ ppm 7.67 (d, J=1.77 Hz, 1H) 7.38-7.45 (m, 2H) 7.32-7.38 (m, 1H) 2.24 (d, J=1.26 Hz, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[OH:12][C:13]1[CH:22]=[C:21]([O:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:25])[CH:20]=[C:19]2[C:14]=1[CH:15]([CH2:39][CH2:40][C:41]#[N:42])[CH2:16][CH:17]1[CH2:38][CH2:37][CH2:36][CH2:35][N:18]12>C(OCC)(=O)C>[OH:12][C:13]1[CH:22]=[C:21]([O:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:25])[CH:20]=[C:19]2[C:14]=1[CH:15]([CH2:39][CH2:40][CH2:41][NH2:42])[CH2:16][CH:17]1[CH2:38][CH2:37][CH2:36][CH2:35][N:18]12
Reactant: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1CCCCC1CC2CCC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1CCCCC1CC2CCCN
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under anhydrous conditions and a nitrogen atmosphere, to a solution of 190 mg. (5 mmole) lithium aluminum hydride in 50 ml. tetrahydrofuran at 10° C. is added dropwise a solution of 2.09 g. (5 mmole) dl-7-hydroxy-6-(2-cyanoethyl)-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline in 25 ml. tetrahydrofuran. The mixture is stirred at room temperature for 6 hours after the addition. Ethyl acetate is added to quench the reaction, the solvent is evaporated in vacuo and the residue partitioned between water and methylene chloride. The organic extracts are dried (MgSO4) and the solvent evaporated to provide the title compound as the free base.