Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[OH-].[Na+].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl.CC1CCCCC1>CC1CCCO1>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: CC1CCCCC1
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Temperature: 32.5 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
To a solution of 97 g (810 mmol) of (tetrahydro-pyran-4-yl)-methanol in 2-methyltetrahydrofuran (190 mL) are added 165 mL of 50% aqueous NaOH solution. To this stirred suspension is added dropwise with cooling a solution of p-toluene-sulfonylchloride (283 g, 1.46 mol) in 2-methyltetrahydrofuran (280 mL). The reaction is stirred at 30-35° C. for 18 h. The suspension is poured into a mixture of ice-water (280 mL) and aqueous HCl solution (37%, 203 mL). After addition of methylcyclohexane (1.4 L) and further ice-water (0.2 L), the reaction mixture is stirred for 2 h in an ice-bath. The resulting crystalline precipitate is isolated by filtration and washed with methylcyclohexane (0.5 L) and water (0.5 L). Drying under reduced pressure at 40° C. gave 216 g of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester as white crystalline solid. Yield: 99%, ES-MS: m/z 271 [M+H]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19-1.35 (2 H, m), 1.54-1.63 (2 H, m), 1.85-2.02 (1H, m), 2.45 (3 H, s), 3.28-3.39 (2 H, m), 3.86 (2 H, d, J=6.60 Hz), 3.93 (2 H, dd, J=11.37, 4.52 Hz), 7.35 (2 H, d, J=9.29 Hz), 7.78 (2 H, d, J=8.31 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([Cl:12])[CH:6]=2.[F:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:15]=1[NH2:16].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:18]3[C:19]([CH3:21])=[CH:20][C:14]([F:13])=[C:15]([CH:17]=3)[NH2:16])[CH:3]=[N:4]2)=[CH:9][N:8]=1
Reactant: Clc1cc2ncc(Br)cc2cn1
Reactant: Cc1cc(F)c(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(F)c(N)cc1-c1cnc2cc(Cl)ncc2c1
Temperature: 75 °C
Yield: 79.6 %

Procedure:
Sparge a solution of 3-bromo-7-chloro-1,6-naphthyridine (0.5 g, 2.053 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.516 g, 2.053 mmol) in dioxane (15 mL) with Ar, add a solution of K2CO3 (0.568 g, 4.11 mmol) in H2O (3 mL), followed by Pd(PPh3)4 (0.237 g, 0.205 mmol), heat at 75° C. for 8 h, then cool to RT. Add H2O, extract with EtOAc (2×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (470 mg, 80%) as an off-white solid. MS(ESI) m/z: 288.1 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=1[CH2:32][C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[CH:37]=1>CN(C)C=O.C(Cl)Cl>[Br:29][C:30]1[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=1[CH2:32][C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[C:37]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9]
Reactant: Cc1cc(Cc2ccccc2Br)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C(C)C
Yield: 49.2 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (0.983 g, 4.16 mmol, RN-117439-59-5), oxalyl chloride (0.398 mL, 4.56 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.535 mL, 4.58 mmol) and 2-(2-bromo-benzyl)-4,5-dimethyl-furan (1.10 g, 4.16 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 0.990 g (49%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ1.15 (d, 12H), 1.84 (s, 3H), 2.18 (s, 3H), 3.27 (septet, 2H), 3.73 (s, 3H), 3.91 (s, 2H), 7.12-7.16 (m, 2H), 7.29 (t, 1H, 7.44 (s, 2H), 7.50 (d, 1H).
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][Si:7]([CH3:20])([CH3:19])[CH2:8][CH2:9][O:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].O>CCOCC>[CH3:23][Si:22]([CH3:25])([CH3:24])[C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[O:12][CH2:11][O:10][CH2:9][CH2:8][Si:7]([CH3:20])([CH3:19])[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: C[Si](C)(C)CCOCOc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)CCOCOc1cnccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Add t-BuLi dropwise to a −78° C. solution of 3-(2-trimethylsilanyl-ethoxymethoxy)-pyridine (1.98 g, 8,8 mmol) in Et2O (25 mL, freshly distilled over Na0). After 1 hour, add chlorotrimethylsilane (1.33 mL, 10.5 mmol) dropwise and allow reaction to warm slowly to RT. After 1.5 hours, add water (5 mL) dropwise to quench. Wash with saturated NaHCO3 solution and brine. Dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-30% EtOAc/hexanes to afford the title compound (1.57 g, 60%) as yellow oil. MS(IS) 298 (M+1). TLC: Rf=0.38 (35% EtOAc/hexanes).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:5][CH:4]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[CH:4][CH:5]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:28][CH:29]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([C@H](c3ccc(Cl)cc3)N3CC(=C(c4cc(F)cc(F)c4)S(C)(=O)=O)C3)cc2)CC1
Yield: 44.4 %

Procedure:
The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane, and 0.020 g of N-methylpiperazine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 3 to 9 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.025 g of 1-{(R*)-(4-chlorophenyl)[4-(4-methylpiperazin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.28 (s, 3H), from 2.30 to 2.60 (unresolved complex, 8H), 2.80 (s, 3H), 3.45 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:38]O)[C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:24]([F:37])[CH:23]=1>>[F:37][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:38]=2)[CH:36]=[CH:35][C:25]=1[O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(N)=NO)cc1F
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3ccc(OCC(=O)OC(C)(C)C)c(F)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (1 281.50 mg; 5 mmol) and Intermediate 49 (1 421.44 mg; 5 mmol). The reaction mixture was filtered through a SPE NH2 column (10 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (10 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a white powder. 1H NMR (CDCl3) δ 8.41 (d, J=1.3 Hz, 1H), 8.15 (dd, J=7.8, 1.8 Hz, 1H), 7.98-7.91 (m, 2H), 7.36-7.23 (m, 4H), 7.13 (d, J=7.1 Hz, 1H), 7.03-6.97 (m, 1H), 4.68 (s, 2H), 4.22 (s, 2H), 3.33 (s, 3H), 2.07 (s, 3H), 1.49 (s, 9H). LC/MS (Method B): 505.2 (M+H)+. HPLC (Method A) Rt 6.36 min (Purity: 98.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([Cl:20])=[O:6]
Reactant: O=C(O)c1cc(F)cc(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
10 g of 3-bromo-5-fluoro-benzoic acid are suspended in 100 ml of DCM, 0.5 ml DMF and 4.5 ml oxalyl chloride (1.15 Eq) are added and the resulting mixture is stirred for 100 minutes at RT. The solvent is removed by vacuo and the benzoic acid chloride is isolated by distillation.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O-:13].[Na+]>CN(C)C=O.CO>[CH3:12][O:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(N)c1
Temperature: 80 °C
Yield: 99 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (5.0 g) in dimethylformamide (25 ml) was added 24% sodium methoxide in methanol (11 ml) and the mixture was heated at 80° C. for 4 hours. At the end of this time, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The extract was washed with 20% aqueous sodium chloride solution and insoluble material was filtered off. The filtrate was concentrated in vacuo to give the desired compound (4.8 g, yield 99%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH2:11]([N:13]([CH2:35][CH3:36])[CH2:14][CH:15]([N:17]1[C:30]2[CH:29]=[C:28]([C:31](=[NH:34])OC)[CH:27]=[CH:26][C:25]=2[S:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[CH3:12].O>CO>[CH2:1]([NH:8][C:31]([C:28]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:15]([CH3:16])[CH2:14][N:13]([CH2:35][CH3:36])[CH2:11][CH3:12])[C:30]=2[CH:29]=1)=[NH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)OC)cc21
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)NCc3ccccc3)cc21
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of benzylamine (3.18 cc) in methanol (5 cc) is added dropwise in the course of 5 minutes to a solution, cooled to 0°-5° C., of methyl 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboximidate dihydrochloride (3.49 g) in methanol (21 cc). The mixture is stirred for 2 hours at 5° C. and is then concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is taken up with distilled water (50 cc). The solution is washed with distilled water (50 cc) alkalinized to a pH in the region of 9 with N sodium hydroxide. The two phases are allowed to settle and the organic phase is separated and washed with half-saturated sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is purified by chromatography on a column of neutral alumina (height: 24 cm; diameter: 2.1 cm), eluting successively with mixtures of cyclohexane and ethyl acetate in proportions of 50:50 (500 cc) and 25:75 (500 cc), then with pure ethyl acetate (500 cc) and finally with mixtures of ethyl acetate and methanol in proportions of 95:5 (500 cc) and 90:10 (500 cc) and collecting 50-cc fractions. Fractions 35 to 53 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give N-benzyl-10-[ (2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboxamidine (0.96 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:28]N1C(=O)CCC1=O>ClCCl>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[C:17]([CH2:20][CH3:21])=[CH:18][C:19]=1[Br:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCc1ccc(OCc2ccccc2)cc1OCCCC#N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1cc(Br)c(OCc2ccccc2)cc1OCCCC#N
Reaction time: 5.5 h
Yield: 47.4 %

Procedure:
Carbon tetrachloride (30 mL) was used to dissolve 4-(Benzyloxy)-2-[(3-cyanopropyl)oxy]-1-ethylbenzene (2.5 g). N-bromosuccinimide (1.66 g) was added to the solution and it was stirred for 5.5 hours. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil was crystallized from hexane/ethyl acetate at −20° C. to afford 1-(benzyloxy)-2-bromo-4-ethyl-5-[(3-cyanopropyl)oxy]-benzene as a white crystalline solid (1.5 g). NMR (CDCl3) 1.14, t (3H); 2.14, m (2H); 2.55, m (4H); 3.98, t (2H); 5.12, s (2H); 6.45, s (1H); 7.37, m (6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.9 %

Procedure:
A mixture of 3,4-dihydroxybenzonitrile (540 mg, 4 mmol), K2CO3 (552 mg, 4 mmol) and benzyl bromide (476 mg, 4 mmol) in acetone (20 mL) was stirred at room temperature for 3 days. The mixture was evaporated under vacuum and subjected to flash column chromatography (2% MeOH in toluene-hexane, 2:1) to give the desired product (224 mg, 25%): MP 101° C.; 1H NMR (Acetone-d6, 500 MHz) δ 8.55 (s, 1H), 7.50 (d, 2H, J=7.3 Hz), 7.39 (dd, 2H, J=7.0 and 7.3), 7.34 (dd, 1H, J=7.0 and 7.3), 7.2 (m, complex, 3H). 5.25 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][S:23]2(=[O:29])=[O:28])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12]CC1C=CC=CC=1)=[O:5])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][S:23]2(=[O:28])=[O:29])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[OH:12])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1O
Yield: 82.6 %

Procedure:
A solution of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-benzyloxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (4.05 g, 9.61 mmol) in a mixture of ethanol (250 ml) and ethyl acetate (250 ml) was hydrogenated over 10% palladium on activated carbon (0.9 g) and under 1 atmosphere of hydrogen for 1 h. The catalyst was then filtered and the solvent was evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate gave 2.63 g (82% yield) of the title ester as white crystals; mp 186–189° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.42 (3H, t, J=7.0 Hz, CH3), 1.6–1.63 (1H, m, CH), 2.3–2.6 (3H, m, CH2 and CH), 3.2 (1H, m, CH), 3.55–3.75 (2H, m, CH2), 3.65 (3H, s, NCH3), 3.95–4.05 (1H, m, CH), 4.44 (2H, q, J=7.0 Hz, OCH2). HRMS (FAB POS) calculated for C12H18N3O6S [M+H+]: 332.091632. found: 332.092342.
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])SC.[NH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>C(O)C>[Cl:18][C:15]1[N:16]=[CH:17][C:12]([CH2:11][NH:10][C:3]([NH:2][CH3:1])=[N:6][N+:7]([O-:9])=[O:8])=[CH:13][CH:14]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CNC(=N[N+](=O)[O-])SC
Solvent: CCO
Product: CNC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 34 %

Procedure:
A mixture of 0.45 g of 1,2-dimethyl -3-nitroisothiourea, 0.43 g of 5-(aminomethyl)-2-chloropyridine and 25 ml of ethanol was refluxed for 6 hours and concentrated. The residue was purified by a column chromatography [developing solvent: chloroform-ethanol (5:1)] to afford 0.25 g of 1-(6-chloro-3-pyridylmethyl)-3-methyl2-nitroguanidine (Compound No. 5).
Reaction SMILES: [CH2:1]([S:3]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)=[O:4])[CH3:2].[CH2:10]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].C(N(CC)CC)C>O1CCCC1>[CH2:10]([N:13]([CH2:17][CH3:18])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:3]([CH2:1][CH3:2])=[O:4])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: C=CCN(CC)C(=O)Cl
Reactant: CCS(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC)C(=O)n1cnc(S(=O)CC)n1

Procedure:
A mixture of 7.25 g. 3-ethylsulphinyl-1,2,4-triazole, 7.8 g. N-allyl-N-ethylcarbamoyl chloride, 7.5 ml. dry triethylamine and 100 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 4 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give 1-(N-allyl-N-ethylcarbamoyl)-3-ethylsulphinyl-1,2,4-triazole as a residual oil, nD25 1.5328.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[I:8][C:4]1[CH:3]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Ic1cccc(I)c1
Reactant: C1COCCN1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Ic1cccc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 40.9 %

Procedure:
To a solution of 1,3-diiodobenzene (5.05 g, 15.3 mmol) in isopropanol (16 mL) under nitrogen was added morpholine (1.33 g, 1.33 mL, 15.3 mmol), potassium phosphate (6.50 g, 30.6 mmol), ethylene glycol (1.90 g, 1.70 mL, 30.6 mmol) and copper (I) iodide (146 mg, 0.765 mmol). The mixture was heated at 80° C. for 15 h, and then cooled to room temperature. The solids were removed by filtration and the solution was concentrated. The residue was purified by silica gel column chromatograghy eluted with EtOAc:hexanes (5 to 25% EtOAc) to give 4-(3-iodo-phenyl)-morpholine (1.81 g, 41%) as a colorless oil. MS (ES+): m/z=290.0; 1H NMR (CDCl3, 500 MHz): δ 3.15 (t, 4H), 3.85 (t, 4H), 6.87 (dd, 1H), 6.96-7.00 (m, 1H), 7.20 (d, 1H), 7.22-7.25 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:4])=[O:3].[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:32]=1)[C:27](O)=[O:28]>>[CH3:1][S:2]([CH2:5][CH2:6][N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=1)[C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:32]=[C:24]([C:23]([F:38])([F:22])[F:37])[CH:25]=1)(=[O:3])=[O:4]
Reactant: COc1ncccc1-c1ccncc1NCCS(C)(=O)=O
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1ncccc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2-methanesulfonyl-ethyl)-(2-methoxy-[3,4]bipyridinyl-3′-yl)-amine and 2,6-bis(trifluoromethyl) isonicotinic acid (Key Organics Ltd.) after a reaction time of 15 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (14%). MS (ESI): m/z=549.10 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=C)[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:29])[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cccc(C2(C)CCN(C(=O)CCCCC)CC2C)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCC(=O)N1CCC(C)(c2cccc(C=O)c2)C(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-hexanoyl-3,4-dimethyl-4-(3-vinylphenyl)piperidine (Preparation 8, 2.4 g, 7.67 mmol) in acetone (20 mL) at room temperature was added water (5 mL), 4-methylmorpholine N-oxide (1.1 g, 9.20 mmol) and finally osmium tetroxide (3.83 mL, 2.5 wt % solution in tert-butanol). The yellow solution was stirred at room temperature for 1 hour and then sodium periodate (4.92 g, 23.0 mmol) was added in one portion. After stirring the reaction for 3 hours a heavy precipitate had developed and the reaction mixture was filtered through Celite®, washing with acetone. The filtrate was concentrated in vacuo, the crude oil was dissolved in dichloromethane, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate:hexane (1:1). The title compound was isolated as clear oil (2.0 g).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=3[CH:11]=2)=[CH:3][CH:2]=1.[CH:19](=NC1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]1([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=3[CH:11]=2)=[CH:5][CH:6]=1
Reactant: C(=Nc1ccccc1)c1ccccc1
Reactant: COc1ccc2cc(-c3ccc(C)cc3)oc2c1
Product: COc1ccc2cc(-c3ccc(C=Cc4ccccc4)cc3)oc2c1

Procedure:
Following the procedure given in Example 1b 2-(p-tolyl)-6-methoxybenzofuran was interacted with an equimolar quantity or benzalaniline to produce 2-(4-stilbenyl)-6-methoxybenzofuran, which, when recrystallized from toluene, melted at 223.5°-225.5° C. The wavelength of maximum excitation of this compound was 371 nm., and the wavelength of maximum emission was 446 nm.