Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][CH3:27])[CH2:20][CH2:19]4)=[C:14]([CH3:28])[CH:13]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[C:45]([N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)=[O:46]>>[CH3:27][O:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[O:9][C:10]4[C:2]([C:34]5[CH:33]=[CH:32][C:31]([C:45]([N:47]6[CH2:48][CH2:49][O:50][CH2:51][CH2:52]6)=[O:46])=[C:30]([CH3:29])[CH:35]=5)=[CH:3][CH:4]=[CH:5][C:6]=4[N:7]=3)=[CH:13][C:14]=2[CH3:28])[CH2:19][CH2:20]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(=O)N1CCOCC1
Reactant: COCCN1CCN(c2ccc(Nc3nc4cccc(Br)c4o3)cc2C)CC1
Product: COCCN1CCN(c2ccc(Nc3nc4cccc(-c5ccc(C(=O)N6CCOCC6)c(C)c5)c4o3)cc2C)CC1

Procedure:
The title compound is prepared from (7-bromo-benzooxazol-2-yl)-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-3-methyl-phenyl}-amine and [2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-phenyl]-morpholin-4-yl-methanone using methodology described in the preparation of example 65. The title compound is obtained as an off-white foam. Rt=2.00 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 570 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:29][CH2:28][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][C:17]=2[CH3:16])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Product: CCOC(=O)COc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C

Procedure:
(4-Hydroxy-2-methylphenoxy) acetic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester were coupled as described in Example 24, Step C. 1H NMR (400 MHz, CDCl3) δ 1.28 (t, 3H, J=7.0 Hz), 2.25 (s, 3H), 2.36 (s, 3H), 2.94 (t, 2H, J=6.8 Hz), 4.17 (t, 2H, J=6.6 Hz), 4.23 (q, 2H, J=7.0 Hz), 4.55 (s, 2H), 6.65 (s, 2H), 6.72 (s, 1H), 7.38-7.44 (m, 3H), 7.94-7.97 (m, 2H); MS (ES) m/e 396.2 (M+1).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[NH2:21][C:22]1[CH:29]=[CH:28][C:27](C)=[CH:26][C:23]=1[C:24]#[N:25].[C:31](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCCCCC.C(OCC)(=O)C>[C:24]([C:23]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][C:22]=1[NH:21][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1)#[N:25]
Reactant: Cc1ccc(N)c(C#N)c1
Reactant: CC(=O)O
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](Nc3cccc(C)c3C#N)CC[C@H]2CN1C(=O)OC
Yield: 6.9 %

Procedure:
Following the procedures from Example 3A, and using 1.076 g (3.8 mmol) of ethyl 6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate, 1.36 g (10.0 mmol) of 2-amino-5-methylbenzonitrile, 0.67 mL (12 mmol) of glacial acetic acid, and 1.14 g (5.4 mmol) of sodium triacetoxyborohydride, flash chromatography (silica gel, hexane-ethyl acetate 3:1) afforded 105 mg (13% yield) of the title compound.
Reaction SMILES: [OH-:1].[K+].ClCC([O:7][C:8](=[O:11])[CH2:9]Cl)=O.[C:12]1(C)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:1]([CH2:9][C:8]([OH:7])=[O:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: Cc1ccccc1
Reactant: [OH-]
Agent: [K+]
Product: O=C(O)COc1ccccc1
Reaction time: 0.67 h

Procedure:
304 g of alkyl phenol derived by partial hydrogenation of distilled cashew nut shell liquid and 650 ml of toluene was charged to a 2 liter reactor equipped with agitator and condenser. The contents were warmed to 40 degree C. Subsequently 112 g of potassium hydroxide was added to the reactor and stirred for 40 minutes. Later, 85 g of chloro acetic anhydride was added slowly in 30 minutes. After the completion of addition of reactants, the reaction mixture was refluxed for 6 hours. On completion of the reaction, the solvent was removed and contents taken in water and acidified with dilute sulfuric acid. The product got separated from the aqueous mixture, which was filtered and recrystallised from methanol.
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N([CH2:20][CH3:21])CC)C.[CH3:22][O:23][CH2:24][CH2:25][NH2:26].C(Cl)Cl>C1(C)C=CC=CC=1>[P:2]([N:26]([P:2]([C:21]1[CH:20]=[CH:14][CH:9]=[CH:10][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:25][CH2:24][O:23][CH3:22])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCN(CC)CC
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: COCCN
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COCCN(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
Chlorodiphenylphosphine (4.5 mL, 24 mmol, 2.3 equiv.) was dissolved in dry toluene (150 mL). Under an atmosphere of argon, an excess of triethylamine (5.0 mL, 36 mmol) was syringed into the reaction flask, which was stirred for 5 minutes. 2-Methoxyethylamine (0.9 mL, 10 mmol) was then syringed dropwise under argon. A precipitate immediately formed. The reaction mixture was then allowed to stir for 36 hrs at 110° C. The ammonium salt was filtered off and the solvent and the excess triethylamine and diphenylphosphine were removed in vacuo to leave a yellow residue. The residue was passed through a silica gel plug using a CH2Cl2 (15%)/petroleum ether (85%) mixture as the eluent. Removing the solvent afforded 2.905 g of a fine white powder in 63% yield. 1H NMR (RT, 300 MHz, CDCl3): δ=2.90 (2H, t, JHH=7.4 Hz, CH2O), 3.02 (3H, s, OCH3), 3.47 (2H, m, CH2), 7.29-7.44 (20H, m, ArH). 31P NMR (RT, 121 MHz, CDCl3): δ=64.6 ppm (s). MS (FAB+): 444 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[CH2:12]([N:14]([CH2:17]C)CC)[CH3:13].[CH3:19][OH:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1>[CH3:19][O:20][CH2:13][CH2:12][N:14]([CH3:17])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 1-bromomethyl-4-nitro-benzene (86.4 mg, 0.4 mmol) in tetrahydrofuran (800 μL) is added triethylamine (200 μL) and 2-(methoxyethyl)methylamine (43 μL, 0.4 mmol). The reaction mixture is shaken at 50° C. for 5 hours. To the reaction mixture is then added 500 μL each of tetrahydrofuran and methanol followed by 350 mg of PS-Ph3P resin to remove unreacted alkyl bromide and shaken for 1 h. The resin is filtered off, rinsed with dichloromethane and the filtrate concentrated. To the residue is added 500 μL each of tetrahydrofuran and methanol followed by 350 mg of PS-TsOH resin to remove unreacted amine. This is then shaken for two hours, filtered, washed with dichloromethane, and concentrated to yield (2-methoxy-ethyl)-methyl-(4-nitro-benzyl)-amine, which is used as such for the subsequent reaction.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[CH2:12]([C@H:15]1[O:17][C@@H:16]1[CH2:18][OH:19])[CH2:13][CH3:14].O>C1COCC1.[Cl-].[Na+].O.ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[O:11][C@@H:15]([CH2:12][CH2:13][CH3:14])[C@H:16]([OH:17])[CH2:18][OH:19]
Reactant: CCC[C@H]1O[C@@H]1CO
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC[C@H](Oc1cc(Cl)cc(Cl)c1)[C@H](O)CO
Temperature: 75 °C
Yield: 26 %

Procedure:
Add sodium hydroxide (1N, 9 mL) to a stirred solution of 3,5-dichlorophenol in THF (9 mL) followed by a solution of (R,R)-(3-propyl-oxiranyl)-methanol in THF (5 mL). Heat the reaction mixture at 75° C. overnight, cool to room temperature, add water, brine and dichloromethane, and separate the layers. The aqueous layer is extracted with dichloromethane, the combined organic extracts are washed successively with 1N sodium hydroxide and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Analysis of the crude reaction mixture by 1H NMR reveals a ˜2:1 mixture of the C-3:C-1 adducts. Purification of the crude residue on silica gel eluting with 0-25% EtOAc/hexanes gives the major title compound (332 mg, 26%). 1H NMR (DMSO-d6): 0.86 (dd, 3H, J=4, 4 Hz), 1.21-1.48 (m, 2H), 1.52-1.72 (m, 2H), 3.28-3.45 (m, 2H), 3.60-3.67 (m, 2H), 4.37-4.44 (m, 1H), 4.69 (dd, 1H, J=6, 6 Hz), 4.88 (d, 1H, J=5 Hz), 7.01-7.10 (m, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[Cl:33][C:34]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:35]=1[O:36][CH2:37][C:38]([OH:40])=O.[Cl:49][C:50]1[CH:51]=[C:52]([NH:64][CH3:65])[CH:53]=[CH:54][C:55]=1[O:56][CH2:57][CH2:58][N:59]([CH2:62][CH3:63])[CH2:60][CH3:61].C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:49][C:50]1[CH:51]=[C:52]([N:64]([CH3:65])[C:38](=[O:40])[CH2:37][O:36][C:35]2[CH:41]=[CH:42][C:43]([C:45]([F:48])([F:47])[F:46])=[CH:44][C:34]=2[Cl:33])[CH:53]=[CH:54][C:55]=1[O:56][CH2:57][CH2:58][N:59]([CH2:62][CH3:63])[CH2:60][CH3:61]
Reactant: CCN(CC)CCOc1ccc(NC)cc1Cl
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(N(C)C(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
293 mg (0.911 mmol) of TBTU and 123 mg (0.911 mmol) of HOBT were added to a suspension of 231 mg (0.911 mmol) of (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (intermediate product Z2b) in 5 mL abs. THF and the mixture was stirred for 10 minutes at RT. 180 mg (0.701 mmol) of [3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-methyl-amine and 0.18 mL (1.051 mmol) of ethyl-diisopropylamine were added, the mixture was stirred for 16 hours at RT and evaporated down i. vac. The residue was purified by column chromatography (silica gel, silica gel, dichloromethane/MeOH/conc. aqueous ammonia 85:15:1).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@@H:3]1[O:8][C:7](=[O:9])[C@@H:6]([CH3:10])[C@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@@H:6]([C@@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: CC(C)O
Reactant: C[C@@H]1O[C@H](C(Cl)(Cl)Cl)OC(=O)[C@H]1C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@@H](C)[C@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of (2S, 5S, 6S)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan-4-one obtained by procedure similar to Example 1-(7) were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol, stirred at room temperature for one hour, and 20 ml of water was added followed by ether extraction. The ether phase was dried over anhydrous sodium sulfate and the residue was subjected to distillation to give 0.4 g of isopropyl (2S, 3S)-2-methyl-3-hydroxybutanoate of the following formula. ##STR51##
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[N:26]=[C:27]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:28]=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(Cl)(=[O:39])C>>[C:14]([OH:35])(=[O:39])[CH3:15].[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]4[N:26]=[C:27]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:28]=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:19][CH:20]=2)=[O:35])[CH2:12][CH2:13]1
Reactant: CCCCNc1ccc2ncc(-c3ccc(C(=O)N4CCC(NC(=O)OC(C)(C)C)CC4)cc3)n2n1
Reactant: CC(=O)Cl
Product: CC(=O)O
Product: CCCCNc1ccc2ncc(-c3ccc(C(=O)N4CCC(N)CC4)cc3)n2n1
Temperature: 25 °C
Yield: 150.3 %

Procedure:
The solution of tert-butyl(1-(4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)benzoyl)piperidin-4-yl)carbamate (47 mg, 0.1 mmol) was cooled to 0° C. and treated with acetyl chloride (225 mg, 2.86 mmol). The reaction was maintained at room temperature for overnight. The resulting solution was concentrated under reduced pressure and the residue was purified by preparative HPLC (neutral) to afford (4-aminopiperidin-1-yl)(4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)phenyl)methanone acetic acid salt (34 mg, 79% yield) as a white solid: 1H NMR (METHANOL-d4) δ: 8.17-8.42 (m, J=8.3 Hz, 2H), 7.86 (s, 1H), 7.63 (d, J=9.6 Hz, 1H), 7.48-7.57 (m, J=8.6 Hz, 2H), 6.74 (d, J=9.6 Hz, 1H), 3.36-3.49 (m, 3H), 1.90-1.99 (m, 9H), 1.72 (quin, J=7.3 Hz, 2H), 1.63 (br. s., 2H), 1.44-1.55 (m, 2H), 1.01 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 393.2 [(M+H)+, calcd for C22H29N6O 393.2].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]#[CH:12])=O)=[CH:4][CH:3]=1.[ClH:13].O1CCOCC1>O1CCOCC1>[Cl:13][CH2:12][C:11]1[C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:8][CH:10]=1
Reactant: Cl
Reactant: C#CCS(=O)c1ccc(C)cc1
Solvent: C1COCCO1
Product: Cc1ccc2scc(CCl)c2c1
Temperature: 100 °C
Yield: 61 %

Procedure:
In 15 mL of dioxane, was dissolved 873.4 mg (4.9 mmol) of the compound obtained in Example 11. The resulting solution was stirred with heating at 100° C. for 70 minutes. The reaction system was cooled to room temperature, and 1.5 mL (6 mmol) of a 4 M hydrogen chloride-dioxane was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction system was vacuum concentrated, and was added 0.80 mL of cyclohexane. The obtained mixture was heated at 70° C. for 10 minutes and cooled to room temperature. The resulting precipitates were filtered to obtain 590.6 mg of 3-(chloromethyl)-5-methylbenzo[b]thiophene. The yield was 61%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([CH2:9][C:10]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Br:20])[CH:14]=1)([OH:12])[CH3:11])=[N+:7]=[N-:8].CCN(CC)CC>C(Cl)Cl>[N:6]([CH2:9][C:10]([O:12][S:2]([CH3:1])(=[O:4])=[O:3])([C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Br:20])[CH:14]=1)[CH3:11])=[N+:7]=[N-:8]
Reactant: CC(O)(CN=[N+]=[N-])c1cc(Br)ncc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CN=[N+]=[N-])(OS(C)(=O)=O)c1cc(Br)ncc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., methanesulfonyl chloride (2.04 ml, 3.00 g, 26.20 mmol) was dropwise added to a solution of 1-azido-2-(2-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol (6.00 g, 21.81 mmol) and NEt3 (3.65 ml, 2.65 g, 26.2 mmol) in DCM (200 ml). The reaction mixture was stirred at 0° C. for 1 h, then for another 1 h at 0° C. to rt. The reaction mixture was quenched with 1M aq. NaHCO3 soln. and diluted with DCM. The phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were dried over Na2SO4, filtered and concentrated. HPLC purification (Alltech Grom Saphir 65 Si 10 μM column, 250×50 mm, gradient n-heptane:EtOAc 0-1.6 min 85:15, 1.6-16 min 0:100, 16-21.2 min 0:100, flow 100 ml/min, detection 254 nm) yielded the title compound as well as recovered starting material that could be reacted again according to the above procedure. HPLC RtH4=0.96 min; ESIMS: 353, 355 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.28 (d, 1H), 7.56 (d, 1H), 4.08 (d, 1H), 3.82 (d, 1H), 3.22 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:8]=[C:9]([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)[CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])(=[O:6])=[O:5])[CH2:2][CH3:3].[Br:33][CH2:34][CH2:35]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)C>CN(C=O)C.O>[CH2:1]([S:4]([C:7]1[CH:8]=[C:9]([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)[CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[O:13][CH2:35][CH2:34][Br:33])(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCCBr
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of trans-2-(3-n-propylsulfonyl-4-hydroxy-5-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (4.66 g, 10 mmol), 1,2-dibromoethane (1.84 mL, 20.5 mmol) and K2CO3 (4.0 g) in DMF (20 mL) was heated with stirring at 80° C. for 1 h. The reaction mixture was cooled and partioned between ethyl ether and water. The organic layer was separated, dried, and evaporated to a crystalline mass. Recrystallization from ethyl ether-hexane afforded the title compound, mp 135°-136° C.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[C:17]([CH3:19])[C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:10]([CH3:20])[CH:9]=2)=O)[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][OH:23].Cl>N1C=CC=CC=1>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:6](=[N:22][OH:23])[C:8]1[CH:18]=[C:17]([CH3:19])[C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:10]([CH3:20])[CH:9]=1
Reactant: NO
Reactant: Cc1cc(C(=O)c2cccs2)cc(C)c1OCC(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C(=NO)c2cccs2)cc(C)c1OCC(=O)O
Reaction time: 3 h

Procedure:
4 g of 4-(2-thenoyl)-2,6-dimethyl-phenoxyacetic acid and 4 g of hydroxylamine hydrochloride were dissolved in 30 ml of pyridine and the mixture was kept for 3 hours at reflux. The mixture was then poured into an N aqueous solution of hydrochloric acid and the oxime extracted in ethyl ether. The remaining solid, after evaporation of the solvent, was a mixture of the two isomers of the oxime which melted at 152° C.
Reaction SMILES: [CH:1]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)=[N:6]1)([CH2:3][CH3:4])[CH3:2].[I:16]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]([N:5]1[CH:9]=[C:8]([I:16])[C:7]([C:10]2[S:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)=[N:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)n1ccc(-c2cc(C)cs2)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: CCC(C)n1cc(I)c(-c2cc(C)cs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 1-sec-butyl-3-(4-methyl-2-thienyl)-1H-pyrazole (4.9 mmol) in 14 mL dry 1V, N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (5.1 mmol) in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:dichloromethane 100:0 to 0:100) to afford 1.36 g 1-sec-butyl-4-iodo-3-(4-methyl-2-thienyl)-1H-pyrazole (78% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:44])[CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[C:32](Cl)=[N:31][C:30]=2[N:29]([CH3:43])[C:27]1=[O:28])([O-:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O>[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:44])[CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH2:37][CH:38]=[C:39]([CH3:40])[CH3:41])[C:32]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]3)=[N:31][C:30]=2[N:29]([CH3:43])[C:27]1=[O:28])([O-:17])=[O:16]
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Temperature: 65 °C
Reaction time: 16 h

Procedure:
2.20 g of 3-tert-butyloxycarbonylaminopiperidine is added at 65° C. to 4.40 g of 1-[2-(2-nitrophenyl)-2-oxoethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloroxanthine and 1.30 g of sodium carbonate in 50 mL of dimethylsulfoxide. The reaction mixture is stirred for approximately 16 hours at 65° C. After cooling to ambient temperature, it is poured onto a mixture of 600 mL of water and 100 g of ice. The precipitate formed is suction filtered and washed with water. The filter cake is dissolved in diethyl ether, and the solution is dried and evaporated down. The brown resinous flask residue is brought to crystallization with diisopropylether. Yield: 3.30 g (54% of theory); Rf value: 0.52 (silica gel, cyclohexane/ethyl acetate (3:7)); mass spectrum (ESI+): m/z=596 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].C(N(CC)CC)C>CN(C=O)C.O>[O:37]=[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3ccccc3)nc12
Reaction time: 48 h
Yield: 64.4 %

Procedure:
0.20 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.125 g 1,1′-carbonyl-diimidazole in 1 ml DMF were stirred at room temperature for 1 hour. 0.13 g 2-aminoacetophenone hydrochloride and 0.08 g triethylamine were added and stirring was continued for two days at room temperature. 200 ml water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with ethylacetate/hexane 4:6 yielded 0.18 g (64%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-2-phenyl-ethyl)-amide as a yellow solid; M.p.: 197–200° C.; MS (ISP): m/e=412 (M+H+).
Reaction SMILES: C(O)(=O)C.[N:5]1[C:14]2[CH:13]=[CH:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Na+].[OH-].[Na+]>CO.O>[C:16]1([NH:15][CH:12]2[CH2:13][C:14]3[N:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1=Cc2ncccc2CC1
Reactant: Nc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(NC2CCc3cccnc3C2)cc1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
Glacial acetic acid (1.2 ml, 20 mmol) was added dropwise to a stirred solution of 5,6-dihydroquinoline (1.31 g, 10 mmol) and aniline (1.86 g, 20 mmol) in methanol (4 ml). The solution was heated under reflux for 21h, cooled to room temperature, poured onto a mixture of saturated aqueous sodium chloride (25 ml) and water (25 ml), and the mixture was basified with 10N-NaOH and extracted with ether (3×25 ml). The extracts were concentrated in vacuo to give a dark orange oil which was chromatographed [alumina; ethyl acetate-toluene (1:24 to 1:4)] to give a solid. Recrystallisation from di-isopropyl ether gave the product (1.50 g), mp 102°-103°. (Found: C, 80.4; H, 76.2; N, 12.5. C15H16N2 requires C, 80.3; H, 7.2; N, 12.5%)