Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)CN.[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][NH:11][CH2:12][CH2:13][NH2:14].[C:15]([NH:17][C:18](=[N:21][CH3:22])SC)#[N:16]>>[C:15]([NH:17][C:18]([NH:21][CH3:22])=[N:14][CH2:13][CH2:12][NH:11][CH2:10][C:6]1[S:5][CH:9]=[CH:8][N:7]=1)#[N:16]
Reactant: NCCNCc1nccs1
Reactant: CN=C(NC#N)SC
Solvent: NCCN
Product: CNC(=NCCNCc1nccs1)NC#N

Procedure:
Reacting ethylenediamine with 2-chloromethylthizaole by the procedure of Example 34, then reacting the resulting N-(2-thiazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a), gives N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N' -[2-(2-thiazolylmethylamino)ethyl]guanidine trihydrochloride.
Reaction SMILES: [C:1]1([C:7]([CH:14]2[CH2:19][CH2:18][N:17]([O:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:16][CH2:15]2)=[CH:8][C:9](OCC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[CH3:3][CH2:2][CH2:1][CH:7]([CH3:14])[CH3:8].[C:1]1([CH:7]([CH:14]2[CH2:19][CH2:18][N:17]([O:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:16][CH2:15]2)[CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=C(c1ccccc1)C1CCN(OC(=O)C(C)(C)C)CC1
Solvent: CCO
Product: CC(C)(C)C(=O)ON1CCC(C(CC=O)c2ccccc2)CC1
Product: CCCC(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 133.6 %

Procedure:
Ethyl 3-phenyl-3-(1-tert-butylcarbonyloxypiperidin-4-yl)acrylate (˜25 mmol) was dissolved in ethanol (200 mL) and the solution purged with argon. 20% Palladium hydroxide (2 g) was added and the resulting mixture was stirred at room temperature under an atmosphere of hydrogen (balloon) for 72 h. The mixture was purged with argon, filtered and the filtrate evaporated. The crude product was purified by silica gel chromatography (eluent:isohexane then 35% ethyl acetate in isohexane) to give the sub-titled compound (5.3 g).
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].N1CCCCC1>C1(C)C=CC=CC=1>[OH:13][C:4]1[C:3]([CH:1]=[C:17]([N+:14]([O-:16])=[O:15])[CH3:18])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC[N+](=O)[O-]
Reactant: COC(=O)c1cccc(C=O)c1O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C=C(C)[N+](=O)[O-])c1O
Yield: 81.9 %

Procedure:
A mixture of 1.90 g of methyl 3-formyl-2-hydroxybenzoate, 3.0 g of nitroethane, 0.15 ml of piperidine and 30 ml of toluene is refluxed overnight while removing water. The reaction mixture is poured into ice-water and the aqueous mixture is extracted with ethyl acetate. The extract is washed successively with 10% hydrochloric acid and an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is recrystallized from methanol to give 2.05 g of methyl 2-hydroxy-3-(2-nitro-1-propenyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])[C:20]=2[CH3:31])(=[O:18])=[O:17])[C:12]([OH:14])=O)=[O:8])=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[ClH:1].[CH3:31][C:20]1[C:21]([N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])=[CH:22][CH:23]=[CH:24][C:19]=1[S:16]([NH:15][C@H:11]([C:12]([N:36]1[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]1)=[O:14])[CH2:10][NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])(=[O:17])=[O:18]
Reactant: CN1CCNCC1
Reactant: Cc1c(N2CCCC2=O)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(N2CCCC2=O)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)N1CCN(C)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 87 (802 mg, 1.65 mmol) was dissolved in 10 ml DCM and N-methyl piperazine (0.73 ml, 6.60 mmol) was added followed by DIPEA (0.55 ml, 3.3 mmol) and TBTU (636 mg, 1.98 mmol). After 1 h stirring at RT the solution was evaporated to dryness and purified by silica gel chromatography. The compound was dissolved in DCM, HCl (2 M in diethyl ether (5 ml)) was added and the solvents were evaporated yielding a white powder. Yield: 651 mg, 70%. MS (ES+): m/e=568.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.Cl.[NH4+].[O-][Mo:17]([O-])(=O)=O.[O-][Mo]([O-])(=O)=O>O>[Mo:17].[CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1
Reactant: O=[Mo](=O)([O-])[O-]
Agent: CC1CC(C)(C)NC2CCCCC12
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: [Mo]

Procedure:
2,2,4-Trimethyl decahydroquinoline molybdate having a 2/1 molybdenum/2,2,4-trimethyl decahydroquinoline molar ratio was prepared as follows. 10 grams 2,2,4-trimethyl decahydroquinoline, 16.30 grams of a 37 wt.% aqueous HCl solution and 250 ml water were dissolved together and heated to reflux in a 500 ml round-bottomed flask equipped with a stirrer and water-cooled condenser. 28.12 grams ammonium dimolybdate was dissolved in 50 ml hot water. The second solution was added to the first solution. A yellow precipitate formed immediately.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].CN1CCOCC1.ClC(OCC(C)C)=O.[C:21]([O:25][C:26](=[O:35])[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH2:34])([CH3:24])([CH3:23])[CH3:22]>ClCCl>[C:21]([O:25][C:26](=[O:35])[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:1](=[O:5])[CH:2]=[CH2:3])([CH3:24])([CH3:22])[CH3:23]
Reactant: C=CC(=O)O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of acrylic acid (2.50 g, 34.7 mmol) in dichloromethane (80 mL) at 0 degrees Celsius was added N-methyl-morpholine (4.73 g, 46.8 mmol), followed by isobutyl chloroformate (6.37 g, 46.8mmol). After 30 minutes, a solution of (2-amino-phenyl)-carbamic acid tertbutyl ester (5.80 g, 27.8 mmol) in dichloromethane (50 mL) was added dropwise to the refluxing reaction mixture over 30min. After the reaction was completed (2 hours later), the reaction mixture was allowed to cool down to room temperature, poured into ice water, and extracted with dichloromethane (30 mL×3). The organic layer was washed with water, dilute sodium bicarbonate solution, 0.1M HCl, water, and brine in turn. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/petroleum ether=1/4 (v/v) to obtain the desired product (2.5g, 34%). MS: calc'd 263 (MH+), exp 263 (MH+).
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl>>[OH:14][C@@H:13]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:12]1[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COP([O-])OC
Agent: Cl
Product: COc1ccc([C@@H](O)P(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
The solution of ALE in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring for 30 minutes at room temperature, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then, p-methoxybenzaldehyde (0.40 mmol) was added thereto. After reacting for 115 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy(p-methoxyphenyl)methylphosphonate as a final product in a yield of 88%. The chemical reaction in this Example is shown in chemical formula 30. ##STR24##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11](=[O:16])[N:10]2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[N:18]=2)=[CH:5][CH:4]=1.CO.N(CC)CC>C(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C:13]([CH3:14])([CH3:15])[O:12][C:11](=[O:16])[N:10]2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[N:18]=2)=[CH:7][CH:8]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:13]([CH3:14])([CH3:15])[O:12][C:11](=[O:16])[N:10]2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[N:18]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2N(c3ccnc(N[C@@H](C)c4ccccc4)n3)C(=O)OC2(C)C)cc1
Agent: O=C=O
Solvent: CCNCC
Solvent: CO
Product: COc1ccc([C@@H]2N(c3ccnc(N[C@@H](C)c4ccccc4)n3)C(=O)OC2(C)C)cc1
Product: COc1ccc([C@H]2N(c3ccnc(N[C@@H](C)c4ccccc4)n3)C(=O)OC2(C)C)cc1

Procedure:
4-(4-methoxyphenyl)-5,5-dimethyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one (example 54, 62 mg) was resolved in on a column (AD-H 4.6×100 mm) with 30% MeOH modified with 0.2% Et2NH in CO2 to give (S)-4-(4-methoxyphenyl)-5,5-dimethyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one and (R)-4-(4-methoxyphenyl)-5,5-dimethyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 4-(phenylethynyl)benzoate (7.81 g, 31.2 mmol) in THF (80 mL) was added MeOH (15 mL) and a solution of LiOH (5.24 g, 124 mmol) in water (15 mL). The reaction was stirred at room temperature and for 4 h. The reaction was acidified with 1 N HCl (50 mL), and 4-(phenylethynyl)benzoic acid was isolated (5.78 g, 83%) as a white solid; 1H-nmr (400 MHz, CDCl3) δ 8.11 (d, J=8.0 Hz, 2H), 7.75-7.68 (m, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.62-7.56 (m, 2H), 7.52-7.47 (m, 1H), 7.43-7.36 (m, 3H); LC (275 nM) 5.12 min (>98%); MS (ESI) m/z=222.9.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([Br:24])[CH:7]=[C:8]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:9]=2CO)[NH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:24][C:6]1[C:5]2[NH:4][N:3]=[CH:2][C:10]=2[C:9]2[CH2:18][O:17][C:15](=[O:16])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:8]=2[CH:7]=1
Reactant: COC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Br)c2c1CO)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2COC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
(S)-Dimethyl 2-((3,7-dibromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (440 mg, 1.065 mmol) was dissolved in toluene (30 mL). p-Toluenesulfonic acid monohydrate (28 mg, 0.147 mmol) was added to the mixture. Reaction was warmed to reflux and held for 18 hours with stirring. Mixture was cooled to room temperature and then diluted with ethyl acetate. Material was washed with aqueous sodium bicarbonate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as amber oil in 42% yield. MS (M+H)+=367.2, 369.2.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:34])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([S:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:33])[CH2:3][CH2:2]1.[OH:35]OS([O-])=O.[K+].[OH2:41]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:34])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([S:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)(=[O:35])=[O:41])[CH:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:33])[CH2:3][CH2:2]1
Reactant: O
Reactant: Cc1cc(-c2cnc3c(NCC(C)C)cc(Sc4ccccc4)nn23)ccc1C(=O)NC1CC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cnc3c(NCC(C)C)cc(S(=O)(=O)c4ccccc4)nn23)ccc1C(=O)NC1CC1
Temperature: 0 °C

Procedure:
To a solution of 105 mg (223 μmol) of N-cyclopropyl-2-methyl-4-{8-[(2-methylpropyl)amino]-6-(phenylsulfanyl)imidazo[1,2-b]pyridazin-3-yl}benzamide, which was prepared according to example 197, in 15 mL of DMF was added and 684 mg (1113 μmol) OXONE (potassium peroxymonosulfate) in small portions. The mixture was stirred over night, then cooled to 0° C. and poured onto 200 mL of cold water. The precipitate was collected and purified with normal phase chromatography to yield 97 mg of the title compound as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][CH3:10].C([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:20][CH2:21][CH2:22]C#N)CC.C(Cl)Cl.[CH3:28][OH:29]>CCOCC.C(Cl)Cl>[CH2:7]([CH:18]1[CH2:19][CH2:14][N:15]([CH2:20][CH2:21][CH2:22][C:28]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][O:9][CH3:10])=[O:29])[CH2:16][CH2:17]1)[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: COCc1ccccc1I
Reactant: CCCC1CCCCN1CCCC#N
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC1CCN(CCCC(=O)c2ccccc2COC)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A 10 mL oven-dried flask was charged with Mg turnings (88 mg, 3.6 mmol) andweactivated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of 1-Iodo-2-methoxymethylbenzene (0.67 g, 2.7 mmol) in Et2O (4 mL) and the reaction mixture was allowed to reflux for 1 hours. A suspension of compound 8 (0.38 g, 1.8 mmol) in CH2Cl2 (4 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) and stirred at rt for 2 hours followed by addition of NaOH (10 mL, 2 M). Addition of THF (15 mL) was followed by extraction with ethyl acetate (3×50 mL) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), and the organic phases were dried (MgSO4) and evaporated to dryness to produce 0.51 g of crude 22. The crude product was subjected to CC [eluent:CH2Cl2:MeOH (99:1)] to give pure 22 (0.14 g, 23%); LC-MS [M+H]+ 331 (cald. 331.5).
Reaction SMILES: Cl.CN.C[CH2:5][N:6](CC)CC.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18].Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([S:19]([NH:6][CH3:5])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methylamine hydrochloride (5.5 g, 81.46 mmol) was dissolved in DCM (300 ml), and Et3N (40 ml, 285.11 mmol) was added thereto. The reaction solution was then cooled to 0° C.; 3,4-dichlorobenzenesulfonyl chloride (20.00 g, 81.46 mmol) dissolved in DCM (50 ml) was then added dropwise, and stirring was carried out overnight at room temperature (TLC monitoring, silica gel, ethyl acetate). When the reaction was complete, 0.5 N HCl was added, the phases were separated, and the organic phase was washed with water and dried (sodium sulfate). The solvent was removed using a rotary evaporator. Purification was carried out by column chromatography on silica gel (gradient heptane/ethyl acetate 4:1 to 2:1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41](=[O:43])[CH3:42])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([C:30]2[CH:31]=[CH:39][C:35]([C:36]([CH:6]3[NH:1][CH2:2][CH2:3][O:4][CH2:5]3)=[O:37])=[C:34]([O:40][C:41](=[O:43])[CH3:42])[C:33]=2[CH3:32])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(c2ccc(C(=O)C3COCCN3)c(OC(C)=O)c2C)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.9 %

Procedure:
Morpholine (0.034 g, 0.385 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.074 g, 0.385 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.048 g, 0.128 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.017 g, 0.0383 mmol, 30%).
Reaction SMILES: [CH2:1](C1C2N=C(OC)C=CC=2CC2(OCCO2)C1)C.[CH3:19][O:20][C:21]([C:23]12[C:38](=[O:39])[CH:27]([CH:28]([CH3:37])[C:29]3[C:34]1=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[N:30]=3)[CH2:26][C:25](=[CH2:40])[CH2:24]2)=[O:22]>>[CH3:19][O:20][C:21]([C:23]12[C:38](=[O:39])[CH:27]([CH:28]([CH2:37][CH3:1])[C:29]3[C:34]1=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[N:30]=3)[CH2:26][C:25](=[CH2:40])[CH2:24]2)=[O:22]
Reactant: CCC1CC2(Cc3ccc(OC)nc31)OCCO2
Reactant: C=C1CC2C(=O)C(C(=O)OC)(C1)c1ccc(OC)nc1C2C
Product: C=C1CC2C(=O)C(C(=O)OC)(C1)c1ccc(OC)nc1C2CC

Procedure:
10-Ethyl-7,8,9,10-tetrahydro-2-methoxy-7-methylene-11-oxo-5,9-methanocycloocta[b]pyridine-5(6H)-carboxylic Acid Methyl Ester (6c) was prepared from 4c in the same manner as described for the preparation of compound 6b: IR (neat) 2953, 1743, 1724, 1601, 1577, 1479, 823 cm-1 ; 1H NMR (major isomer) δ6.94 (d, 1H, J=8.7 Hz), 6.56 (d, 1H, J=8.7 Hz), 4.73 (s, 1H), 4.41 (s, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.01 (m, 1H), 2.90 (m, 2H), 2.75 (m, 1H), 2.55 (m, 2H), 1.85 (m, 1H), 1.60 (m, 1H), 1.22 (t, 3H, J=7.4 Hz); 13C NMR δ209.0, 208.6, 171.5, 171.4, 162.9, 162.4, 155.2, 154.2, 139.3, 139.1, 137.3, 124.6, 124.2, 115.9, 115.7, 109.7, 62.9, 62.3, 53.4, 53.3, 53.0, 52.6, 50.0, 48.1, 47.6, 47.3, 43.5, 36.0, 29.9, 21.6, 11.6, 11.4; MS m/z 315 (M+), 287, 256, 228.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2)=[CH2:2].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[N:14]/[OH:15])/[CH2:7][CH2:6]2)=[CH2:2]
Reactant: C=Cc1ccc2c(c1)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=Cc1ccc2c(c1)CC/C2=N\O
Temperature: 60 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a mixture of 5-vinyl-2,3-dihydro-1H-inden-1-one (Preparation 87A, 1.05 g, 6.64 mmol), hydroxylamine hydrochloride (0.553 g, 7.96 mmol) and methanol (20 mL) at room temperature was added sodium acetate (0.653 g, 7.96 mmol). The reaction mixture was stirred at 60° C. for 1 hr and at room temperature overnight. The heterogeneous mixture was concentrated and water (20 mL) was added. The mixture was heated to ˜60° C. and then cooled. The solid was filtered, washed with a mixture of water and ethanol (1:1) and dried to give (E)-5-vinyl-2,3-dihydro-1H-inden-1-one oxime (1.13 g, 6.52 mmol, 98% yield) as a yellow solid. The product had an HPLC ret. time=2.72 min. (condition C); LC/MS M+1=174.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29].[N:40]1([CH2:46][C:47]2[CH:48]=[C:49]([CH:55]=[CH:56][CH:57]=2)[O:50][CH2:51][CH2:52][CH2:53][NH2:54])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:28]([NH:54][CH2:53][CH2:52][CH2:51][O:50][C:49]2[CH:55]=[CH:56][CH:57]=[C:47]([CH2:46][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:48]=2)=[O:29])[CH3:25])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(CCN(C)CCCCCCN)c2ccccn2)cc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(CN(CCN(C)CCCCCCNC(=O)NCCCOc2cccc(CN3CCCCC3)c2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 63, using 0.58 g (1.5 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propylamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=645 ([M+H]+, 8), 121 (100); IR (KBr): 1635 cm-1 (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 75° C. (ethanol/ether).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[CH:8]=1)#[N:2].Cl.[OH-:20].[Na+]>>[C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[CH:8]=1)(=[O:20])[NH2:2]
Reactant: [OH-]
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Product: Cc1cccc(C)c1-n1cc(C(N)=O)c(=O)[nH]c1=O

Procedure:
A mixture of 5-cyano-1-(2,6-dimethylphenyl)uracil (0.01 mol) and 50 ml of NaOH (2.5 N) is heated for 2 hours at about 90°. After cooling, a small amount of dilute HCl is added to precipitate product. The mixture is filtered and the collected precipitate washed with water to yield 5-carbamoyl-1-(2,6-dimethylphenyl)uracil.
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=O)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1>[N:19]1([C:18]2[C:13]([N:10]3[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]3)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N2CCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: c1cnc(N2CCNCC2)c(N2CCCC2)c1
Reaction time: 0.33 h

Procedure:
1-[1,1-Dimethylethoxycarbonyl]-4-[3-(1-pyrrolidinyl)-2-pyridinyl]piperazine (PREPARATION 47, 0.26 g) is dissolved in 1.3 ml of THF and cooled to 0°. Trifluoroacetic acid (1.3 ml) is added and the reaction is stirred at 0° for 20 min, and then warmed to 20°-25° for 20 min. Then the reaction is poured into 1N aqueous sodium hydroxide and extracted with (10/90, 2×50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 7.64, 6.81, 661, 3.05-2.94, 2.86-2.79 and 1.78-1.65 δ.