Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].[BrH:3].[CH3:4][NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[C:12]=2[OH:16])[C:7]1=[O:18]>O.[Pt](=O)=O>[BrH:3].[CH3:4][NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[C:12]=2[OH:16])[CH:7]1[OH:18]
Reactant: CNC1CCc2c(ccc(O)c2O)C1=O
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Br
Solvent: O
Product: CNC1CCc2c(ccc(O)c2O)C1O

Procedure:
In 5 volume parts of water is dissolved 0.200 part of 3,4-dihydro-2-methylamino-5,6-dihydroxy-1(2H)-naphthalenone hydrobromide and, using 0.050 part of platinum dioxide, the catalytic reduction is carried out in a current of hydrogen gas until a substantially stoichiometric amount of hydrogen gas is absorbed. The catalyst in the reaction mixture is filtered off and to the filtrate is added a mixture of ethyl ether, methanol and water. The procedure gives white prisms of 2-methylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide. Melting point: 165° to 169° C.(decomp.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13].CCN(CC)CC.[Cl:21][C:22](OC(Cl)(Cl)Cl)=[O:23]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][O:13][C:22]([Cl:21])=[O:23]
Reactant: O=[N+]([O-])c1cccc(Br)c1CCO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1c(Br)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
A solution of 2-(2-bromo-6-nitrophenyl)ethanol (500 mg, 2.03 mmol) and Et3N (206 mg, 2.03 mmol, dist. over KOH) in THF (5 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (442 mg, 2.23 mmol) in THF (5 ml, see above) for 10 min. It was stirred for 5 min while being cooled in an ice bath and for 1 h 45 min at room temperature. The mixture was filtered over Celite. Rewashing the filter cake with THF and removing the solvent and the excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2-bromo-6-nitrophenyl)ethoxycarbonyl chloride (625 mg, 99.8%) as a light brown oil.
Reaction SMILES: P(=O)(O)(O)O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[OH-].[NH4+:16]>C(O)(=O)C>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:9]2[CH2:10][CH2:11][NH:16][CH2:7][CH:8]=2)=[CH:7]1
Reactant: [NH4+]
Reactant: c1ccc2[nH]ccc2c1
Agent: O=P(O)(O)O
Agent: [OH-]
Solvent: CC(=O)O
Product: C1=C(c2c[nH]c3ccccc23)CCNC1
Temperature: 100 °C

Procedure:
50 ml of N aqueous phosphoric acid and 39.3 g of 4-piperidine-monohydrate hydrochloride were added with stirring under nitrogen to a solution of 10 g of indole in 200 ml of acetic acid heated at 95°-100° C and the mixture was heated for an hour at 100° C and then allowed to cool. The mixture was poured into 350 ml of concentrated ammonium hydroxide containing ice and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and water containing sodium chloride, were dried over magnesium sulfate and evaporated to dryness to obtain 14.7 g of raw product. The latter was crystallized from 75 ml of methanol and the mixture was filtered under reduced pressure. The product was washed with methanol and ether to obtain 1.42 g of 4-([1H]-indol-3-yl)-1,2,3,6-tetrahydro-pyridine melting at 185°-186° C.
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[N:24]=[N:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29](O)=[O:30].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH:5][C:6]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([NH:21][C:29]([C:28]3[CH:27]=[C:26]([CH3:32])[N:25]=[N:24][C:23]=3[Cl:22])=[O:30])[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C1CCN(Cc2cccc(N)c2)CC1
Reactant: Cc1cc(C(=O)O)c(Cl)nn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(C(=O)Nc2cccc(CN3CCC(C(=O)NC(C)(C)C)CC3)c2)c(Cl)nn1

Procedure:
A solution of 1-(3-amino-benzyl)-piperidine-4-carboxylic acid tert-butylamide BB-4 (400 mg, 1.4 mmol) in DCM (15 mL) is treated successively with 3-chloro-6-methyl-pyridazine-4-carboxylic acid (239 mg, 1.4 mmol), EDC (344 mg, 1.8 mmol) and DMAP (25.3 mg, 0.207 mmol) at RT overnight. The reaction mixture is washed twice with sat.aq. NaHCO3 (15 mL). The aqueous phase is extracted twice with DCM (2×10 mL). The combined organic layers are dried over MgSO4 and filtered. The solvent is evaporated under reduced pressure. The residue is purified by prep HPLC E delivering the title compound (53 mg, 36%) as a light brownish powder, LC-MS A: tR=0.60 min; [M+H]+=444.12.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[CH3:19][O:20][CH2:21]Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:19][O:20][CH3:21])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COCCl
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCn1ncc(Cl)c(Cl)c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 583.7 %

Procedure:
4,5-Dichloro-2H-pyridazin-3-one (30 g, 182 mmol), N,N-diisopropylethylamine (47.5 mL, 258 mmol) and 4-dimethylaminopyridine (2.20 g, 18.2 mmol) were dissolved in 200 mL of methylene chloride, to which was slowly added dropwise chloromethyl methyl ether (16.6 mL, 21.8 mmol) while maintaining at 0° C. The mixture was stirred for 3 h at room temperature. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution, distilled under reduced pressure, and separated-purified by column chromatography (10% methylene chloride/ethyl acetate) to give the title compound (26.6 g, Yield: 70%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH2:40](I)[CH3:41]>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:40][CH3:41])[C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc2n1CC
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
To a suspension of NaH (0.01 g, 0.38 mmol) in DMF (5 mL) was added 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid ethyl ester (0.1 g, 0.19 mmol), obtained in step (vi) of Example 124, at 0° C., and stirred for 15 min. Ethyl iodide (0.09 g, 1.08 mmol) was added to this at the same temperature and this reaction was stirred for 1 h. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 15% ethyl acetate and pet ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (0.08 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([F:14])[C:3]=1[CH:15]([OH:20])S([O-])(=O)=O.[Na+].C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([F:14])[C:3]=1[CH:15]=[O:20]
Reactant: COC(=O)/C=C/c1cc(F)c(C(O)S(=O)(=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.4 %

Procedure:
Under an atmosphere of nitrogen, sodium {2,6-difluoro-4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl}(hydroxy)methanesulfonate (1.211 kg, 3.52 mol) was to a 100 L vessel followed by potassium carbonate (0.974 kg, 7.05 mol). Water (9.1 L) was added and the agitator was started. Ethyl acetate (9.1 L) was added. The mixture was agitated at 25° C. for 5 hours. The agitator was stopped and the mixture was allowed to stand for 14 hours at 25° C. The lower aqueous phase was removed and discarded. The upper organic phase was concentrated under reduced pressure to afford a pale brown solid. The solid was dried in vacuo to afford (E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate as a brown solid (608 g, 76%). 1H NMR (500 MHz, DMSO, 27° C.) δ 3.77 (3H, s), 6.94 (1H, d), 7.66 (1H, d), 7.71 (2H, d), 10.20 (1H, s).
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6])=[CH:13][CH:12]=1
Reactant: C#CC(C)(C)C(=O)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CC(C)(C)C(=O)COc1ccc(Cl)cc1
Yield: 94 %

Procedure:
A solution of 98 g (0.67 mole) of 1-chloro-3,3-dimethyl-pent-4-in-2-one is added dropwise, with stirring, to a boiling mixture of 86.1 g (0.67 mole) of 4-chlorophenol and 92.5 g (0.67 mole) of potassium carbonate powder in 500 ml of acetone. After five hours the mixture is filtered, the filtrate is evaporated, the residue is taken up in 250 ml of methylene chloride and this solution is washed with 200 ml of 1N sodium hydroxide solution and 200 ml of water. After the solvent has been distilled off, 149 g (that is to say 94% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-pent-4-in-2-one are obtained as a colorless viscous oil, which upon standing solidifies to crystals.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH:9]([CH3:11])[CH2:8][N:7]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH2:6][CH:5]1[OH:21])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH:4]1[CH2:10][CH:9]([CH3:11])[CH2:8][N:7]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH2:6][CH:5]1[OH:21]
Reactant: CC1CC(N=[N+]=[N-])C(O)CN(S(=O)(=O)c2ccccn2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1CC(N)C(O)CN(S(=O)(=O)c2ccccn2)C1
Temperature: 45 °C

Procedure:
4-Azido-6-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol (0.33 g, 1.06 mmol) was dissolved in THF (50 ml) and H2O (0.2 ml). PPh3 (0.42 g, 1.59 mmol) was added to this solution. The reaction mixture was stirred at 45° C. over night. TLC showed no starting material left. THF was evaperated, azeotroped by toluene (2×100 ml). The resulting thick oil was dissolved in MeOH, treated with HCl in ether to adjust pH to acidic. More ether was added and the solution turned cloudy to give the title compound as a white precipitate (0.21 g, 71% yield) MS (M+H+) 286.0; 1H-NMR (400 Hz, CD3OD): d (ppm): 8.72(d, 1H), 8.14-7.99(m, 2H), 7.68(m, 1H), 3.85-3.69(m, 2H), 3.38-3.22(m, 3H), 3.10-3.04(m, 2H), 2.04(m, 1H), 1.82-1.66(m, 2H), 1.02(d, 3H)
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])=[CH:15][CH3:16])[C:8]=1[NH2:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])=[CH:15][CH3:16])[C:8]=1[NH:9][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: CC=C(C)c1cccc(C)c1N
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=C(C)c1cccc(C)c1NC(=O)CCl
Reaction time: 8 h
Yield: 102.2 %

Procedure:
0.007 mole of chloroacetyl chloride was added dropwise to a mixture of 0.007 moles of 2-methyl-6-(1-methylprop-1-enyl)-aniline and 0.008 moles (1.15 ml) of triethylamine in methylene chloride at about but below 20° C. The mixture was then refluxed and then allowed to stand overnight at room temperature. The mixture was then again refluxed and allowed to stand for two days (over the weekend) at room temperature. Thin layer chromatographic (plate) analysis showed the presence of a small amount of starting material. An additional 0.55 ml of triethylamine and 0.3 ml of chloroacetyl chloride was added and the mixture again refluxed and allowed to stand overnight at room temperature. The mixture was then washed with aqueous sodium bicarbonate, dried and evaporated affording 1.7 g of the title compound as a slightly crystallized oil (m.p. 71°-74° C.).
Reaction SMILES: O[C:2](=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([C:33](=[O:35])[CH3:34])[C:22]1=[O:36])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:38]>C1(C)C=CC=CC=1>[Cl:38][C:2](=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([C:33](=[O:35])[CH3:34])[C:22]1=[O:36])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[CH:5][CH:4]=1
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1C(=O)C(=C(Cl)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 2b from 3-[1-hydroxy-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone and phosphorus pentachloride in toluene.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C:21]2=[O:26].CCN(CC)CC>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C:21]2=[O:26])(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCc2c(O)cccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2c(OS(=O)(=O)C(F)(F)F)cccc21
Temperature: 25 °C
Yield: 67 %

Procedure:
Triflic anhydride (152 g, 0.54 mol) was added dropwise to solution 80 g of compound 86 and 60 g of NEt3 in 1 L CH2Cl2 at 0° C. The resulting mixture was refluxed for 2 h, cooled to room temperature, filtered, washed with water (0.5 L), aqueous citric acid (50 g/0.5 L), brine (0.5 L), dried on Na2SO4, and evaporated to give about 100 g (67%) of compound 87 as dark liquid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>>[N:22]([C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[N+:23]=[N-:24]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1ccc(N(C)c2nc(N=[N+]=[N-])nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), sodium azide (97.5 mg, 1.5 mmol) in 5 mL of solvent (THF:MeOH:water=3:1:1) by a procedure similar to that of Example 120 (4%). 1H NMR (CDCl3): 8.45 (d, J=8.4 Hz, 1H), 7.78-7.72 (m, 1H), 7.27-7.22 (m, 2H), 7.19-7.14 (m, 2H), 6.95 (d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [C:1]1(=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[N:10]O.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=[O:22])=CC=1>>[C:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[C:1]([OH:12])=[O:22])#[N:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1C(=NO)Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: N#CCc1ccccc1C(=O)O
Temperature: 50 °C
Yield: 73.3 %

Procedure:
Indan-1,2-dione-2-oxime (35 g, 0.22 mol) was added to a solution of 402.5 ml 8% NaOH, and the mixture was heated to 50° C. Then p-toluenesulfonyl chloride (54.25, 0.28 mol) was added in portions to the mixture, and the mixture was heated at 80° C. for 15 min. After cooled to room temperature, the precipitate was removed from the mixture. The filtrate was acidified with concentrated HCl to pH=3-4 and the precipitate was collected and dried to give colorless solid (26 g, 74% yield). LC-MS: 162 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)CC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2c(c1)Nc1sc3ccccc3c1C(N1CCNCC1)=N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 136.4 %

Procedure:
8-Fluoro-12-(4-tert-butoxycarbonylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (1.6 g) was dissolved in trifluoroacetic acid (8 ml) and the mixture was stirred at room temperature for 3 hours. Trifluoroacetic acid was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution was added. The mixture was stirred at room temperature for 2 hours and the ethyl acetate layer was dried over magnesium sulfate. After natural filtration, the solvent was evaporated and the residue was separated and purified by silica gel column chromatography (chloroform:methanol=4:1) to give 8-fluoro-12-(piperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (1.7 g), which was treated with maleic acid to give 8-fluoro-12-(piperazin-1-yl)-6H-[1]betzothieno[2,3-b][1,5]benzodiazepine.{fraction (3/2)} maleate.½ hydrate (347 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([NH:8]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][CH3:19])=[O:17])[CH2:3]1.[H][H]>[Pd].CO>[NH2:8][CH:7]1[CH2:6][CH2:5][N:4]([C:16]([O:18][CH3:19])=[O:17])[CH2:3][CH:2]1[CH3:1]
Reactant: COC(=O)N1CCC(NCc2ccccc2)C(C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)N1CCC(N)C(C)C1

Procedure:
A mixture of 40 parts of methyl 3-methyl-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and 160 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dry. The residue was distilled (bp. 80° C. at 0.1 mm. pressure). The distillate was further purified by gas-chromatography (at 215° C. and at 10 lbs/sq. inch), yielding 8.6 parts of methyl 4-amino-3-methyl-1-piperidinecarboxylate (interm. 27)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([NH:8][C:9]#[N:10])[CH:7]=1.C[NH:18]C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([NH:8][C:9]([NH2:18])=[NH:10])[CH:7]=1
Reactant: N#CNc1cc(Cl)ccc1N1CCOCC1
Reactant: CNC
Solvent: CCO
Product: N=C(N)Nc1cc(Cl)ccc1N1CCOCC1

Procedure:
In a similar manner to that described in Example 272, N-(5-chloro-2-morpholinophenyl)cyanamide (2.3 g) in ethanol (10 ml) and a 33% ethanolic solution of dimethylamine (6 ml) were heated under reflux for 4 hours to give 1,1-dimethyl-2-(5-chloro-2-morpholinophenylguanidine (m.p. 135°-138° C.) which was recrystallised from hexane and then was converted into its monofumarate salt (m.p. 223°-225° C.) which was recrystallised from methanol.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([CH3:32])[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH2:26][O:25]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:33](O)[CH2:34][OH:35].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH2:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([CH3:32])[CH2:30][CH2:29][CH2:28][C:27]2([O:35][CH2:34][CH2:33][O:31]2)[CH2:26][O:25]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1(CCCCOCc2ccccc2)CCCC(=O)CO1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1(CCCCOCc2ccccc2)CCCC2(CO1)OCCO2
Yield: 99 %

Procedure:
p-Toluenesulfonic acid (200 mg) is added to a solution of 2-(4'-benzyloxybutyl)-2-methyl-oxepan-6-one (5.9 g, 0.021 mol), ethylene glycol (30 ml) and dry benzene (200 ml) and the mixture is refluxed for 17 hours in a nitrogen atmosphere with a Dean-Stark apparatus. The solution is cooled and poured into a satd. NaHCO3 solution. The benzene layer is separated and the aqueous phase is extracted with ether (3×50 ml). The organic layers are combined, dried (MgSO4) and the solvents removed at reduced pressure. The crude product is chromatographed on SilicAR CC-7 (125 g) in hexane. Elution with 10% ethyl acetate/hexane gives 2-(4'-benzyloxybutyl)-6,6-ethylenedioxy-2-methyloxepane as a clear colorless oil (6.7 g, 99%): nmr (CDCl3) δ1.10 (s., 3H, CH3), 3.5 (m, 4H, O--CH2 --and O--CH2 --CH2), 3.96 (s, 4H, ketal) 4.48 (s, 2H, O--CH2 --Ph), 730 (s, 5H, aromatic).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:15])[CH2:7][CH:8]([OH:14])[CH:9]([OH:13])[CH2:10][CH2:11][OH:12].N1C=CC=CC=1.Cl>>[CH3:1][S:2]([O:15][CH2:6][CH2:7][CH:8]([O:14][S:2]([CH3:1])(=[O:4])=[O:3])[CH:9]([O:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:11][O:12][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(O)C(O)CCO
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC(OS(C)(=O)=O)C(CCOS(C)(=O)=O)OS(C)(=O)=O

Procedure:
Methanesulfonyl chloride (30.4 mL) was added to a solution of hexane-1,3,4,6-tetraol (8.3 g) in pyridine (150 mol) at −45° C. After a reaction time at ice-bath temperature of three hours, the mixture was poured into hydrochloric acid (4 N). The resulting precipitate was filtered off with suction. The product with a molecular weight of 462.54 (C10H22O12S4) was obtained in this way; MS (ESI): 463 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCCO)o1
Reactant: Cc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol (1.32 g), 2-methylphenol (865 mg), tributylphosphine (1.21 g) and tetrahydrofuran (30 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.51 g) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[4(2-methylphenoxy)butyl]oxazole was obtained as crystals (1.61 g, 96%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. Recrystallization from acetone-isopropyl ether gave colorless prisms. Melting point 71-72° C.