Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:14]3[C:10](=[CH:11][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:13]=3)[CH:9]=[C:8]([Br:23])[CH:7]=2)=[CH:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]1=2.[CH2:28]([Li])CCC.CI.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.O>[S:1]1[C:5]([C:6]2[C:14]3[C:10](=[C:11]([CH3:28])[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:20])[CH3:21])[N:13]=3)[CH:9]=[C:8]([Br:23])[CH:7]=2)=[CH:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]1=2
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)CCOCn1cc2cc(Br)cc(-c3cc4ccccc4s3)c2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c2cc(Br)cc(-c3cc4ccccc4s3)c2nn1COCC[Si](C)(C)C
Temperature: -65 °C

Procedure:
A mixture of 7-benzo[b]thiopen-2-yl-5-bromo-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole (Preparation #24, 1.0 g, 2.18 mmol) in tetrahydrofuran (15 mL) was cooled to about −65° C. then a solution of n-butyllithium (1.6 M, 1.5 mL, 2.4 mmol) was added dropwise. After about 5 minutes methyliodide (0.37 g, 2.6 mmol) was added then the solution was warmed to about −20° C. Saturated ammonium chloride (1 mL) was added then the mixture was diluted with ethyl acetate (25 mL) and water (10 mL). The layers were separated then the organic layer was dried over magnesium sulfate, filtered and evaporated to give the crude 7-benzo[b]thiophen-2-yl-5-bromo-3-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole which was converted to 7-benzo[b]thiophen-2-yl-3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole (0.29 g, 25% over 2 steps) using general procedure E. The boronate (200 mg, 0.385 mmol) was coupled with 2-(dimethylamino-methyleneamino)-7-iodo-pyrrolo[3,2-d]pyrimidine-5-carboxylic acid tert-butyl ester (0.135 g, 0.32 mmol) using general procedure F and the resulting product deprotected using general procedure G to give 7-(7-benzo[b]thiophen-2-yl-3-methyl-1H-indazol-5-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-ylamine (24 mg, 19%); (DMSO-d6, 400 MHz) δ 12.48 (bs, 1H), 11.44 (s, 1H), 8.50 (m, 3H), 8.18 (d, 1H), 8.07 (bs, 1H), 8.02 (d, 1H), 7.90 (d, 1H), 7.43 (m, 2H), 5.94 (bs, 2H), 2.61 (s, 3H); RP-HPLC (Table 1, Method e) Rt 1.76 min; m/z: (M−H)− 394.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:30][CH2:31][C:32](Cl)=[O:33]>>[F:30][CH2:31][C:32]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:33]
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(Cl)CF
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CF)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 19 mg, 50 μmol) and fluoroacetyl chloride (14 mg, 150 μmol). Yield 16 mg (71%).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].N12CCCN=C1CCCC[CH2:13]2.IC.C(OCC)(=O)C>C(#N)C>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:13])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CI
Product: C=Cc1ccc(C(=O)OC)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-vinylbenzoic acid (Aldrich, 2.18 g, 14.7 mmol) in anhydrous acetonitrile (14.0 mL) was added 1.8-diazabicyclo [5.4.0]undec-7-ene (Aldrich, 2.46 g, 16.2 mmol) and iodomethane (Aldrich, 3.13 g, 22.1 mmol) at 0° C. The reaction mixture was then warmed to room temperatue and allowed to stir for 3 h. Ethyl acetate (100 mL) was added to the mixture and the solution was washed with brine (50 mL). The organic phase was then separated and concentrated in vacuo. The residue was chromatographed on silica gel (eluted with 5% ethyl acetate in hexane) to give 1.05 g (Y: 44%) of the title product; 1H-NMR (CDCl3): δ 8.00 (d,J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 6.76 (m, 1H), 5.87 (d, J=17.6 Hz, 1H), 5.38 (d, J=11.0 Hz, 1H), 3.91 (s, 3H); MS (DCI) m/e: 163 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Reaction time: 2 h
Yield: 105.4 %

Procedure:
A mixture of (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.67 mmol), 10% palladium on carbon (80 mg) in methanol (10 mL) was hydrogenated at 50 psi in a Parr Shaker at room temperature for 2 h. The reaction mixture was then filtered through a plug of celite and the filtration pad was washed with ethyl acetate. The organic layers were collected and concentrated to give (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (490 mg, crude) as a light red solid, which was directly used in the next step without further purification.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH:37]([NH2:43])[C:38]1[CH:42]=[CH:41][S:40][CH:39]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH:37]([NH:43][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)[C:38]1[CH:42]=[CH:41][S:40][CH:39]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccsc1
Reactant: CS(=O)(=O)c1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccsc1

Procedure:
(2-{4-[6-(2-Morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester was prepared from [3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) and (2-amino-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester (from Example 6 supra) by following the method in Example 61.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=O)=O)=CC=1.[CH:24]([NH2:27])([CH3:26])[CH3:25].O.C(Cl)(Cl)Cl>O1CCOCC1>[CH3:25][CH:24]([NH:27][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)N
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)NCCCc1ccc([N+](=O)[O-])cc1

Procedure:
3-(4-nitrophenyl)propyl p-toluenesulfonate (1 g) and 5 ml of isopropylamine were dissolved in 15 ml of dioxane, and the solution was stirred under heating with reflux for 4 hours. To the solution were added 100 ml of water and 100 ml of chloroform, and the mixture was thoroughly mixed for extraction. The chloroform-layer fraction was taken, washed with water and dried over sodium sulfate anhydrous. The solvent was removed in vacuo, and thus 0.61 g of an oil of N-(1-methylethyl)-3-(4-nitrophenyl)propylamine was obtained.
Reaction SMILES: O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.N1C=CC=CC=1.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH3:39])[C:31]=1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH3:39])[C:31]=1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=[O:23]
Reactant: Cn1c(-c2cccnc2)c(CCCCCCO)c2ccccc21
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(-c2cccnc2)c(CCCCCC=O)c2ccccc21
Reaction time: 0.5 h

Procedure:
To a solution of Collins Reagent prepared with chromium trioxide (5.6 g) and pyridine (8.86 g, 112 mmol) in dichloromethane (150 ml) at 0°-5° under a nitrogen atmosphere is added all at once 1.8 g of 3-(6-hydroxyhexyl)-1-methyl-2-(3-pyridyl)-indole in dichloromethane (15 ml). The mixture is stirred for an additional 30 minutes, the filtered through celite. The filtrate is then passed through a silica gel column. The product is eluted from the silica gel with a mixture of ethyl acetate:dichloromethane (500 ml). Concentration in vacuo yields 3-(5-formylpentyl)-2-(3-pyridyl)-1-methylindole.
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.[C:13]([O:21][CH2:22][C@@H:23]1[C@@H:29]([CH2:30][O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH:27]2[CH:25]([O:26]2)[CH2:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O>CN(C=O)C.CO>[C:32]([O:31][CH2:30][C@@H:29]1[C@@H:23]([CH2:22][O:21][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:24][C@@H:25]([N:7]2[CH:8]=[N:9][C:10]3[C:6]2=[N:5][CH:4]=[N:3][C:11]=3[NH2:12])[C@H:27]([OH:26])[CH2:28]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=C(OC[C@H]1CC2OC2C[C@@H]1COC(=O)c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
In an atmosphere of argon gas, 60% sodium hydride (20 mg, 0.65 mole) was added to a suspension of adenine (202.5 mg, 1.34 mmoles) in anhydrous DMF (10 ml). After stirring the mixture at room temperature for one hour, (3S,4S)-3,4-bis(benzoyloxymethyl)-7-oxabicyclo-[4.1.0]heptane (245 mg, 0.67 mmole) was added and the resulting mixture was heated in an oil bath kept at 140° C. for 3 hours. After adding 0.2M phosphate buffer (pH 7.0) to the reaction mixture and stirring the mixture for a while, the mixture was subjected to extraction with ethyl acetate. After drying the extract solution on anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1, v/v) to obtain 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-hydroxycyclohexyl]-adenine (161 mg, Yield 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[C:11](N)(=[NH:14])[CH2:12][CH3:13]>>[CH2:12]([C:11]1[N:14]=[C:7]([OH:9])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:1]=1)[CH3:13]
Reactant: COC(=O)c1sccc1N
Reactant: CCC(=N)N
Product: CCc1nc(O)c2sccc2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 12.5 %

Procedure:
Methyl 3-amino-2-thiophenecarboxylate (4.67 g,) and propionamidine (3 g,) were combined and heated in an oil both for 1/2 hour at 60° C.; 1/2 hour at 80° C.; 1/2 hour at 100° C. and finally for 4 hours at 120° C. The mixture was cooled, triturated with ether, filtered and washed with ether to obtain 0.67 g of the product; m.p. 233°-237° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:24][OH:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH3:26][S:27]([O:25][CH2:24][C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)COS(C)(=O)=O
Reaction time: 3 h

Procedure:
A solution of Nα-Boc-Nδ-Cbz-ornithinol (363 mg) in dichloromethane (10 ml) at 0° C., under nitrogen atmosphere, was treated sequentially with methanesulfonyl chloride (110 μl, 1.4 eq) and triethylamine (200 μl, 1.4 eq). After 3 hrs, the solution was poured into dichloromethane and worked up as usual. The crude product, which is very pure (400 mg), is a white solid: 1H NMR (400 MHz, CDCl3) δ1.45 (s, 9H), 1.63 (m, 4H), 3.02 (s, 3H), 3.24 (m, 2H), 3.84 (m, 1H), 4.19 (dd, J=9.5; 3.7 Hz, 1H), 4.23 (d, J=9.5 Hz, 1H), 5.14 (s, 2H), and 7.39 (m, 5H).
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH:14]([OH:16])[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.OS(O)(=O)=O>CC(C)=O>[CH2:1]([S:7][C:8]1[N:13]=[C:12]([C:14](=[O:16])[CH3:15])[CH:11]=[C:10]([CH3:17])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSc1nc(C)cc(C(C)O)n1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCCSc1nc(C)cc(C(C)=O)n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
1-(2-Hexylsulfanyl-6-methyl-pyrimidin-4-yl)-ethanol (2.2 g, 8.65 mmol) was dissolved under nitrogen in acetone (20 mL). Then 2 M Jones' reagent prepared from 20 g CrO3 in 100 mL 4 M H2SO4 (6.5 mL, 13 mmol) was add dropwise. After stirring for 2 h at 20° C., the resulting green solution was decanted from the chromium salts and extracted with AcOEt and sat. NaCl solution. The crude product was purified by chromatography on silica gel with a heptane/AcOEt gradient. One obtained 960 mg (44 %) of white crystals. MS: m/z=252 (M).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:17])[O:12]2)=[CH:7][C:6]=1[CH2:18][CH:19]=C)(=[O:3])[CH3:2].I([O-])(=O)(=O)=[O:22].[K+]>[Os](=O)(=O)(=O)=O.CCOC(C)=O.O>[C:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:17])[O:12]2)=[CH:7][C:6]=1[CH2:18][CH:19]=[O:22])(=[O:3])[CH3:2]
Reactant: C=CCc1cc2ccc(=O)oc2c(OC)c1OC(C)=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(OC(C)=O)c(CC=O)cc2ccc(=O)oc12
Reaction time: 5 h

Procedure:
A solution of 0.274 g. (0.001 mole) of 7-acetoxy-6-allyl-8-methoxycoumarin in 10 ml. EtOAc/water, 1:1 was treated with 0.8 g. (0.0033 mole) of potassium periodate and 0.5 ml. of a 10% aqueous solution of osmium tetroxide (10 mg. OsO4 /ml H2O). The reactants were stirred at 25° for 5.0 hours. The organic layer was separated, and the aqueous phase was further extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate, and evaporated to yield pure 7-acetoxy-8-methoxycoumarin-6-acetaldehyde as a colorless oil.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[H][H].[OH-].[Na+]>C(O)(=O)C.O>[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: [H][H]
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(c1)CCN2
Reaction time: 3 h
Yield: 75 %

Procedure:
28.74 g (457 mmol) of sodium cyanoborohydride are added in small portions at below 20° C. to a solution of 20.0 g (152 mmol) of 5-methylindole in 300 ml of glacial acetic acid. The addition, which is slightly exothermic, is made over 3 hours and is accompanied by slight evolution of hydrogen. The mixture is stirred for 12 hours at below 20° C., and then 300 ml of water are added and the pH of the reaction medium is adjusted to between 10 and 12 by addition of 500 ml of 30% sodium hydroxide solution. The mixture is extracted twice with dichloromethane and the organic phase is washed with 100 ml of water. It is evaporated and the residue is purified by flash chromatography on a silica column, the eluent used being a mixture of increasing polarity of methanol in methylene chloride. 15.3 g (yield=75%) are obtained of a colourless oil which develops a brown colour on storage (under a nitrogen atmosphere with the exclusion of light).
Reaction SMILES: N[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([F:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].N([O-])=O.[Na+].[BrH:18]>[Cu](Br)Br>[Br:18][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([F:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1cc(F)cc(C(C)=O)c1N
Reactant: Br
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cc(F)cc(C(C)=O)c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
1-(2-Amino-5-fluoro-3-methoxy phenyl)ethanone (2.66 g, 14.2 mmol), which had been obtained in Reference example 5 (5b), was suspended in 10% aqueous hydrogen bromide solution (22 mL). Then, a 9% aqueous sodium nitrite solution (11 mL, 14.4 mmol) was slowly added dropwise thereto at 0° C. After stirring the mixture solution for 1 hour at 0° C., a solution in which copper bromide (I) (2.24 g, 15.7 mmol) was dissolved in 47% aqueous hydrogen bromide solution (15 mL) was added thereto, and the mixture was refluxed with heating at 110° C. for 2 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a pale yellow solid (2.15 g, yield 61%).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:37])[CH2:10][C:11]1([C:24]2[S:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1.Cl>CO>[OH:7][NH:8][C:9](=[O:37])[CH2:10][C:11]1([C:24]2[S:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1
Reactant: COc1ccc(-c2ccc(C3(CC(=O)NOC4CCCCO4)CCN(S(C)(=O)=O)CCS3(=O)=O)s2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2ccc(C3(CC(=O)NO)CCN(S(C)(=O)=O)CCS3(=O)=O)s2)cc1
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-methoxyphenyl)-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (110 mg) in methanol (2 ml) was added 10% hydrogen chloride in methanol (0.5 ml) at room temperature. After being stirred for 30 minutes, the reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent; 0.5-5% methanol in chloroform) to give N-hydroxy-2-[7-(5-(4-methoxyphenyl)-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (50 mg) as an amorphous powder.
Reaction SMILES: [H-].[K+].[CH2:3]([N:6]([CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH3:9])[CH2:4][CH3:5].Br[CH2:22][C:23]1[C:31]2[N:30]=[CH:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:27]=2[CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:37][C:35]([CH3:38])([O:34][C:32]([N:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:22][C:10]([N:6]([CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH3:5])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:31]=2[N:30]=[CH:29]1)=[O:33])[CH3:36]
Reactant: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(CCC)C(Cc1cccc2c1ncn2C(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC
Reaction time: 0.08 h
Yield: 80.7 %

Procedure:
Potassium hydride (3.3 g of 40% oil suspension, washed with ether to remove oil, 0.03 mol) was added to a stirred solution of diethyl (dipropylamino)-malonate (10.2 g, 0.039 mol) in dry THF (100 mL). After 5 minutes, t-butyl 4-(bromomethyl) -1H-benzimidazole-1-carboxylate (6.22 g, 0.02 mol) was added and the solution was refluxed for 6 hours. The solvent was removed under reduced pressure and the residual oil was partitioned between ethyl acetate and water. After evaporation of the ethyl acetate, the crude product was chromatographed on silica gel using ethyl acetate:hexane as the eluant to give 7.9 g of diethyl {((1,1 -dimethylethoxycarbonyl)-1H-benzimidazole-4-yl)methyl}(dipropyl amino)-propanedioate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[CH:13]([NH:15][NH2:16])=O>C(O)CCC.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:13]=[N:15][N:16]=[C:7]1[CH2:6][CH2:5]2
Reactant: S=C1CCc2cc(Br)ccc2N1
Reactant: NNC=O
Solvent: O
Solvent: CCCCO
Product: Brc1ccc2c(c1)CCc1nncn1-2
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 6-bromo-3,4-dihydroquinoline-2(1H)-thione (74-4; 0.17 g, 0.0007 mol) in n-butanol (2 mL) was added formic hydrazide (0.105 g, 0.0017 mol) at room temperature. Reaction mass was allowed to stir at 140° C. for 1 h under microwave irradiation conditions. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford title compound. MS (M+3): 252.2.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Br-].[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N+:15]=1[CH2:21][C:22]([O:24][CH2:25]C)=O.[C:27]([C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30]OCC)#[N:28].CI>ClCCl.CC(C)=O>[C:27]([C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][C:21]1[N:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:14]2=[N:13][C:22]=1[O:24][CH3:25])#[N:28]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCOC(=O)C[n+]1cccc(C)c1N
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(C#N)=Cc1c(OC)nc2c(C)cccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
Eight ml of 1,8-diazabicyclo[5,4,0]-7-undecene was added dropwise to a mixture of 2-amino-1-(ethoxycarbonylmethyl)-3-methylpyridinium bromide (5.5 g; 20 mmol) and dichloromethane (200 ml), and then the mixture was stirred for 30 min at room temperature. To the stirred mixture was dropped 1-cyano-1-(ethoxycarbonyl)-2-ethoxyethylene (3.4 g; 20 mmol) in dichloromethane (100 ml) and the mixture was further stirred for 30 min at room temperature. The mixture was evaporated, and the resultant residue was dissolved in 200 ml of acetone. Methyl iodide (20 ml; 32 mmol) was added to the acetone solution and the solution was heated under reflux for 1.5 hour at 60° C. After standing for several hours at room temperature, the resultant precipitates were removed by filtration. The filtrate was concentrated, and the residue was dissolved in dichloromethane, the solution was washed with water, dried over anhydrous magnesium sulfate, successively. The residue, obtained by evaporating the solvent, was chromatographed over silicagel [eluant: hexane-ethyl acetate (2:1)] to give 3.12 g (yield: 55%) of the titled compound as yellow needles.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)sc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 73.6 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(4-bromobenzyl)4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone (4.05 g, 8.39 mmol) and 1M boron tribromide/CH2Cl2 (26.0 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 2.90 g (74%) of the title compound. (DMSO-d6) δ 1.41-1.48 (m, 2H), 1.59-1.74 (m, 4H), 1.82 (s, 3H), 1.89-1.96 (m, 2H), 2.27 (s, 3H), 3.20 (quintet, 1H), 3.84 (s, 2H), 6.88 (d, 1H), 7.03 (d, 2H), 7.39-7.43 (m, 3H), 7.54 (d, 1H), 10.47 (s, 1H).