Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:1][C@H:2]([CH3:3])[CH2:4][OH:5]
Reactant: Clc1ccccn1
Reactant: C[C@@H](N)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](CO)Nc1ccccn1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
(R)-Alaninol (107.3 g, 1.43M) was added dropwise with stirring to a solution of potassium tertiary butoxide (160 g, 1.43M) in tetrahydrofuran (1 L). After the exothernic reaction had cooled to room termperature, 2-chloropyridine (162.4 g, 1.43M) was added dropwise. The reaction mixture was heated under reflux overnight, cooled, filtered and evaporated to an oil. The oil was dissolved in xylene (1.5 L) and toluene-p-sulphonic acid (0.5 g) was added. The mixture was heated under reflux overnight. On cooling to room temperature the product crystallised to give (R)-N-(2-pyridyl)-2-aminopropanol (190 g), [α]D26=30° (c=1 in CHCl3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2)=[O:8].[OH:25]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2)(=[O:25])=[O:8]
Reactant: O=C1CCc2cc(OCCCCS(=O)c3ccccn3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)(=O)c3ccccn3)ccc2N1

Procedure:
Prepared analogous to Example 3 from 6-[4-(2-pyridyl-sulfinyl)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:26]1([CH2:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:37]([C:36]3[CH:35]=[CH:34][C:33]([CH2:32][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:40][CH:39]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: CC(c1ccccc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccccc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-[4-(1-phenyl-ethyl)-piperazin-1-yl]-pyridin-2-ylamine (0.060 g, 0.15 mmol) and EtOH (6.0 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.039 g, 0.19 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.60 ml, 0.60 mmol). The reaction mixture was stirred at 70° C. for 5 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 9%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid which was triturated with diethyl ether. The precipitate was collected by filtration, successively washed with diethyl ether, water, diethyl ether, and dried (0.002 g, 3%). 1H-NMR (500 MHz, DMSO-d6) 1.37 (d, J=6.6 Hz, 3H, CHCH3), 2.38 (br s, 4H) and 3.59 (t, J=4.6 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.54 (br s, 2H), 2.63 (br s, 2H) and 3.65 (br s, 4H) piperazine N(CH2)2), 3.50 (q, 1H, CHCH3), 3.57 (s, 2H, C6H4CH2), 7.26 (m, 1H) and 7.37 (m, 4H) (PhH), 7.47 (d, J=8.9 Hz, 2H) and 8.13 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 8.22 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.45 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH3:1][C:2]1[S:16][C:5]2=[N:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([OH:10])=[C:4]2[CH:3]=1.[H-].[Na+].[CH2:19](I)[CH3:20]>CN(C)C=O>[CH2:19]([N:6]1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9](=[O:10])[C:4]2[CH:3]=[C:2]([CH3:1])[S:16][C:5]1=2)[CH3:20]
Reactant: CCOC(=O)c1cnc2sc(C)cc2c1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2sc(C)cc2c1=O
Temperature: 70 °C

Procedure:
A mixture of 0.237 part of ethyl 2-methyl-4-hydroxythieno-(2,3-b)pyridine-5-carboxylate, 5 parts by volume of dry dimethylformamide and 0.048 part of 50% sodium hydride in mineral oil is heated at 70° C for 30 minutes, and 0.12 part by volume of ethyl iodide is added thereto. The mixture is heated at 70° C for 2 hours and the solvent is evaporated under reduced pressure. The residue is extracted with chloroform, and the extract is washed with saturated aqueous sodium chloride and dried over sodium sulfate. Evaporation of the solvent gives ethyl 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno(2,3-b)pyridine-5-carboxylate as crystals. Recrystallization from ethyl acetate yields colorless plates melting at 140°-142° C. This product is identical with the product in Example 24.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=2)=[N:10][N:11]=1.[CH3:19][N:20](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)=[N:10][N:11]=1
Reactant: Ic1cccc(-c2nnc(-c3ccccn3)o2)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2nnc(-c3ccccn3)o2)c1
Temperature: 80 °C
Yield: 30 %

Procedure:
Under an argon atmosphere, a mixture of 2-(2-pyridyl)-5-(3-iodophenyl)-1,3,4-oxadiazole (0.03 g, 0.08 mmol), zinc cyanide (0.01 g, 0.12 mmol), and Pd(PPh3)4 (9.1 mg, 0.01 mmol) in N,N-dimethylformamide (2ml) was heated at 80° C. for 2.5 hours. After cooling the reaction mixture was diluted with ethyl acetate and sequentially washed with water (3×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Recrystallization of the crude product from 5% ethyl acetate in hexanes, afforded 5.8 mg (30%) of 2-(2-pyridyl)-5-(3-cyanophenyl)-1,3,4-oxadiazole.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C@H:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:7]21[CH3:18])[CH3:2].F[B-](F)(F)F.[O:24]=[N+:25]=[O:26]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([N+:25]([O-:26])=[O:24])[CH:12]=1)[N:9]([CH3:13])[C@H:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C@@:7]21[CH3:18])[CH3:2]
Reactant: O=[N+]=O
Reactant: CCOc1ccc2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOc1cc([N+](=O)[O-])c2c(c1)[C@]1(C)CCN(C)[C@@H]1N2C

Procedure:
A degassed solution, under nitrogen, of 3.70 g of (3aS-cis)-5-ethoxy-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole in 50 ml of dry chloroform was treated with 2.00 g of nitronium tetrafluoroborate at a reaction temperature of +10°. After twenty minutes, the reaction was quenched by the addition of ice and saturated sodium bicarbonate solution with vigorous stirring. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to an oil. This was purified by chromatography over silica gel using ethyl acetate as the eluent. The fractions containing the product were combined and concentrated to an oil which crystallized from hexane to afford crystals of pure (3aS-cis)-5-ethoxy-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethyl-7-nitropyrrol[2,3-b]indole, mp 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][OH:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>CO.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][O:13][C:30](=[O:31])[NH:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]([F:21])([F:33])[F:32])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1C(F)(F)F)ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
2 g of 7-chloro-2-hydroxyamino-5-phenyl-3H-1,4-benzodiazepine are reacted with 1 g of 2-trifluoromethylphenyl isocyanate, analogously to Experiment 1a. Yield: 1.8 g of colorless crystals of melting point 190° C. (from methanol/dimethylformamide).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)=[O:4].[H][H]>CC(O)C.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:1])([F:16])[F:17])[CH:12]=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: [Pd]
Solvent: CC(C)O
Product: Nc1cccc(CNC(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[(3-nitrophenyl)methyl]acetamide (0.5 g, 2.0 mmol) in i-PrOH was added 10% Pd/C (40 mg, 0.04 mmol). A balloon filled with hydrogen gas was installed, and the reaction was stirred vigorously at rt. After 15 h, the reaction mixture was filtered through celite, adsorbed onto silica gel, and purified by column chromatography to generate the title compound in 85% yield. 1H NMR (400 MHz, CDCl3) δ 7.14-7.27 (m, 1H), 6.59-6.68 (m, 3H), 4.43 (s, 2H), 3.74 (s, 2H). ES-LC/MS m/z=219 [M+H]+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1O.C(=O)=O>S([O-])([O-])(=O)=O.[Cu+2]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1
Reactant: OC1CCc2ccccc2O1
Agent: [Cu+2]
Agent: O=C=O
Agent: O=S(=O)([O-])[O-]
Product: C1=Cc2ccccc2OC1

Procedure:
In 50 cc of anhydrous ether was dissolved 2.78 g (0.01 mole) of the chromanone compound obtained in Example 2, represented by the following formula: ##STR69## and the solution was cooled to 0° C. and 0,012 mole of Grignard reagent CH3MgI newly prepared in 50 cc of anhydrous ether was dropped into the solution over a period of about 1 hour. After termination of the dropwise addition, the mixture was stirred at room temperature for 2 hours and was gradually poured into cold water to extract the product with ether. The ether extract was dried on magnesium sulfate and ether was removed under reduced pressure to form a chromanol compound from the chromanon compound. Then, the obtained chromanol compound was heated at 200° C. together with anhydrous copper sulfate in a carbon dioxide current for about 10 minutes, and the obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 2.24 g of a chromene compound represented by the following formula: ##STR70##
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH:10]1([NH2:14])[CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>>[C:6]([O:5][C:3](=[O:4])[CH2:2][NH:14][CH:10]1[CH2:13][CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: NC1CCC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
An ethanolic solution of t-butyl bromoacetate (39 g, 0.2 mol) was added dropwise to a stirred chilled ethanolic solution containing cyclobutyl amine (28.4 g, 0.4 mol) and triethylamine (25.3 g, 0.25 mol). After stirring overnight at room temperature, the reaction mixture was concentrated and the residue redissolved in methylene chloride (300 ml). This solution was washed with water (3×500 ml), dried over MgSO4, filtered, and evaporated to dryness, yielding 24.9 g (67%) of the desired product as a light brown oil.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1.CCOCC>[CH3:12][O:11][C:1](=[O:10])[CH:2]([O:3][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 16 h
Yield: 90.9 %

Procedure:
To a solution of commercially available methyl (S)-mandelate (2.39 g, 14.4 mmol) in dichloromethane (50 mL) is added imidazole (1.18 g, 17.3 mmol), tert-butyldimethylsilyl chloride (2.38 g, 15.8 mmol) and 4-dimethylaminopyridine (176 mg, 1.44 mmol). The mixture is stirred for 16 hrs then diluted with ether, washed with water, brine, then dried (MgSO4), filtered and concentrated. The residue is purified by chromatography on silica gel; elution with EtOAc:heptane (25:75) gives 3.67 g of the product. 1H NMR (CDCl3) δ 7.45-7.40 (m, 2 H), 7.35-7.25 (m, 3 H), 5.20 (s, 1 H), 3.65 (s, 3 H), 0.90 (s, 9 H), 0.10 (s, 3 H), 0.05 (s, 3 H); MS: m/z 281 (M++1)
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:26]=1)C1C=CC=CC=1.C.[H][H]>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:26]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(C=CCCCCCCCCCCCCCCOCc3ccccc3)c3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)n2cc(CCCCCCCCCCCCCCCCO)c3ccccc32)cc1
Yield: 91.9 %

Procedure:
3-(16-benzyloxyhexadecenyl)-1-(4-methoxybenzensulfonyl)indole (530 mg, 0.86 mmol) was dissolved in 25 mL of ethanol and added to palladium supported on activated charcoal (5%, 50 mg). The resulting mixture was allowed to stand at room temperature for 3 hours under 1 atmospheric pressure of hydrogen. After filtration, the reaction mixture was extracted with ethyl ether. The organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography to give 3-(16-hydroxyhexadecyl)-1-(4-methoxybenzenesulfonyl)indole as a white solid (417 mg, 92%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].CCN(C(C)C)C(C)C.[CH2:16]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([N:20]([C:1](=[O:5])[C:2]([Cl:4])=[O:3])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNCCCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)C(=O)Cl
Reaction time: 0.08 h

Procedure:
To a 0° solution of oxalyl chloride (479 mL, 5.49 mmol) in THF (10 mL) under nitrogen was added DIPEA (2.28 mL, 13.07 mmol) and dibutylamine (925 mL, 5.49 mmol). The resulting mixture was stirred at 0° for 5 min, whereby (dibutylamino)oxoacetyl chloride is formed, then transferred via syringe to a solution of 4-(4-aminophenyl)-2-aminothiazole (corresponding to the deprotected title compound of either Example 1(a) or 1(b)). The resulting mixture was stirred under nitrogen for 4 h, after which time another batch of freshly prepared (N,N-dibutylamino)oxalylchloride (prepared in the same manner and with the same amounts as above) was added to the reaction mixture. The stirring was continued for 1 h. The mixture was then diluted with EtOAc and extracted with 10% aqueous HCl. This aqueous extract was washed with EtOAc:Hex (1:1), then filtered. The collected solid, containing the desired product as its hydrochloride salt, was treated with 2N aqueous NaOH and extracted with EtOAc. This latter extract was washed with H2O, dried (MgSO4) and concentrated under reduced pressure to give a solid (398 mg) which was further purified by crystallization from EtOAc/MeOH to give the title compound (240 mg, 12% yield) as a beige solid: M.p. 178-179° C.; 1H NMR (400 MHz, DMSO-d6) δ10.68 (s, 1H), 7.75 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=9.0 Hz), 7.02 (s, 2H), 6.92 (s, 1H), 3.33 (m, 4H), 1.50-1.60 (m, 4H), 1.33 (sixt., 4H, J=7.5 Hz), 1.25 (sixt., 4H, J=7.5 Hz), 0.92 (t, 3H, J=7.5 Hz), 0.82 (t, 3H, J=7.5 Hz); MS (FAB) m/z 375 (MH)+. Anal. Calcd for C19H26N4O2S: C, 60.94; H, 7.00; N, 14.96. Found: C, 60.82; H, 6.85; N, 14.95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:23][C:24]1[CH:28]=[CH:27][N:26]([CH2:29][C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:39])[CH3:38])[CH:33]=[CH:34][CH:35]=2)[N:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:37]([NH:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:26]1[CH:27]=[CH:28][C:24]([NH:23][C:13](=[O:15])/[C:12](/[C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)=[N:16]/[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:25]1)(=[O:39])[CH3:38]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: CC(=O)Nc1cccc(Cn2ccc(N)n2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(Cn2ccc(NC(=O)/C(=N/OC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Yield: 41.4 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 100 mg, 0.29 mmol), N-[3-(3-amino-pyrazol-1-ylmethyl)-phenyl]-acetamide (67 mg, 0.29 mmol) and N,N-diisopropylethylamine (151 μL, 0.87 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol) was added and the ice bath was removed. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/chloroform to 80% ethyl acetate/hexanes) to afford (E)-N-[1-(3-acetylamino-benzyl)-1H-pyrazol-3-yl]-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetamide (67 mg, 42%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C26H28ClN5O5S [M+] 557.15, found 558 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.63 (m, 4 H, 2×CH2), 1.84 (m, 4 H, 2×CH2), 2.16 (s, 3 H, CO2CH3), 3.29 (s, 3 H, SO2CH3), 4.86 (m, 1 H, OCH), 5.20 (s, 2H, NCH2), 6.75 (d, J=2.3 Hz, 1 H, Ar), 6.92 (brd, J=7.7 Hz, 1 H, Ar), 7.29 (brt, J=8.0 Hz, 1 H, Ar), 7.37 (m, 3 H, 2 Ar and NH), 7.43 (brd, J=7.9 Hz, 1 H, Ar), 7.54 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.64 (d, Jm=1.5 Hz, 1 H, Ar), 8.17 (d, Jo=8.2 Hz, 1 H, Ar), 9.20 (s, 1 H, NH).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:10][C:9]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:8]=2[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH:2]([C:6]1[S:10][C:9]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:8]=2[CH:7]=1)=[O:1]
Reactant: NS(=O)(=O)c1cc2cc(C3OCCO3)sc2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cc2cc(C=O)sc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
5-(2-Dioxolanyl)thieno[2,3-b]thiophene-2-sulfonamide (2.59 g, 8.89 mmol) was suspended in acetone and p-toluenesulfonic acid (2.50 g, 13.1 mmol) was added. The mixture was stirred at room temperature for one hour at which time a solution was obtained. Water (2.0 mL) was added and stirring continued for 3 hours. A saturated solution of sodium bicarbonate (30 mL) was added dropwise, followed by the slow addition of water (40 mL). The resulting solution or mixture was seeded with a few crystals of product and the acetone was evaporated in vacuo. The crystals were collected, washed with water and dried in vacuo to give 2.10 g of 5-formylthieno[2,3-b]thiophene-2-sulfonamide, m.p. 188°-189° C. This product was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1)=O)(C)(C)C.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[CH:31]1([CH2:30][N:15]2[C:11]([CH2:10][CH2:9][NH:8][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:12][C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:14]2)[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N(CCc1nc(-c2ccccc2)n[nH]1)C(=O)OC(C)(C)C
Reactant: BrCC1CC1
Product: CC(C)(C)OC(=O)NCCc1nc(-c2ccccc2)nn1CC1CC1

Procedure:
The product was obtained starting from 5-[2-bis(tert-butoxycarbonyl)aminoethyl]-3-phenyl-[1,2,4]triazole (250 mg, 644 μmol, example 22, step 1) and (bromomethyl)cyclopropane (104 mg, 73.9 μL, 772 μmol) according to the method described in example 34, step 1 as colorless oil (69 mg, 201 μmol, 31.3%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:21][O:22][CH3:23])[C:10]([CH:19]=O)=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].[CH2:24]([O:26][C:27](=[O:48])[CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:25]>C1COCC1>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:21][O:22][CH3:23])[C:10](/[CH:19]=[CH:28]/[C:27]([O:26][CH2:24][CH3:25])=[O:48])=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(-c3cncc(C)c3)c(C=O)c(COC)nn12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(COC)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carbaldehyde (48 mg) and ethyl(triphenylphosphoranylidene)acetate (56.8 mg) in THF (3 mL) was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (5:1-2:1) to give ethyl(2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate as a yellow powder (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][CH:9]([C:11]1[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[C:14]([O:22][CH3:23])=[CH:13][CH:12]=1)O.C[Si]([C:29]#[N:30])(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:29]([CH:9]([C:11]1[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[C:14]([O:22][CH3:23])=[CH:13][CH:12]=1)[CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:24])#[N:30]
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(C#N)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
A solution (70 ml) obtained in Step A of Example 45 of Compound 45a (2.5 g) in methylene chloride was cooled to 0° C. and then trimethylsilylcyanide (5.4 ml) and boron trifluoride ether complex (2.5 ml) were successively added thereto, followed by stirring at 0° C. for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 63 (0.61 g, 23.8%) as pale-yellow crystals.