Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.[CH3:25][N:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31]O>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:31][C:27]2[N:26]([CH3:25])[CH:30]=[CH:29][CH:28]=2)[CH:23]=1
Reactant: Cn1cccc1CO
Reactant: O=c1ncc(Cl)c[nH]1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: Cn1cccc1Cn1cc(Cl)cnc1=O
Temperature: 90 °C
Yield: 37 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (3.04 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (881 mg) and N-methyl-2-hydroxymethylpyrrole (1.050 g) in dry N,N-dimethylformamide (17 ml) under nitrogen. The resulting pale yellow solution was then stirred and heated at 90° C. under nitrogen. After 1 h the reaction mixture was evaporated to a brown crystalline solid (1.891 g). The solid was subjected to column chromatography on silica (70-230 mesh) (200 g) developing with chloroform-ethanol, 29:1. The resulting pale brown crystalline solid (1.479 g) was crystallised twice from acetone to give off white needles of the title pyrrole (559 mg), m.p. 137°-141° C., λmax 226.5 nm (ε 15,920), 334 nm (ε 2,680).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:3]1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:3][CH:2]2[O:1][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: COc1cccc(OCCCOc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3O)cc2)c1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cccc(OC)c4)cc3)cc21

Procedure:
Analogously to Method D, 1.0 g of tert-butyl 3-hydroxy-4-{4-[3-(3-methoxyphenoxy)propoxy]-phenyl}piperidine-1-carboxylate and 0.608 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as an opaque oil. Rf=028 (1:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]([CH3:20])[C:9]1[C:10](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:11](OCC)=[O:12])=[O:7].Cl>>[CH3:20][N:8]1[C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11](=[O:12])[N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[C:6]1=[O:7]
Reactant: CCOC(=O)c1ccccc1N(C)C(=O)C1CCCN1
Agent: Cl
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 10 g. of ethyl N-(2-pyrrolidinylcarbonyl)-N-methylanthranilate and 200 ml. of 3N alcoholic hydrogen chloride is heated on the steam bath for 6 hours and then concentrated. The residue is purified by chromatography on a hexane/methanol/celite system and racemic 1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10](Cl)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)=O.[OH-].[NH4+:19]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([NH2:19])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: NS(=O)(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A solution of (3,4-dichloro-phenyl)-methanesulfonyl chloride (500 g, 1.93 mol) and acetone (470 mL) was added over 2 h to cooled (0-5° C.), stirred concentrated ammonium hydroxide (28%, 900 mL, 227 g NH3, 13.3 mol). The reaction mixture was maintained below 12° C. during the addition. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Water (900 mL) was added to the reaction mixture and it was stirred for 1 h. The white solid was collected by filtration, washed with cold water (2×500 mL), and vacuum dried to give 375 g (81%) of (3,4-dichloro-phenyl)-methanesulfonamide with 99% purity (as determined by HPLC).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Na].[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])(=[O:29])[CH2:27][CH3:28]>C1C=CC=CC=1>[C:26]([CH:30]([C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[CH:24][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:14][CH:15]=1)[CH3:22])[C:31]([O:33][CH3:34])=[O:32])(=[O:29])[CH2:27][CH3:28]
Reactant: CCC(=O)CC(=O)OC
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Agent: [Na]
Solvent: c1ccccc1
Product: CCC(=O)C(C(=O)OC)C(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
Following the procedure of Example 4, 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid chloride is added to the sodium salt of methyl propionylacetate in benzene to give methyl 2-propionyl-4-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-oxopentanoate (cpd. 27, Table C). This pentanoate is then heated with sodium chloride and DMSO to give 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-3,5-heptanedione (cpd. 27, Table D).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=2)[C:11]=1O)=[O:5])[CH3:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:11]1[N:10]2[N:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:9]2[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cnc2nc(C(=O)OC)nn2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1cnc2nc(C(=O)OC)nn2c1Cl

Procedure:
The product obtained in Step 1 (12 g) was suspended in 100 ml of phosphorus oxychloride, 5.9 g of N,N-dimethylaniline was added dropwise to this suspension at 0° C. with stirring over a period of ten minutes, and the mixture was stirred at room temperature for 30 minutes and then refluxed for four hours. Removing excess phosphorus oxychloride by distillation under normal pressure gave about 50 ml of a reddish brown oil. It was dissolved in 300 ml of dichloromethane, the solution was washed with 500 ml of saturated sodium bicarbonate solution, then with 80 ml of saturated sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The dried reddish yellow filtrate was concentrated to about 30 ml, and crystallized from 20 ml of n-hexane, affording 8.5 g of the objective compound as faint yellow crystals.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:5]=1)([CH3:3])[CH3:2].[CH3:22][O:23][CH2:24][CH2:25]Br>>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:25][CH2:24][O:23][CH3:22])=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(C(C)C)n2)n[nH]1
Reactant: COCCBr
Product: COCCOc1ccc2c(C(C)C)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 328 was used, starting from 1-Isopropyl-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol and 2-bromoethyl methyl ether to give [1-Isopropyl-6-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 341(MH+).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: NCCc1ccc(N)cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCCc1ccc(N)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (1.0 g, 5.3 mmol) was dissolved in methanol (15 ml), and 2-(4-aminophenyl)ethylamine (0.80 g; 5.8 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was crystallized from methanol-diethyl ether to give N-cyano-N'-[2-(4-aminophenyl)ethyl]-3-pyridinecarboximidamide (0.88 g, 3.3 mmol, yield: 63%) as colorless needles.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:13]([O:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH3:14]>C(Cl)Cl>[CH2:13]([O:15][C:16]([C:18]1[NH:19][CH:20]=[C:21]([C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH:22]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: O=C(Cl)C1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)C2CCCC2)c[nH]1
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
A mixture of cyclopentanecarbonyl chloride and aluminum chloride in dry DCM were stirred in an inert atmosphere at 0-5° C. for 15 minutes. To this, a solution of 1H-pyrrole-2-carboxylic acid ethyl ester in dry DCM was added drop wise under stirring at 0-5° C., stirred further at room temperature for 4 hrs. After completion of reaction, the reaction mixture was poured into ice water and extracted with DCM, DCM layer was washed with 1N NaOH followed by water and brine. The organic layer was dried over anhydrous sodium sulfate and was evaporated to get 4-Cyclopentanecarbonyl-1-H-pyrrole-2-carboxylic acid ethyl ester (A1-I).
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>CCOCC>[CH3:9][O:8][C:5]1[N:4]=[C:3]([O:10][CH3:11])[C:2]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)=[CH:7][N:6]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COc1ncc(Br)c(OC)n1
Solvent: CCOCC
Product: COc1ncc(C2(O)CCC3(CC2)OCCO3)c(OC)n1

Procedure:
The title compound was prepared as a white solid from 5-bromo-2,4-dimethoxy-pyrimidine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([OH:15])[CH:6]=1)(=[O:3])[CH3:2].[N+](C1C=C(S(O[CH2:29][C@@H:30]2[CH2:32][O:31]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([O:15][CH2:29][C@@H:30]2[CH2:32][O:31]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(=O)Nc1ccc(OC(C)=O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(OC(C)=O)cc1OC[C@@H]1CO1
Yield: 34.9 %

Procedure:
A solution of 4-(acetylamino)-3-hydroxyphenyl acetate (669 mg, 3.2 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (748 mg, 2.9 mol) and caesium carbonate (1.05 g, 3.2 mmol) in 1-methyl-pyrrolidinone (10 mL) was stirred over night at room temperature, and then partitioned between water and ethyl acetate. The organic phase was washed twice with water and concentrated to an yellow oil, which was suspended in methanol/diethyl ether, ½. The precipitated beige solid was filtered off and dried to give the titled compound (296 mg, 38%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O.O1CCOCC1>[CH2:14]([O:21][C:22]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To 500 mg (4.95 mmol) azetidine-3-carboxylic acid was added 10 mL dioxane and 10 mL H2O and the solution cooled to 0° C. 1.38 g (10 mmol) potassium carbonate was added followed by 0.78 mL (11 mmol) benzylchloroformate, and the reaction stirred at room temperature for 18 hours. The mixture was acidified with 25 mL 1 M HCl, extracted with DCM (2×20 mL), the combined organic layers dried over Na2SO4. After filtration the solvent was evaporated to give the desired product which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)=[O:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[O:20][N:19]=1.[OH-].[Na+]>CN(C=O)C>[Cl:28][C:25]1[S:24][C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][N:13]3[C:8]4=[N:9][CH:10]=[CH:11][CH:12]=[C:7]4[CH:6]=[C:5]3[C:3]([OH:2])=[O:4])[CH:22]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc2cccnc2[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.195 g (1.1 mmol) of 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester was dissolved in 4 mL of DMF and 48.7 mg (1.2 mmol) of sodium hydride (60% in mineral oil) was added. The reaction was stirred at RT for 20 min, cooled to −78° C. then 324 mg (1.2 mmol) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001) 460 pp. WO 0107436 A2] was added. The reaction was allowed to warm to RT overnight. 0.3 mL of 2N aqueous sodium hydroxide was added and the reaction was stirred at RT for 24 h. The product was purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a solid.
Reaction SMILES: [C:1]([C:4]([CH2:21][CH:22]=[CH:23][CH:24]([O:30]C(=O)C)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)(=[O:3])[CH3:2].[OH-].[Na+]>O.C(O)C>[C:1]([CH:4]([CH2:21]/[CH:22]=[CH:23]/[CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CCCCCC(C=CCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(O)/C=C/CC(CCCCCCC(=O)O)C(C)=O

Procedure:
A solution of diethyl 2-acetyl-2-(4-acetoxy-2-nonen-1-yl)azelate (22.9 g., 0.049 mole) and sodium hydroxide (15.7 g., 0.392 mole) in water (150 ml.) and ethanol (150 ml.) is boiled under reflux for 2 hours. Solvents are removed under reduced pressure, the residue is dissolved in water, and the solution extracted with ether. The aqueous layer is acidified with concentrated hydrochloric acid to the Congo Red endpoint. The crude product separates as an oil, weight 18.9 g. 8-Acetyl-12-hydroxy-(E)-10-heptadecenoic acid is isolated in pure condition from the crude product by chromatography on silica gel with 4% methanol in chloroform as the eluant. There is obtained 3.5 g. of yellow oil showing a single spot, Rf 0.63, in thin layer chromatography (silica gel, 1% acetic acid in ether); pmr (CDCl3) δ 0.88 (3H,t), 2.10 (3H,s, CH3C=O), 4.03 (1H,m HCO), 5.50 (2H,m, HC=CH), 6.58 (2H,s COOH, OH).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[N+:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([O-:30])=[O:29]>C1(C)C=CC=CC=1>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:36])=[CH:38][CH:39]=1)([O-:30])=[O:29]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (0.5 g) and triethylamine (1.0 ml), and 4-nitrobenzoyl chloride (0.5 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Si:22]([O:29]C1CCCCC(O)CCCC1)(C(C)(C)C)([CH3:24])[CH3:23].[C:41]([CH:45]1[CH2:54][CH2:53][CH2:52][CH2:51][C:50]([O:56][SiH](C)C)(O)[CH2:49][CH2:48][CH2:47][CH2:46]1)([CH3:44])([CH3:43])[CH3:42].CCOCC>ClCCl>[C:41]([CH:45]1[CH2:46][CH2:47][CH2:48][CH2:49][C:50](=[O:56])[CH:51]([O:29][SiH:22]([CH3:24])[CH3:23])[CH2:52][CH2:53][CH2:54]1)([CH3:42])([CH3:43])[CH3:44]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCCC(O)CCCC1
Reactant: C[SiH](C)OC1(O)CCCCC(C(C)(C)C)CCCC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[SiH](C)OC1CCCC(C(C)(C)C)CCCCC1=O
Temperature: 25 °C

Procedure:
1.5 g of pyridinium dichromate was dissolved in 30 ml of dichloromethane, to the solution was added 0.77 g of 6-tert-butyldimethylsilyloxy-1-cyclodecanol prepared in above-described (a). The mixture was stirred at room temperature for one and a half hours. Then, another 2.5 g of pyridinium dichromate was added to the reaction solution and the reaction solution was stirred at room temperature for further three hours. To the reaction solution was added 50 ml of ether, followed by purifying by column chromatography on Florisil, and the eluate with ether was collected, to afford 0.73 g of the titled compound (b) as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)[S:17][C:13]=2[N:12]2[C:28]([CH3:31])=[N:29][N:30]=[C:11]2[CH2:10][N:9]=1.NC(C(O)=O)CCSC.C(=O)([O-])O.[Na+]>CS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[S:17][C:13]=2[N:12]2[C:28]([CH3:31])=[N:29][N:30]=[C:11]2[CH2:10][N:9]=1
Reactant: COc1ccc(CCc2cc3c(s2)-n2c(C)nnc2CN=C3c2ccccc2Cl)cc1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Agent: O=C([O-])O
Product: Cc1nnc2n1-c1sc(CCc3ccc(O)cc3)cc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 24 h
Yield: 61.9 %

Procedure:
A mixture of 1.5 g of thienotriazolodiazepine compound obtained in Example 4 and 5 g of DL-methionine in 100 ml of methanesulfonic acid is allowed to stand at room temperature for 24 hours. The mixture is poured into 300 ml of ice-water, neutrarized with an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer is washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated to precipitate colorless crystals. The crystals are collected by filtration, washed with isopropyl ether and dried to give 0.9 g of 4-(2-chlorophenyl)-2-[2-(4-hydroxyphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, melting at 100°-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:1])[CH:11]=1
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(=O)[nH]c2ccccc12
Yield: 54 %

Procedure:
To a suspension of 2,4-dihydroxy quinoline (3.00 g, 18.6 mmol) and potassium carbonate (5.14 g, 37.2 mmol) in acetone (500 mL) was added dimethyl sulfate (2.1 mL, 22 mmol) and the resulting mixture heated at reflux during 5 hrs. The solvent was removed in vacuo and the residue triturated in water. The product was collected by filtration, washed with water and triturated from methanol to give 4-methoxy 2-quinolone 187a (1.76 g, 54%) as a white solid, that had identical 1H NMR data as reported (Reisch et al., Arch. Pharm., 1980, 313, 751-755).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=O)[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.[NH2:36][OH:37].Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[N:36][OH:37])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: NO
Reactant: CCS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C=O)ccc23)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C=NO)ccc23)CC1
Reaction time: 1 h
Yield: 71.2 %

Procedure:
A 25 ml round-bottomed flask is charged with 30 mg of 5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde, prepared in example 19, in 2 ml of pyridine. 7 mg of hydroxylamine as the hydrochloride are added. After 1 h at RT, the mixture is evaporated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol mixture (95/5 by vol.), to give 22 mg of 5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde oxime (yellow solid). 1H NMR (500 MHz, DMSO-d6) δ ppm with the E or Z isomerism: 1.23 (t, J=7.4 Hz, 3 H) 1.63 (m, 2 H) 2.09 (m, 2 H) 2.97 (m, 2 H) 3.05 (q, J=7.4 Hz, 2 H) 3.61 (m, 2 H) 3.80 (m, 1 H) 6.08 (broad m, 1 H) 7.33 (m, 2 H) 7.66 (m, 1 H) 7.86 (broad s, 1 H) 8.14 (broad d, J=8.3 Hz, 1 H) 8.30 (5, 1 H) 8.41 (d, J=8.3 Hz, 1 H) 11.45 (broad m, 1 H) 12.82 (broad m, 1 H). [M+H]+m/z=515.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1F
Yield: 68.8 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11(v), ethyl 2-chloro-3-(2-fluorophenyl)-3-oxopropanoate (1.0 g, 4.09 mmol) produced in the above and 2-propanol (25 mL) as starting materials and in the same manner as in Example 11(vi), the title compound (341 mg, 68%) was obtained as a yellow solid.