Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14](OC)=[O:15])[C:11]([CH3:18])=[N:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH3:18])=[N:10]1
Reactant: COC(=O)c1cn(-c2ccccc2OC)nc1C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccccc1-n1cc(C=O)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
A solution (50 mL) of methyl 1-(2-methoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate (10.3 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (350 mL) of lithium aluminum hydride (1.6 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was ice-cooled again, and water (4.2 mL), 1N aqueous sodium hydroxide solution (21.0 mL) and water (4.2 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (2.5 g) of 1-(2-methoxyphenyl)-3-methyl-1H-pyrazole-4-methanol as a pale-yellow oil. This was dissolved in toluene (50 mL), manganese dioxide (1.0 g) was added, and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title object compound (2.2 g, 87%) as a colorless solid.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C:12]1[NH:13][N:14]=[C:15]2[C:20]=1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)=O>C(O)C>[ClH:1].[NH:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[C:10]1[C:12]1[NH:13][N:14]=[C:15]2[C:20]=1[CH2:19][CH2:18][NH:17][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(n[nH]c2C(=O)Nc2ccccc2N)C1
Agent: Cl
Solvent: CCO
Product: c1ccc2[nH]c(-c3[nH]nc4c3CCNC4)nc2c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
2.2 ml of an aqueous 5N hydrochloric acid solution are added to a solution of 200 mg of tert-butyl 3-(2-aminophenylcarbamoyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridine-6-carboxylate in 1 ml of ethanol. After stirring for 20 hours at 80° C., the reaction medium is brought back to ambient temperature. The insoluble material is removed by filtration through sintered glass and the filtrate is concentrated under reduced pressure. 84 mg of 3-(1H-benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine hydrochloride are thus obtained in the form of an orange-coloured powder, the characteristics of which are as follows:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](I)[CH3:26].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][CH3:26])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CCn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.035 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using ethyl iodide (0.27 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-ethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C15H18ClN3, 275.12; found, m/z 276.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.34 (m, 4H), 7.11 (q, J=7.3 Hz, 2H), 3.38-3.36 (m, 2H), 3.27-3.24 (m, 2H), 3.15-3.13 (m, 2H), 2.94-2.92 (m, 2H), 1.30 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[N+:24]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[NH2:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1c(F)cccc1CCNC1CCN(Cc2ccccc2)CC1
Solvent: CO
Product: Nc1c(F)cccc1CCNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
14.4 g (40.3 mmol) (1-benzyl-piperidin-4-yl)-[2-(3-fluoro-2-nitro-phenyl)-ethyl]-amine in 100 mL MeOH were stirred with 2.00 g rhodium charcoal (10%) and shaken at RT under a hydrogen atmosphere (3 bar). The catalyst was filtered off and the solvent was eliminated i. vac. The residue was further reacted immediately as the crude product.
Reaction SMILES: [C:1]([N:8](C)[CH2:9][C:10]1[C:11]([CH2:16][N:17](C)[C:18](OC(C)(C)C)=O)=[CH:12][CH:13]=[CH:14][CH:15]=1)(OC(C)(C)C)=O.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH3:18][NH:17][CH2:16][C:11]1[C:10]([CH2:9][NH:8][CH3:1])=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(Cc1ccccc1CN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccccc1CNC

Procedure:
Representative Procedure I: A solution of this crude N,N'-bis(Boc)-bis(methyl)xylylenediamine in 50% trifluoroacetic acid in dichloromethane (10 mL) was stirred at 23° C. for 0.5 h. The brown solution was concentrated. Diethyl ether was added to the residue, and the mixture was concentrated. The residue obtained was washed with diethyl ether (two portions), providing the N,N'-bis(methyl)-xylylene diamine bis(trifluoroacetate) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[C:15]([OH:18])(=[O:17])C>CO.[Rh]>[CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([C:15]([O:18][C:7]([CH3:12])([CH3:8])[CH3:6])=[O:17])[CH2:11][CH2:12]1
Reactant: CC(=O)O
Reactant: CON(C)C(=O)/C=C/c1ccncc1
Agent: [Rh]
Solvent: CO
Product: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 165.7 %

Procedure:
A solution of (2E)-N-methoxy-N-methyl-3-(pyridin-4-yl)prop-2-enamide (2.00 g), 5% rhodium/carbon (containing water (50%), 0.4 g) and acetic acid (1.25 g) in methanol (40 mL) was stirred for 4 hr under ice-cooling under a hydrogen atmosphere (5 atm). The reaction mixture was allowed to cool to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of THF (25 mL) and water (10 mL), di-tert-butyl dicarbonate (4.36 g) and 2M aqueous sodium hydroxide solution (25 mL) were added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.59 g).
Reaction SMILES: [CH:1]([C:4]1[N:5]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=2[N+:20]([O-])=O)[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].CO>[H][H].[C].[Pd]>[NH2:20][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:9]=1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH:1]([CH3:2])[CH3:3])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(-n2ccnc2C(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(-n2ccnc2C(C)C)c(N)c1

Procedure:
A mixture of ethyl 4-(2-isopropyl-1H-imidazol-1-yl)-3-nitrobenzoate as synthesized in above Production Example 9, 4.94 g, methanol 150 mL and 10% palladium carbon 500 mg was stirred for 16 hours in hydrogen atmosphere. After removing the insoluble matter by filtration, the solvent was distilled off to provide 4.12 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Reactant: CC(C)(C)CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 56.9 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Pall E) (0.400 g, 1.53 mmol), 4,4-dimethylpentylamine (0.194 g, 1.68 mmol) (Example 97, Part B) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes). Concentrate the fractions containing the product. Take the solid up in dichloromethane (100 mL) and wash with 1.0 N NaOH (2× 25 mL) to give the title compound (0.314 g, 57%): TOF MS ES+ 361.2 (M+H)+, HRMS calcd for C19H26N4O2F 361.2040 (M+H)+, found 361.2042, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=12.0 min. 100% purity.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][O:15][C:16](=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(Cl)Cl.O.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>[CH3:14][O:15][C:16](=[O:35])[CH2:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Temperature: 90 °C

Procedure:
2-Bromo-5-trifluoromethyl-benzaldehyde (4.152 g, 16.4 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester (4.988 g, 16.41 mmol), and potassium carbonate (5.67 g, 41.03 mmol) were combined in DME (40 mL) and H2O (20 mL) under N2. The mixture was purged with N2, and then tetrakis(triphenylphosphine)palladium(0) (1.9 g, 1.64 mmol) was added, and the reaction was heated to 90° C. for 10 hours. Once no starting material was seen by analytical LCMS, the mixture was cooled to room temperature and diluted with CH2Cl2 and H2O. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[CH3:16][N:17]([CH:19]=[C:4]1[CH2:3][CH:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:12])[CH3:18]
Reactant: CC1CCC(=O)c2ccccc21
Reactant: CCOC(OCC)N(C)C
Product: CC1CC(=CN(C)C)C(=O)c2ccccc21

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-4-methyl-1(2H)-naphthalenone starting material was prepared from 4-methyl-1-tetralone (4.0 g, 25 mmol) and N,N-dimethylformamide diethyl acetal (17 ml, 100 mmol) to give the desired product as a thick yellow oil (4.53 g). δH (CDCl3) 8.03 (1H, dd, J 7.7, 1.5 Hz), 7.77 (1H, s), 7.39 (1H, td, J 7.4, 1.5 Hz), 7.29 (1H, td, J 7.5, 1.3 Hz), 7.20 (1H, dm, J 7.5 Hz), 3.12 (6H, s), 3.10-2.90 (2H, m), 2.75 (1H, apparent q, 6.9 Hz) and 1.30 (3H, d, J 6.9 Hz). MS (ES+) 216 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13]CC)=[O:12])[CH:9]=2)[N:4]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[Li+].[OH-].Cl>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[N:4]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of ethyl 3-bromo-1-trityl-1H-indazole-5-carboxylate (5.3 g, 20 mmol) in THF (80 mL), was added LiOH (30 mL, 1 N) and the reaction mixture was stirred at 50° C. for overnight. HCl (1 N) was added to adjust the pH˜4. Then ethyl acetated (100 mL) was added. The organic layer was separated and the aqueous layer was extract three times with ethyl acetate (20 mL each). The combined organic was washed with water (30 mL×3). Dry over Na2SO4 and concentrated on vacuum to give desired product as light yellow solid (4.8 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=2[CH3:20])=[C:4]([CH3:21])[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:6]2[C:5]([CH2:9][O:10][C:11]3[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=3[CH3:20])=[C:4]([CH3:21])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,4-dichloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine (978 mg, 3.01 mmol) in DMA (4 mL) is added piperazine-1-carboxylic acid tert-butyl ester (560 mg, 3.01 mmol) and potassium carbonate (832 mg, 6.02 mmol). The resulting colorless suspension is stirred at room temperature under nitrogen for 16 h. The reaction mixture is partitioned between EtOAc (60 mL) and water (20 mL), the organic layer is separated, washed with water (20 mL×2), brine (20 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to obtain a colorless oil consisting of a ˜2:1 mixture of isomeric addition products. Purification on a 30 g cartridge of silica gel (10-30% EtOAc/Hexanes) affords the title compound (lower Rf material) as a colorless solid foam. 1H NMR (CDCl3) δ=7.11 (d, 1H), 6.83 (d, 1H), 6.75 (s, 1H), 4.84 (s, 211), 3.52 (m, 8H), 2.90 (m, 1H), 2.47, (s, 3H), 2.16, (s, 3H), 1.45, (s, 9H), 1.27 (d, 6H).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+:2]=[N-:3].CC(C)=O.C(O)(C)C>S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[N:1]([C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C:5]1=[O:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+:2]=[N-:3]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](N=[N+]=[N-])C[C@@H]12
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](N=[N+]=[N-])C[C@@H]12
Reaction time: 2 h

Procedure:
To a solution of 20 g 16α-azido-3-methoxy-estra-1,3,5(10)-triene-17β-ol in 11 acetone, 40 ml of 8 N chromium trioxide solution in conc. sulfuric acid is added dropwise at 0° C. and under stirring. After 2 h, 2 ml isopropanol are added and the reaction product is precipitated in crystalline form by dropwise addition of water. The product is filtered off, washed with water, dried and recrystallized from acetone/water. Yield: 16 g (81%), F=118-122° C.; [α]D+405°. IR: 1747 cm (CO), 2095 (N3).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[OH:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:2]2[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:22][CH:23]=1
Reactant: Nc1ccc(O)cc1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COCCN1C(=O)C(Nc2ccc(O)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-aminophenol in a similar manner as described for Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 3.37 (s, 3H), 3.72 (t, 2H), 3.90 (t, 2H), 6.40-6.45 (m, 2H), 6.65-6.71 (m, 2H), 6.82 (bs, 1H), 7.10-7.20 (m, 4H), 7.23-7.29 (m, 1H), 7.63 (bs, 1H); Mass Spectrum: M−H+ 373.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C@H:7]1[CH2:16][CH2:15][CH2:14][C@@:13]2([CH3:17])[C@H:8]1[CH2:9][CH2:10][CH2:11][C:12]2=O)([CH3:4])([CH3:3])[CH3:2].[CH:21](=O)[CH:22](C)C>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1.C(OCC)C>[C:1]([Si:5]([O:6][C@@H:7]1[C@H:8]2[C@@:13]([CH3:17])([C:12](=[CH:21][CH3:22])[CH2:11][CH2:10][CH2:9]2)[CH2:14][CH2:15][CH2:16]1)([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@]2(C)C(=O)CCC[C@@H]12
Reactant: CC(C)C=O
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC=C1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reaction time: 3 h
Yield: 95 %

Procedure:
A suspension of 11.8 g (31.7 mMol) of ethyltriphenylphosphoniumbromide in 64 ml of tetrahydrofuran is treated under stirring and argon atmosphere with 31.9 ml of a one molar solution of potassiumtertiobutylate and the resulting orange suspension treated with a solution of 3.17 g (10.7 mMol) of (4aR,5S,8aS)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-octahydro-naphtalen-1-one in 64 ml of tetrahydrofuran and kept at room temperature for 3 hours. An additional 11.8 g (31.7 mMol) of ethyltriphenylphosphoniumbromid and 31.9 ml of a one molar solution of potassiumtertiobutylate in tetrahydrofurane are added and the reaction mixture kept overnight. Isobutyraldehyde (5.4 ml) is added, the reaction is stirred for 10 minutes, diluted with diethylether and filtered over Florisil using diethylether as eluent. After evaporation in vacuo, the residue (4.79 g) is chromatographed over 120 g of silica gel with hexane to yield 3.15 g (95%) of pure (1S,4aS,8aR)-tert-Butyl-(5-ethylidene-4a-methyl-decahydro-naphtalen-1-yloxy)-dimethyl-silane (E/Z 4/1) as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[C:9]([F:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:23][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][C:9]=1[F:17]
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1F
Reactant: NCc1cccc(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(-c2ccccc2)cc1F)NCc1cccc(F)c1
Reaction time: 8 h

Procedure:
4-phenyl-2-fluorophenylacetic acid (0.2 gm, 0.9 mmole), 3-fluorobenzylamine (0.14 ml, 1.1 mmole), PyBOP (0.57 gm, 1.1 mmole), and DIEA (0.36 ml, 2.2 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol. (0.20 gm, 70%); H1-NMR INOVA-500 (DMSO d6) δ 3.612 (s, 2H), 4.318 (d, J=6 Hz, 2H), 7.064-7.117 (m, 3H), 7.345-7.503 (m, 7H), 7.695 (d, J=7.5 Hz, 2H), 8.660 (t, J=6 Hz, 1H). MS (m/z) 338.1 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:8]2[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:25]=[C:7]2[C:6]=1[OH:32])=[O:4].[NH2:33][CH2:34][C:35]([O-:37])=[O:36].[Na+]>>[OH:32][C:6]1[C:7]2[N:8]([CH:23]=[C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:25]=2)[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)[C:10](=[O:11])[C:5]=1[C:3]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4]
Reactant: COC(=O)c1c(O)c2cc(-c3ccccc3)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(-c3ccccc3)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 4-hydroxy-2-oxo-6-phenyl-1-(4-trifluoromethyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (5 eq.). ESI (m/z): 486 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[CH2:14]([CH:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][NH2:18])[CH3:15]>>[CH2:14]([CH:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][N:18]1[C:2]([CH3:1])=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=[C:4]1[CH3:13])[CH3:15]
Reactant: CCCCC(CC)CN
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)O1
Product: CCCCC(CC)CN1C(C)=CC(=C(C#N)C#N)C=C1C

Procedure:
A solution of 0.5 g (2.9 mmol) of (2,6-dimethyl-4H-pyran-4-ylidene)malononitril in 7.6 ml (6 g, 46.4 mmol) 2-ethyl-1-hexylamine was refluxed for 1 h under nitrogen. Removal of the excess of ethyl-1-hexylamine at reduced pressure left a solid which was recrystallized from 15 ml EtOAc/MeOH 2/1 yielding 0.45 g (55%) of 1-N-(2-ethylhexyl)-4-dicyanomethylene-2,6-dimethyl-1,4-dihydropyridine.
Reaction SMILES: [N:1]1([CH2:6][CH:7]=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br-].[F:10][C:11]1[CH:48]=[CH:47][C:14]([CH2:15][CH2:16][C:17]2[CH:42]=[CH:41][C:20]([CH2:21][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:19][C:18]=2[C:43]([O:45][CH3:46])=[O:44])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:1]1([CH2:6][CH:7]=[CH:21][C:20]2[CH:41]=[CH:42][C:17]([CH2:16][CH2:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:48][CH:47]=3)=[C:18]([CH:19]=2)[C:43]([O:45][CH3:46])=[O:44])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc1CCc1ccc(F)cc1
Reactant: O=CCn1ccnc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1cc(C=CCn2ccnc2)ccc1CCc1ccc(F)cc1
Yield: 70 %

Procedure:
A solution of 2-(imidazol-1-yl)acetaldehyde (2.8 g; 0.021 mmol), 4-(4-fluorophenethyl)-3-methoxycarbonylbenzyl triphenylphosphonium bromide (6.2 g; 0.01 mmol), potassium carbonate (2.8 g; 0.02 mmol) and 18 crown-6 (0.1 g; 0.37 mmol) in dichloromethane (100 ml) was stirred under argon atmosphere at ambient temperature overnight. After extraction and evaporation to dryness, the residue was purified by flash chromatography eluting with a mixture of dichloromethane/ethanol (98/2) to give methyl 5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate as a mixture of E and Z isomers.