Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.C[O-].[Na+].Cl.[NH2:7][C:8]([NH2:10])=[NH:9].Cl.Cl[C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:16]=1)=[O:14]>O1CCCC1.ClCCl>[N:27]1[CH:28]=[CH:29][C:24]([N:17]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:23]3[C:15]([C:13]([NH:9][C:8]([NH2:10])=[NH:7])=[O:14])=[CH:16]2)=[CH:25][CH:26]=1
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cn(-c2ccncc2)c2ncccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: N=C(N)NC(=O)c1cn(-c2ccncc2)c2ncccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
20 cm3 of methanol and then a solution of 70 cm3 of 0.5M sodium methoxide were added, at a temperature in the region of 20° C. under an argon atmosphere, to 3.34 g (35 mmol) of guanidine hydrochloride and the reaction mixture was stirred at a temperature in the region of 20° C. for 1 h. The reaction mixture was subsequently concentrated to dryness under reduced pressure (2.7 kPa) and the residue was 3 times in succession taken up in 20 cm3 of dichloromethane (stabilized over amylene) and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained was taken up in 50 cm3 of tetrahydrofuran under an argon atmosphere at a temperature in the region of 20° C. and 1.8 g (7 mmol) of 3-chlorocarbonyl-1-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride, in suspension in 50 cm3 of dichloromethane, were added with stirring, followed by 50 cm3 of tetrahydrofuran and 50 cm3 of dichloromethane. After stirring at a temperature in the region of 20° C. for 15 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was taken up in 50 cm3 of ethanol and the mixture was heated at reflux for 5 minutes and then reconcentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash chromatography on a column of silica gel (0.04–0.06 mm), elution being carried out with an ethyl acetate/methanol/aqueous ammonia (80/20/5 by volume) mixture. The fractions comprising the expected product were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was taken up in 30 cm3 of water and the solution was basified with 1N sodium hydroxide and then 50 cm3 of ethyl acetate were added. After filtration, the organic phase was separated by settling, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue was triturated in 20 cm3 of diisopropyl ether, filtered and dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 45 mg of N-[1-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine were thus obtained in the form of a white powder melting at 210° C. Mass spectrum: EI: m/z=280 M+ base peak.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:14]([O-])=O)=[C:7]([B:11]([OH:13])[OH:12])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]>CCO.[Pd]>[C:1]([NH:4][C:5]1[C:6]([NH2:14])=[C:7]([B:11]([OH:12])[OH:13])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(B(O)O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1cccc(B(O)O)c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
10% Pd on carbon (cat.) was added as a slurry in EtOH under N2 to [3-(acetylamino)-2-nitrophenyl]boronic acid in EtOH (0.05 M). The atmosphere in the reaction vessel was flushed with hydrogen (1 atm) and the reaction stirred vigorously at RT for 20 min. The hydrogen atmosphere was then replaced with N2 before filtering through a plug of CELITE—washing well with EtOH. The EtOH solution was concentrated in vacuo to afford the crude title compound as a brown solid, which was used immediately in the subsequent cross-coupling step. MS (ES+) m/z 195 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][CH:10]1[CH2:19][C:18](=[O:20])[C:17]2[C:12](=[CH:13][C:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:15][CH:16]=2)[O:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][Mg]Cl>C1COCC1>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][CH:10]1[CH2:19][C:18]([OH:20])([CH3:31])[C:17]2[C:12](=[CH:13][C:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:15][CH:16]=2)[O:11]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Cl
Reactant: CN(CC1CC(=O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CN(CC1CC(C)(O)c2ccc(S(=O)(=O)c3ccccc3)cc2O1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To a solution of (7-benzenesulfonyl-4-oxo-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (216 mg, 0.5 mmol) in THF (25 mL) at 0° C. was added MeMgCl (3.0 M in THF, 0.208 mL). The mixture was allowed to warm at room temperature and was stirred for 6 hours. The reaction was quenched by addition of water and it was concentrated in vacuo. The aqueous residue was extracted with DCM and the organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (DCM/MeOH, 97/3) to give (7-benzenesulfonyl-4-hydroxy-4-methyl-chroman-2-ylmethyl)-methyl-carbamic acid tert-butyl ester (214 mg, 96% yield) as yellow crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][N:3]=1.C(NC(C1C(=O)C2C(=NC=CC=2)N(C2C=CC=C(Br)C=2)C=1)=O)(C)C.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].C1(C(O)(C#C)C)C=CC=CC=1>>[OH:11][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[N:3][CH:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1ccc(Br)nc1
Reactant: C#C[Si](C)(C)C
Agent: C#CC(C)(O)c1ccccc1
Agent: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Product: CC(C)(O)c1ccc(C#C[Si](C)(C)C)nc1

Procedure:
Following the procedure of EXAMPLE 15, but substituting the product 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine from present Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and trimethylsilylacetylene for 2-phenyl-3-butyn-2-ol, the 5-(1-hydroxy-1-methylethyl)-2-[(trimethylsilyl)ethynyl]pyridine compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[NH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=2)[NH:20][N:19]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=2)[N:20]([CH2:11][C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]3)[N:19]=1
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Reactant: COC(=O)c1ccc2[nH]nc(N)c2c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)c(N)nn2Cc1cc(Cl)cc2cnn(CC(C)C)c12

Procedure:
A mixture of compound 17 (0.112 g, 0.47 mmol), methyl 3-amino-1H-indazole-5-carboxylate (0.075 g, 0.39 mmol), di-tert-butyl azocarboxylate (0.135 g, 0.59 mmol), triphenylphosphine (0.155 g, 0.59 mmol), in tetrahydrofuran (4 mL) was heated at 140° C. under microwave conditions for 20 minutes. Then, the reaction was quenched by adding water and diluted with ethyl acetate. The organic layer was separated, washed with Brine, dried (MgSO4), filtered and the solvent was evaporated. Then, the residue was purified by chromatography column on a 20 g SPE cartridge to give the title compound as a colorless solid. (0.090 g, 56%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=2)[CH:8]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Nc2cc(Cl)ccc2[N+](=O)[O-])nc1
Temperature: 130 °C
Yield: 700.2 %

Procedure:
To a well stirred solution of 5-chloro-2-nitroaniline (2.0 g, 11.0 mmol) in dry N,N-dimethylacetamide (DMA; 15 ml), cesium carbonate (Cs2CO3; 757 mg, 2.3 mmol) and 6-chloronicotinonitrile (193 mg, 1.3 mmol) were added and reaction mixture was heated at 130° C. for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (2×100 ml), and the combined organic layers were washed with water (2×50 ml), brine (20 ml), dried (Na2SO4), filtered and concentrated under reduced pressure to yield 2.5 g of the product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[S:16][C:15]([CH3:17])=[N:14][C:13]=3[CH:18]=2)[CH:5]=[N:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:17][C:15]1[S:16][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[CH:5]=[N:4][CH:3]=[C:2]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[N:7]=3)=[CH:18][C:13]=2[N:14]=1
Reactant: Cc1nc2cc(Nc3cncc(Cl)n3)ccc2s1
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nc2cc(Nc3cncc(-c4ccncc4)n3)ccc2s1
Yield: 86.7 %

Procedure:
A mixture of 2,6-dichloropyrazine (0.150 g, 1.006 mmol), 5-amino-2-methylbenzothiazole (0.250 g, 1.51 mmol), BINAP (0.0137 g, 0.02215 mmol), sodium tertiary butoxide (0.136 g, 1.409 mmol) and palladium acetate (0.005 g, 0.02215 mmol) in toluene (8 mL) was heated at 85° C. for 16 h under nitrogen. CH2Cl2 was added, the reaction mixture was filtered through Celite, and the solvent was evaporated. The residue was purified by column chromatography (5% methanol in CH2Cl2 as eluent) to give 0.180 g (65%) of intermediate (6-chloro-pyrazin-2-yl)-(2-methyl-benzothiazol-5-yl)-amine. 1H NMR (CDCl3) δ 7.59-7.54 (d, J=15.6 Hz, 2H), 7.38 (s, 1H), 7.19-7.16 (d, J=8.65 Hz, 1H), 6.98-6.95 (d, J=8.41 Hz, 1H), 6.71 (brs, 1H, NH), 2.31 (s, 3H, CH3); MS (API-ES/Positive); m/z: 277 (M+H)+. A mixture of (6-chloro-pyrazin-2-yl)-(2-methyl-benzothiazol-5-yl)-amine (0.075 g, 0.271 mmol), pyridine-4-boronic acid (0.040 g, 0.326 mmol), sodium carbonate (0.143 g, 1.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0156 g, 0.0135 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield 2-methyl-N-(6-pyridin-4-ylpyrazin-2-yl)-1,3-benzothiazol-5-amine (0.075 g, 86.5%) as a yellow solid. 1H NMR (CD3OD) δ 8.82 (m, 3H), 8.72 (s, 1H), 8.45-8.44 (m, 2H), 8.35 (s, 1H), 7.92-7.90 (d, J=8.67 Hz, 1H), 7.61-7.59 (dd, J=10.63, 1.94 Hz, 1H), 2.89 (s, 3H, CH3); MS (API-ES/Positive); m/z: 320 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:16]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2-c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ccccc2CN2CCNCC2)cc1
Reaction time: 4.5 h
Yield: 92.4 %

Procedure:
To a solution of 4-biphenyl-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (9.89 g, 28.1 mmol) in dichloromethane (112.5 ml) at rt was added TFA (37.5 ml). The reaction was stirred for 4.5 h and then concentrated under reduced pressure. To the crude product was added H2O (20 ml) followed by 1M NaOH and then 5M NaOH to adjust the pH to ˜8-9. The mixture was extracted with dichloromethane (×2) and the combined organic extracts were washed with H2O, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-biphenyl-2-ylmethyl-piperazine (6.55 g, 92%) which was used without further purification. HPLC-MS 253 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:17]([N+:14]([O-:16])=[O:15])[CH3:18])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CC[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: CC(=Cc1ccc(S(C)(=O)=O)c(F)c1)[N+](=O)[O-]

Procedure:
A stirred mixture of 3-fluoro-4-methanesulfonyl-benzaldehyde (Example 64a) (24 g, 0.119 mol), nitroethane (70 ml, 0.97 mol) and ammonium acetate (2.75 g, 35 mmol) is heated at reflux under argon for 24 hours. The mixture is concentrated to give an oil which is dissolved in chloroform (200 ml) and washed with water (2×200 ml), followed by brine (100 ml). The organic extract is dried (MgSO4), filtered and the solvent removed to give the product as an orange oil. This was used immediately in the next step.
Reaction SMILES: CS[C:3](=[N:13][CH3:14])[NH:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1.[N+:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([O-:17])=[O:16]>>[Cl:12][C:9]1[N:8]=[CH:7][C:6]([CH2:5][NH:4][C:3]([NH:13][CH3:14])=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CN=C(NCc1ccc(Cl)nc1)SC
Product: CCOC(=O)C(=C(NC)NCc1ccc(Cl)nc1)[N+](=O)[O-]
Temperature: 77.5 °C
Yield: 57.3 %

Procedure:
A mixture of 1.4 g (0.0061 mole) of S-methyl-N-(6-chloro-3-pyridylmethyl)-N'-methylisothiourea obtained in Example 64 (2) and 2.7 g of ethyl nitroacetate was stirred with heating at 75-80° C. for 3 hours. After cooling, the crystals were collected by filtration, washed with CH3CN and dried. The procedure gave 1.1 g of the title compound as white crystals.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:12]/[C:11](=[CH:25]\[C:26](OCC)=[O:27])/[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCl.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:12]/[C:11](=[CH:25]\[CH2:26][OH:27])/[CH2:10]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)C/C(=C\C(=O)OCC)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)C/C(=C\CO)C[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
The compound of Example 16K (589 mg, 1.3 mmol) was dissolved in 20 mL of toluene and 10 mL of dichloromethane and cooled in a dry ice/acetone bath. Diisobutylaluminum hydride (1 M in hexanes, 5.8 mL, 5.8 mmol) was added dropwise. After 1 hour, the reaction was quenched by the addition of 20 mL of 20% aqueous sodium potassium tartrate. To this mixture was added 25 mL of water followed by 6 mL of 2 N HCl. The resulting mixture was extracted three times with dichloromethane. The combined extracts were washed with 10% aqueous NaCl, dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (70 mL of SiO2, elution with dichloromethane) afforded the titled compound (294 mg, 55%), contaminated with ˜20% of an olefin isomer.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:15]2[C:19](Cl)=[C:18]([S:21]([CH3:24])(=O)=O)[N:17]([CH3:25])[N:16]=2)[C:7]=1[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])#[N:2].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:15]2[CH:19]=[C:18]([S:21][CH3:24])[N:17]([CH3:25])[N:16]=2)[C:7]=1[CH:8]([O:9][CH2:10][CH3:11])[O:12][CH2:13][CH3:14])#[N:2]
Reactant: CCOC(OCC)c1c(C#N)cnn1-c1nn(C)c(S(C)(=O)=O)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: OCCO
Solvent: O
Product: CCOC(OCC)c1c(C#N)cnn1-c1cc(SC)n(C)n1

Procedure:
0.6 g (1.5 mmol) of 4-cyano-5-diethoxymethyl-1-(4-chloro-1-methyl-5-methylsulfonyl-3-pyrazolyl)pyrazole (Example B.2) and 0.5 ml of ethylene glycol together with 10 mg of p-toluenesulfonic acid are heated under reflux in 20 ml of toluene for 3 hours. Shaking with sodium bicarbonate and water, drying (sodium sulfate) and concentration using a rotary evaporator gives, in crystalline form, the desired product which can be further purified, if required, by recrystallization or silica gel column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](=[O:20])[NH:18][CH3:19])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:25][CH2:26][CH:27]4[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:29]1[CH2:30][CH:27]([CH2:26][CH2:25][N:24]([S:38]([CH3:41])(=[O:40])=[O:39])[C:12]2[C:13]([CH:21]3[CH2:22][CH2:23]3)=[CH:14][C:15]3[C:10]([CH:11]=2)=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:16]=3[C:17]([NH:18][CH3:19])=[O:20])[CH2:28]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CN(C(=O)OC(C)(C)C)C3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CNC3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of tert-butyl 3-(2-{[2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}ethyl)azetidine-1-carboxylate (prepared by reacting 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide with tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate), (25 mg, 0.04 mmol) in DCM (3 mL) was added TFA (1 mL) and the reaction stirred at ambient temperature. After 1 h, the reaction was concentrated in vacuo and the residue partitioned between EtOAc (25 mL) and aq. saturated sodium bicarbonate (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3×15 mL). The combined organics were washed with brine (15 mL), dried (MgSO4), concentrated in vacuo and purified by preparative HPLC eluting with acetonitrile:0.1% formic acid in water to afford Compound (6) (8.8 mg, 42%). ESI-MS m/z calculated for [M+H]+: 502.2. found: 502.1 1H NMR (400 MHz, CD3CN) δ 8.40 (s, 1H), 7.83 (s, 1H), 7.64-7.54 (m, 4H), 7.39 (s, 1H), 7.37 (br d, J=3.9 Hz, 1H), 3.94-3.81 (m, 2H), 3.76-3.59 (m, 2H), 3.59-3.50 (m, 2H), 3.09 (d, J=10.3 Hz, 3H), 2.97-2.86 (m, 4H), 2.43-2.33 (m, 1H), 1.95-1.86 (m, 2H), 1.14-1.00 (m, 3H), 0.71-0.59 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH2:18]([CH:20]([CH2:26][CH3:27])[C:21](=O)[CH2:22][C:23]#[N:24])[CH3:19]>>[Cl:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[F:8])[N:1]=[C:21]([CH:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[C:22]([C:23]#[N:24])=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(F)c(Cl)cc1C(=O)c1ccccc1
Reactant: CCC(CC)C(=O)CC#N
Product: CCC(CC)c1nc2cc(F)c(Cl)cc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-4-fluoro-phenyl)-phenyl-methanone (prepared as described in example 105 step D) and 4-ethyl-3-oxo-hexanenitrile (prepared as described in example 101 step A). Off-white solid. MS (ESI): 353.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH2:12])[CH:6]=1
Reactant: Cc1ccc(Oc2ccccc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(Oc2ccccc2F)cc1N
Yield: 0.1 %

Procedure:
4-(2-fluoro-phenoxy)-2-nitrotoluene (15.17 g, 0,061 mol) and Pd/C (1.67 g) in ethanol (150 mL) were stirred under hydrogen atmosphere for 48 h, then the mixture was filtered through celite and the filtrate was concentrated under vacuum and purified by flash chromatography eluting with Hex:EtOAc 9:1 to afford 10.9 g of 5-(2-fluoro-phenoxy)-2-methyl-phenylamine: MS: 218 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:26])[NH:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=2)=[O:16])[CH2:10]1.[C:27]1([N:33]2[CH:37]=[N:36][C:35]([C:38](O)=[O:39])=[N:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]([C:19]1[N:18]=[C:17]([C:15]([N:11]2[CH2:12][CH2:13][N:14]([C:38]([C:35]3[N:36]=[CH:37][N:33]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:34]=3)=[O:39])[C:9]([CH3:26])([CH3:8])[CH2:10]2)=[O:16])[CH:22]=[CH:21][CH:20]=1)([CH3:24])[CH3:25]
Reactant: CC(C)c1cccc(C(=O)N2CCNC(C)(C)C2)n1
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4ccccc4)n3)C(C)(C)C2)n1
Temperature: 25 °C

Procedure:
A mixture of 55 mg (0.15 mmol) (3,3-dimethyl-piperazin-1-yl)-(6-isopropyl-pyridin-2-yl)-methanone trifluoroacetate, 28 mg (0.15 mmol) 1-phenyl-1H-[1,2,4]-triazole-3-carboxylic acid, 52 mg (0.16 mmol) TBTU and 0.10 mL (0.61 mmol) DIPEA in 1.5 mL DMF was stirred at RT over the weekend. The reaction mixture was purified by HPLC.
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:19])([CH3:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[C:16]#[N:17])(=O)C.O=[C:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[NH2:17][C:16]1[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([CH3:18])([CH3:19])[CH2:5][OH:4])[N:15]=[C:21]([CH3:28])[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)OCC(C)(C)COc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)CO)c2c1N

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl acetate (Tachdjian, C. et al. PCT Int. App. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a pale yellow solid (26%). MS 333 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=O)=[N:8][CH:9]=1)([O-:3])=[O:2]>N1CCCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:8]2[CH2:9][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cn1
Solvent: C1CCNCC1
Product: O=C(c1ccc([N+](=O)[O-])cn1)N1CCCCC1

Procedure:
Methyl 5-nitropyridine-2-carboxylate (182 g, 1 mol) was refluxed in piperidine (250 mL) for 1 hour. The reaction mixture was concentrated in vacuo to give crude 5-nitro-2-(piperidin-1-ylcarbonyl)pyridine, which was used for the next stage without additional purification.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.S(OC)(OC)(=O)=O.[O:28]1[CH2:33]COC[CH2:29]1.[OH-].[Na+]>O>[CH3:29][O:28][CH3:33].[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2
Reactant: C1COCCO1
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC
Reaction time: 1 h

Procedure:
Into a mixture of 1 g of estrone, 0.5 ml of dimethyl sulfate and 5 ml of dioxane, 5 ml of 10% NaOH aqueous solution was added over a period of one hour. The reaction temperature was maintained at 15° - 20°C. The resulting mixture was stirred for one hour. Then, 30 ml of water was added and the resulting cyrstals were filtered, washed with water and dried to obtain 1.040 g of the 100% purity methyl ether of estrone in a 98.9% yield.