Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:42])[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[C:32]([O:34]CC1C=CC=CC=1)=[O:33])=[O:26])[CH2:20][CH2:21][CH3:22])=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:32]([C@H:28]1[CH2:29][CH2:30][CH2:31][N:27]1[C:25](=[O:26])[CH2:24][CH2:23][N:19]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:42])([OH:34])=[O:33]
Reactant: CCCN(CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCC(=O)N1CCC[C@@H]1C(=O)O)CCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 97.3 %

Procedure:
A solution of 84 mg (0.15 mmol) (R)-1-[3-[[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-propyl-amino]-propionyl]-pyrrolidine-2-carboxylic acid benzyl ester in 3 ml ethanol was stirred with 10 mg 10% palladium on charcoal under I atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, concentration in vacuo afforded 58 mg (100%) of the title compound as a white solid. MS m/e (%): 398 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:8])[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-methoxy-4-nitrobenzoic acid (6.81 g, 34.54 mmol) in sulfurous dichloride (50 mL) was stirred at reflux for 8 hours. After cooling to ambient temperature, the mixture was concentrated under vacuum and the residue was dissolved in dichloromethane (60 mL). 1-Methylpiperazine (3.6 g, 36.27 mmol) was added at 0° C. and the mixture was stirred at ambient temperature for 4 hours. The mixture was poured into water (100 mL) and extracted with dichloromethane (2×200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide the crude title compound. MS: 280.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[CH:14][CH:13]=2)=[N:8][CH:9]=1)[CH3:2].[NH2:30]OS(C1C(C)=CC(C)=CC=1C)(=O)=O>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:30]=[C:11]([C:12]3[CH:29]=[CH:28][C:15]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:19])=[CH:14][CH:13]=3)[CH:10]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(C#Cc2ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc2)nc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: C1CCOC1
Product: CCOc1ccc2cc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3)nn2c1
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of tert-butyl [(1S)-2-{4-[(5-ethoxypyridin-2-yl)ethynyl]phenoxy}-1-methylethyl]carbamate (2.25 g) in THF (30 mL) was added 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (1.75 g, containing water) at room temperature, and the mixture was stirred for 1 hr, and concentrated under reduced pressure. To the residue were added DMF (20 mL) and potassium carbonate (1.18 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water, and the aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (1.18 g).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH:5][N:4]=1)=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:22]([CH3:24])[CH3:23]>C(#N)C>[CH:1]([C:3]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:5]([CH:22]([CH3:24])[CH3:23])[N:4]=1)=[O:2]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)c1cc(C=O)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)n1nc(C=O)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1,1-Dimethylethyl 3-formyl-1H-pyrazole-5-carboxylate (600 mg) and cesium carbonate (996 mg) were dissolved in acetonitrile (60 ml). 2-Iodopropane (0.305 ml) was added and the mixture was stirred at RT for 20 h. A further portion of 2-iodopropane (0.03 ml) was added and the mixture was stirred at RT for 16 h. The solvent was removed in vacuo. The reaction mixture was diluted with water (80 ml) and DCM (80 ml) and separated using a hydrophobic frit. The aqueous layer was extracted with a further quantity of DCM (2×50 ml) using a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (50 g silica), eluting with a gradient of 0-100% ethyl acetate in cyclohexane to give the title compound (377 mg), and a mixture (213 mg) of both isomers. The mixture was purified by flash chromatography on silica gel (20 g silica), eluting with a gradient of 0-50% ethyl acetate in cyclohexane to give another quantity (114 mg) of the title compound (114 mg) as a colourless oil.
Reaction SMILES: C=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.[O:11]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[O:11]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: O=[O+][O-]
Reactant: C=C1CCC(C(=O)OC)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C1CCC(=O)C1
Reaction time: 8 h
Yield: 54 %

Procedure:
A solution of methyl 3-methylenecyclopentane carboxylate (Trost, B. M., Chan, M. T., J. Am. Chem. Soc., 1983, 105, 2315) (2.84 g, 20.26 mmol) in dichloromethane (60 mL) was cooled to −78° C. and a slow stream of ozone was passed through until the permanent blue color indicated complete ozonide formation. The excess ozone was purged with stream of nitrogen. Triphenylphosphine (10.62 g, 40.52 mmol) was added, and stirring was continued overnight, allowing the temperature to warm up to ambient. Solvent was removed in vacuo, the residue dissolved in 10 mL of ethyl acetate/hexane (1:4) mixture. The crystalline triphenylphosphine oxide was removed by filtration, and the residue was purified by mplc (ethyl acetate/hexanes (1:4) to yield 1.5651 g (54%) of the desired product.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>O1CCCC1.C(#N)C>[C:16]([O:15][C:13](=[O:14])[CH2:12][N:5]([CH2:4][CH2:3][CH2:2][Br:40])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CN(CCCO)C(=O)C(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(CCCBr)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of tert-butyl [(3-hydroxypropyl)-trifluoroacetylamino]acetate (35 mmol) were solubilized in 150 ml of tetrahydrofuran. 12.4 g of triphenylphosphine (47.3 mmol) were added and the reaction mixture was thermostated at 15-20° C. 15.1 g of carbon tetrabromide (45.6 mmol), dissolved in 60 ml of acetonitrile, were added dropwise using a dropping funnel and the whole was stirred at room temperature for 4 hours.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([O:20]C)=O)[CH:12]=1.C[O-].[Na+]>CO>[OH:3][NH:2][C:18](=[O:20])[CH2:17][C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1cccnc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Cc1cccnc1)NO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 13.8 g. (200 mmole) of hydroxylamine hydrochloride and 27.8 ml. (200 mmole) of triethylamine in 500 ml. of methyl alcohol was cooled to a temperature of -5° C. and 30.2 g. (200 mmole) of methyl 3-pyridineacetate were added. The mixture was stirred for 6 hours at room temperature and then 10.8 g. (200 mmole) of sodium methylate were added causing a slight exotherm to occur. The reaction mixture was then stirred for 27.5 hours. The reaction mixture was filtered and the filtrate evaporated to dryness. The crude residue of product was sonicated with 50 ml. of chloroform and filtered. The insoluble crude product (25.10 g) was crystallized from 50 ml. of water. There were obtained 15.54 g. of product melting with decomposition at about 163° C. to about 165° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([O:28]CC)=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([OH:28])=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 13 h
Yield: 79.5 %

Procedure:
Ethyl 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)-amino]phenyl}ethyl)-1,3-thiazole-5-carboxylate (3 g), 1N-aqueous sodium hydroxide solution (17.3 ml) and ethanol (30 ml) were combined, and the mixture was refluxed for 5 hours. After cooled to room temperature, the organic solvent was removed in vacuo. The aqueous solution was acidified (pH=4) with 1N-hydrochloric acid, and extracted with ethyl acetate (twice). The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was dissolved in pyridine (45 ml), and then acetyl chloride (1.48 ml) was added dropwise to the solution at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 13 hours, and pyridine was removed in vacuo. Water was added to the residue, and acidified with 1N-hydrochloric acid. The precipitate was collected in vacuo. The solid was washed with water and ethyl ether to give 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)-amino]phenyl}ethyl)-1,3-thiazole-5-carboxylic acid (2.23 g) as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)[CH:13]=[N:12]2)=[C:5]([CH3:28])[CH:4]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:14]2[CH:13]=[N:12][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:4][C:5]=3[CH3:28])=[O:27])[C:16](=[O:17])[CH:15]=2)=[N:21][CH:22]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccc(F)cn2)cc1=O
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCCC2)ccc1C(=O)Cn1ncc(OCc2ccc(F)cn2)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-fluoro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 6b, 112 mg, 0.25 mmol) in DMF (2 mL) is added pyrrolidine (63 μL, 0.75 mmol). The reaction mixture is stirred for 60 min at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]=O)=[CH:10][C:5]=2[CH2:4][O:3]1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[N:24]3[CH2:23][CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:26][CH2:25]3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(/C=C/c2ccc3c(c2)COC3=O)CC1
Temperature: 25 °C

Procedure:
A mixture of (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (3.5 g, 20 mmol), Boc-piperazine (3.5 g, 20 mmol) and anhydrous MgSO4(20 g, 166 mmol) in 100 mL of anhydrous DCM were stirred at room temperature over night. The solid was filtered and the solvent was evaporated at reduced pressured to get the crude product. The crude product was purified via column chromatograph to afford tert-butyl 4-[(E)-2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethenyl]piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.74 (d, J=8.2 Hz, 1H), 7.29˜7.34 (m, 2H), 6.88 (d, J=13 Hz, 1H), 5.55 (d, J=14 Hz, 1H), 5.25 (s, 2H), 3.49˜3.58 (m, 4H), 3.12˜3.17 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:15](Br)[CH3:16]>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)[CH3:16]
Reactant: CCBr
Reactant: COC(=O)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
Methyl 3-hydroxyphenylacetate (132.5 g, 0.80 mole) was added dropwise to a suspension of 50% NaH (43.2 g, 0.90 mole) in DMF (i.e.) at 0° C. under N2. The solution was stirred 1 hour at room temperature, cooled in an ice bath, and ethyl bromide (120 ml, 1.6 mole) added. The reaction mixture was stirred overnight at room temperature, filtered, and concentrated in vacuo. A solution of the residue in diethyl ether was washed with dilute NaOH solution and saturated NaCl, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate:hexane (1:3→1:9) to give methyl 3-ethoxyphenylacetate (94.9 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.30 (t, J=7 Hz, 3H, ethyl CH3), 3.59 (s, 3H, ester CH3), 3.61 (s, 2H, ArCH2), 3.98 (q, J=7 Hz, 2H, ethyl CH2), 6.28-6.81 (m, 3H), 7.16-7.24 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9](C=O)[CH2:8][CH2:7]1)=O.Cl.[NH2:20][OH:21].C([O-])(=O)C.[NH4+].C(O)C>O>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4](=[N:20][OH:21])[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: O=CN1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(Cl)cc1Cl)C1CCNCC1
Yield: 27.1 %

Procedure:
A mixture of 105 g of 4-(2,4-dichlorobenzoyl)-1-formylpiperidine, 70 g of hydroxylamine hydrochloride, 135 g of ammonium acetate, 1.05 l of ethanol and 350 ml of water was stirred and heated at 130° for 40 hrs. The reaction mixture was evaporated and 2.0 l of water was added to the residue. The water was decanted from the oil and the oil was washed two times with 500 ml of water and dissolved in about 400 ml of dichloromethane. The insoluble material was collected. The dichloromethane extract was washed twice with 600 ml of water. The combined aqueous phases were made basic with potassium carbonate/water. The precipitate was filtered, washed with water and dried over phosphorus pentoxide in vacuo to yield 27.2 g (9.96%) of 4-(2,4-dichlorobenzoyl)piperidine oxime. The insoluble material was dissolved in hot water and made alkaline with potassium carbonate-water. The precipitate was filtered, washed with water and dried over phosporus pentoxide in vacuo. The solid was dissolved in 200 ml methanol and 2 ml of conc hydrochloric acid was added. After heating for 5 mins, the solution was filtered and evaporated in vacuo to dryness. The residue was recrystallized from methanol-ether to yield product as the hydrochloride, mp 284°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[F:18][C:19]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[CH:36][C:20]=1[O:21]C1C=CN=C2C=C(C(N(C)C)=O)SC=12>>[F:18][C:19]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[CH:36][C:20]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Reactant: CN(C)C(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Product: O=C(c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1)N1CCCC1
Yield: 93 %

Procedure:
Starting from (7-chlorothieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone (139, scheme 26) and following the procedure described above for the synthesis of compound 6 (scheme 1, example 1), title compound 193 was obtained in (93% yield). LRMS (M+1) 387.4 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Product: COc1c(Nc2ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n2)ccc2c1CCC(N1CCOCC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner as Example 179 heating at 140° C. Product was isolated as a mixture of diastereomers (27 mg, 20%). LCMS (m/e) 579 (M+H); 1H NMR (400 MHz, CDCl3) δ 12.40 (s, 1H), 12.2 (s, 1H), 10.8 (s, 1H), 10.6 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.48 (d, 1H, J=7.32 Hz), 7.00 (m, 1H), 6.90 (m, 2H), 6.74 (m, 1H), 6.32 (s, 1H), 6.20 (s, 1H), 4.03 (m, 8H), 3.30-3.76 (m, 16H), 2.92-3.08 (m, 13H), 2.76 (m, 2H), 2.33-2.59 (m, 6H), 2.08 (m, 4H), 1.86 (m, 2H), 1.76 (m, 2H), 1.12-1.58 (m, 12H).
Reaction SMILES: [N+](C1C=C(S(O[CH2:14][C@@H:15]2[CH2:17][O:16]2)(=O)=O)C=CC=1)([O-])=O.[OH:18][C:19]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:29][C:27]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([O:18][CH2:14][C@@H:15]2[CH2:17][O:16]2)[CH:28]=1
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (777.7 mg, 3.0 mmol), methyl 2-hydroxy-4-methylbenzoate ((498.5 mg, 3.0 mmol) and Cs2CO3 (1.17 g, 3.6 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-20% ethyl acetate in petroleum spirit) to give the subtitled compound (500 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH3:20])[C:16]=2Br)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C([Sn](CCCC)(CCCC)[C:27]1[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=1)CCC>CN(C=O)C>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH3:20])[C:16]=2[C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: Cc1nsc(NC(=O)c2c(N)nn3cc(F)cnc23)c1Br
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)c2c(N)nn3cc(F)cnc23)c1-c1cncn1C
Temperature: 110 °C
Reaction time: 2 h

Procedure:
2-amino-N-(4-bromo-3-methyl-isothiazol-5-yl)-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxamide (20 mg, 0.05388 mmol), tributyl-(3-methylimidazol-4-yl)stannane (40.01 mg, 0.1078 mmol) dichloropalladium triphenylphosphane (7.566 mg, 0.01078 mmol) in DMF (2 mL) was degassed for 5 min, then heated at 110° C. After 2 h, the reaction mixture was loaded on a SCX column, washed with DCM/MeOH mixtures. The product was eluted with a 2M solution of ammonia in MeOH and the eluent was concentrated in vacuo. The residue was purified by fractionlynx to yield 2-amino-6-fluoro-N-(3-methyl-4-(1-methyl-1H-imidazol-5-yl)isothiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a pale yellow solid. (8.09 mg, 37.4%). MS (ES+) 373.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]([CH2:13][CH3:14])[CH:9]([C:11]#[N:12])[OH:10])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][OH:18]>CO.C[O-].[Na+]>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]([CH:9]([OH:10])[C:11](=[NH:12])[NH:17][OH:18])[CH2:13][CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C#N
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 32.2 %

Procedure:
A solution of (2-cyano-1-ethyl-2-hydroxy-ethyl)-carbamic acid tert-butyl ester (9.53 g, 44 mmol) in methanol (80 ml) was cooled to 0° C. and treated successively with hydroxylamine hydrochloride (3.05, 44 mmol) in methanol (80 ml) and 25% sodium methoxide solution in methanol (10.2 ml). Stirred at 0° C. for 5 minutes, cold bath removed and the reaction mixture stirred at room temperature for 5 hours. Methanol evaporated off under reduced pressure, crude partitioned between ethyl acetate and water. Organic layer separated, dried (MgSO4) and evaporated under reduced pressure to give yellow oil. Purified by mplc, eluting with a mixture of ethyl acetate-heptane to give the title compound as white solid (3.5 g); MS: M(H+) 248.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([F:19])C=1C(O)=O>C1C=CC=CC=1.CN(C=O)C>[F:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([F:19])[C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(F)c(C(=O)Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of oxalyl chloride (36.5 g, 0.29 mol) in dry benzene (50 ml) was added dropwise to a stirred solution of compound 24 (25.5 g, 0.14 mol) and dry DMF (40 drops) in dry benzene (500 ml) at room temperature. The mixture was stirred at room temperature overnight and the excess of oxalyl chloride and benzene were removed in vacuo.
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:10]1=[O:33])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[F:25][C:17]1[C:18]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[N:19][C:12]2[N:11]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:10](=[O:33])[N:9]([OH:8])[C:14](=[O:15])[C:13]=2[CH:16]=1
Reactant: [H][H]
Reactant: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(F)cc2)c(=O)n1O
Yield: 109.3 %

Procedure:
Twenty percent Pd/C (70 mg) was added to a solution of 3-benzyloxy-6-fluoro-1-(4-fluorophenyl)-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example N-4, 0.15 g, 0.33 mmol) in 25 mL of THF, and this was shaken under 50 PSI of hydrogen for 17.5 hours. The mixture was filtered and concentrated to give 0.13 g of the title compound as a solid, mp 172-174° C.