Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C(O)C>[C:1]([C:3](=[CH:12][NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[CH3:16])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: Cc1ccccc1N
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1ccccc1C
Yield: 88.2 %

Procedure:
Ten grams of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide in dissolved by heating in 50 ml of ethanol to 60°. Then 5.32 g of 2-methylaniline in 20 ml ethanol is added and the mixture heated at reflux for 4 hours with stirring. Crystals appear on cooling and the mixture is filtered and washed with ether to yield 11.36 g of α-cyano-β-(2-methylanilino)-N-ethoxycarbonylacrylamide, which is dissolved in tetralin and heated at reflux for 3 hours. After cooling, the mixture is filtered, washed with ether, to yield 5-cyano-1-(2-methylphenyl)uracil, m.p. 251.5°-252.5°.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[F:31][C:13]1([F:12])[CH2:14][CH2:15][C:16]([CH2:29][NH:30][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=2[CH3:11])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: Cc1c(F)cccc1C(=O)O
Product: Cc1c(F)cccc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 3-fluoro-2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=431.2, tR (minutes, Method D)=0.79
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH:18]=O)[CH2:13]1>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:18]([CH:14]1[CH2:15][CH2:16][CH2:17][O:12][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=CC1CCCOC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: O
Solvent: CCO
Product: O=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Yield: 14.1 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (19.45 g, 90.9 mmol), tetrahydro-2H-pyran-3-carbaldehyde (10 g, 90.9 mmol) and borax (34.6 g, 90.9 mmol) in ethanol (120 mL) and H2O (200 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one (4 g, 15%). 1H-NMR (CDCl3): 1.30 (m, 2H), 1.48 (m, 5H), 1.64 (m, 4H), 1.94 (d, 2H), 6.86 (d, 1H), 7.51 (dd, 1H), 7.92 (d, 1H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10]Br.C([O-])([O-])=O.[K+].[K+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[C:1]([O:6][CH2:10][CH:9]([O:12][CH3:13])[O:8][CH3:7])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: COC(CBr)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Solvent: O
Product: CCCC(=O)OCC(OC)OC
Temperature: 134 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
A mixture of butyric acid (1.0 g, 11.35 mmol), bromoacetaldehyde dimethyl acetal (2.25 mL, 19.13 mmol), tetrabutylammonium bromide (1.83 g, 5.67 mmol) and K2CO3 (1.56 g, 11.35 mmol) in 10 mL of anhydrous CH3CN was stirred at 134° C. for 16 h in a sealed tube. It was cooled to room temperature, water was added and the mixture was extracted with Et2O (3×120 mL). The combined organic phases were washed with saturated NaCl (2×60 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 20-30% ethyl acetate/hexanes to give the product 43a (1.56 g, 78%). 1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.43 Hz, 3H), 1.60 (sextet, J=7.43, 7.04 Hz, 2H), 2.24 (t, J=7.04 Hz, 2H), 3.36 (s, 6H), 4.08 (d, J=5.3 Hz, 2H), 4.54 (t, J=5.3 Hz, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c(O)c1
Reaction time: 16 h
Yield: 73.4 %

Procedure:
tert-Butyl N-[2-(2-benzyloxy-4-isopropylphenyl)ethyl]carbamate (12.00 g) was dissolved in 150 mL of ethanol. To the stirred solution was added 1.10 g of 10% palladium on carbon under ice-cooling, and the mixture was stirred under a hydrogen atmosphere and ordinary pressure at 30° C. for 16 hours. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure to give 6.66 g of tert-butyl N-[2-(2-hydroxy-4-isopropylphenyl)ethyl]carbamate.
Reaction SMILES: [Cl:1][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.[CH3:14][NH2:15].S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH:15][CH3:14]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Reactant: CN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(C(F)(F)F)ccc1Cl
Reaction time: 8 h

Procedure:
2.1 g of 2-chloro-5-trifluoromethylbenzaldehyde, 15 ml of methylamine and 2 g of magnesium sulfate were stirred at room temperature for 2 h, the excess methylamine for the most part evaporating. The reaction mixture was diluted with ether, filtered and concentrated in vacuo. The methylbenzimine thus obtained was dissolved in 15 ml of THF and added dropwise to a suspension of 1.5 g of sodium borohydride in 15 ml of THF. After stirring overnight, the mixture was treated with 30 ml of methanol, stirred for a further 30 min and then rendered acidic with dil. hydrochloric acid. It was extracted with tert-butyl methyl ether, and the aqueous phase was rendered alkaline and extracted twice again with tert-butyl methyl ether. After concentrating this extract, 1.0 g of N-(2-chloro-5-trifluoromethylbenzyl)-N-methylamine was obtained.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:5]=1[C:6]([NH2:8])=[NH:7].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1>>[ClH:1].[NH2:7][C:6]1[C:5]2[C:4](=[C:12]([F:13])[CH:11]=[CH:10][C:9]=2[F:14])[NH:3][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:8]=1
Reactant: N=C(N)c1c(F)ccc(F)c1N
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(F)ccc(F)c1N2

Procedure:
This was prepared by the method of Example 173 using 2-amino-3,6-difluorobenzamidine dihydrochloride (Example G) and ethyl 4-oxopiperidine-1-carboxylate to give the title compound, m.p. 228°-229° C.
Reaction SMILES: C(OC(=O)[N:7](C(=O)C)[C@H:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)[CH2:9]1)(C)(C)C.C([Li])CCC.C(O)(=O)C>CO.CCCCCC>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:18]=1)[C:14]([N:11]1[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][C@H:10]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29]
Reactant: CC(=O)N(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc([N+](=O)[O-])cc2)C1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CO
Solvent: CCCCCC
Product: N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 200 mg (0.32 mmol) of (2R*,4S*)-N-acetyl-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-nitro-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester is added in 5 ml of methanol to a solution, stirred under an inert gas, of 0.04 ml (0.06 mmol) of n-butyllithium in hexane (1.6 M). After 1 hour, 5 mg (0.08 mmol) of acetic acid are added and the mixture is concentrated to dryness by evaporation. The residue is taken up in 2 ml of methylene chloride and 1.2 ml of trifluoroacetic acid and the mixture is stirred for 2.5 hours at room temperature. The mixture is diluted with methylene chloride and washed with 2 N sodium hydroxide solution. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness. The title compound is obtained in the form of a beige foam. TLC: dichloromethane/methanol/conc. ammonia (90:9:0.5) Rf =0.38. 1H-NMR (200 MHz, D2O): rotameric mixture; δ: 8.28-8.08 (m, 2H), 7.94-7.79 (m, 1H), 7.60-7.40 (m, 2H), 7.21-7.02 (m, 2H), 5.40-5.22 (m, 0.5H), 4.85-4.68 (m, 0.5H), 4.00-3.86 (m, 0.5H), 3.56-3.00 (m, 3H), 2.82-2.70 (m, 0.5H), 2.20-1.86 (m, 2H), 1.6-1.2 (m, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([NH2:16])[N:15]=[C:10]2[CH:9]=[CH:8]1.[CH2:19]([N:27]=[C:28]=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH2:19]([NH:27][C:28]([NH:16][C:14]1[N:15]=[C:10]2[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:18])([CH3:17])[CH3:1])[C:11]2=[N:12][CH:13]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(N)cnc21
Reactant: O=C=NCCc1ccccc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NCCc3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.5 %

Procedure:
A solution of 5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine (0.260 g, 0.98 mmol) in 15 mL of dichloromethane was cooled to −30° C. Phenethyl isocyanate (0.21 g, 1.5 mmol) was added, and the resulting solution was stirred at room temperature for 14 h, then concentrated to a residue. Column chromatography afforded 0.220 g (55%) of 1-phenethyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[CH:12]([CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([O-])=O)=[O:13].C[Si](OP(=O)=O)(C)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.C(=O)([O-])O.[Na+]>ClCCCl>[CH3:11][O:10][C:8]1[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:7]=1[CH:15]=[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12](=[O:13])[NH:6]2
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=CC(C(=O)[O-])c1ccccc1
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCCl
Product: COc1cc(OC)c2cc(-c3ccccc3)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
1.52 g (9.9 mmol) of 3,5-dimethoxyaniline and 2.30 g (12 mmol, 1.2 eq) of ethyl (α-formylphenylacetate are mixed together in a round-bottomed flask under a nitrogen atmosphere. The medium is stirred for 1 h at room temperature. A solution of trimethylsilyl polyphosphate (PPSE), freshly prepared from 4.56 g (0.03 mol) of P2O5, 10.9 ml (0.17 mol) of hexamethyldisiloxane and 50 ml of 1,2-dichloroethane, is added. The final mixture is maintained at 100° C. for 2 h. The heating is stopped and ice is then added to the reaction mixture. This mixture is then neutralized by addition of saturated sodium hydrogen carbonate solution (portionwise addition, exothermic reaction). The product is extracted with dichloromethane (large amount to be used). The organic phase is dried over MgSO4 and then evaporated under reduced pressure. The residue is taken up in ethyl acetate, which causes precipitation of the desired compound. The final product is isolated by filtration through a sinter funnel. After partial concentration of the filtrate, the final product reprecipitates. The solid is reisolated by filtration, this operation being repeated several times. Compound 34 (444 mg) is obtained in a yield of 16%.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1([CH3:12])[NH:10][C:9](=[O:11])[CH2:8]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[OH:4][CH2:5][CH2:6][C:7]1([CH3:12])[NH:10][C:9](=[O:11])[CH2:8]1
Reactant: CC(=O)OCCC1(C)CC(=O)N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(CCO)CC(=O)N1
Reaction time: 1 h

Procedure:
Under nitrogen at 0°, a solution of 4-(2-acetoxyethyl)-4-methyl-2-azetidinone (0.014 mole) in 25 ml anhydrous methanol is treated with a solution of sodium methoxide (77 mg, 1.4 mmoles) in 5 ml anhydrous methanol. After stirring for 1 hour, the solution is neutralized with glacial acetic acid. Removal of the methanol in vacuo gives crude 4-(2-hydroxyethyl)-4-methyl-2-azetidinone as an oil. The product is purified by chromatography on silica gel eluting with 10% MeOH/CHCl3 to give the alcohol.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[C:19]1([C:25]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:43]1([C:25]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:33]3[CH:29]([CH2:30][N:31]([C:15](=[O:16])[CH2:14][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:32]3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3)CC21
Reaction time: 24 h

Procedure:
0.35 cm3 of triethylamine and then 0.33 cm2 of phenylacetyl chloride are added to a suspension of 1.1 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride in 25 cm3 of dry dichloromethane at room temperature. The reaction mixture is stirred at this temperature for 24 hours, diluted with 200 cm3 of dichloromethane, washed with 100 cm3 of a saturated solution of sodium bicarbonate, with 100 cm3 of water (twice) and then with an aqueous saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm) by eluting under a nitrogen pressure of 50 kPa with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 11 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized from 70 cm3 of acetonitrile and the crystals are filtered off and dried. 0.5 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-(phenylacetyl)perhydroisoindol-4-ol is obtained in the form of a white solid.
Reaction SMILES: OC(COCCCCCCCC)CNC(C)(C)CC1C=CC(OC)=CC=1.[ClH:27].[OH:28][CH:29]([CH2:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:52].[OH:28][CH:29]([CH2:44][O:45][C:46]1[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][C:51]=1[Cl:27])[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: CCCCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2Cl)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 382 (M−15,1), 280 (11), 279 (9), 278 (65), 277 (5), 276 (100), 163 (10), 161 (6), 132 (5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:22]=[C:23]([C:27]2([NH2:30])[CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:20][C:21]1[CH:22]=[C:23]([C:27]2([NH:30][C:17]([C:16]3[C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:12]=4[CH:13]=[N:14][CH:15]=3)=[O:19])[CH2:28][CH2:29]2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: NC1(c2cccc(Br)c2)CC1
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
Product: O=C(NC1(c2cccc(Br)c2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (0.500 g, 1.94 mmol), 1-(3-bromophenyl)cyclopropanamine (453 mg, 2.14 mmol) and N,N-diisopropylethylamine (1.73 mL, 9.72 mmol) in DMF (18 mL) is added TBTU (0.780 g, 2.43 mmol). After 2 hours, the mixture is concentrated in vacuo, dissolved in ethyl acetate (200 mL), and washed with 2N sodium hydroxide (3×100 mL), saturated aqueous ammonium chloride (2×100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL). The organic layer is dried over MgSO4, filtered through a pad of silica gel eluting with ethyl acetate (3×100 mL), and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with a gradient of 50-70% ethyl acetate in heptane to give a solid that is triturated with methylene chloride to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:36]([CH:38]([NH2:41])[CH2:39][CH3:40])[CH3:37]>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:41][CH:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[C:5]2[N:6]=[CH:7][N:8]([C:9]=2[N:10]=1)[C@@H:11]1[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CCC(N)CC
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCC(CC)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-9H-purine ** (10.1 g, 22.6 mM), iso-propanol (300 ml), K2CO3 (5 g) and 1-ethylpropylamine (2.17 g, 24.84 mM) was stirred at 20° C. for 24 hrs. The reaction mixture was heated at 54° C. for 73 hrs. Solvent was removed in vacuo, water (50 ml) was added, extracted with ethyl acetate (3×80 ml), the combined extracts were dried (MgSO4) affording the title compound as a creamy light brown foam (9.44 g). LC/MS system A Rt=2.66 min, m/z=372 MH+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1=[O:32]>CN1C(=O)CCC1.CCOC(C)=O>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][NH:26][C:27](=[O:32])[CH2:28]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Reactant: O=C1CNCCN1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(N3CCNC(=O)C3)nn12
Temperature: 180 °C
Reaction time: 2 h

Procedure:
(rac)-6-Chloro-3-[1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate G, 100 mg, 0.303 mmol), KF (88 mg, 1.5 mmol), piperazin-2-one (91 mg, 0.91 mmol) were suspended in NMP (1 mL). The RM was stirred at 180° C. for 2 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative UPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3 to remove the TFA salt. The filtrate was evaporated and the residue was triturated with pentane. The precipitate was filtered off and dried to afford the title compound as a white solid (tR 0.88 min (conditions 4), MH+=394, 1H-NMR in DMSO-d6: 8.10 (br. s, 1H); 7.95-7.87 (m, 2H); 7.65 (s, 1H); 7.51 (s, 1H); 7.54 (d, 1H); 7.49 (s, 1H); 7.22 (d, 1H); 4.79 (q, 1H); 3.95 (s, 4H); 3.87-3.78 (m, 1H); 3.67-3.55 (m, 2H); 3.22 (dd, 1H); 3.29-3.14 (m, 1H); 1.71 (d, 3H)).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([C@H](C(C)C)C)[N:3]=1.[CH:16]1([NH:19][C:20]([C:22]2[CH:23]=[C:24]([F:32])[C:25]([CH3:31])=[C:26](B(O)O)[CH:27]=2)=[O:21])[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CC(O)C.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>[CH:16]1([NH:19][C:20]([C:22]2[CH:23]=[C:24]([F:32])[C:25]([CH3:31])=[C:26]([C:2]3[N:3]=[CH:4][C:5]([C:6]([NH:8][C@@H:9]([CH3:10])[CH:5]([CH3:6])[CH3:4])=[O:7])=[CH:9][CH:10]=3)[CH:27]=2)=[O:21])[CH2:18][CH2:17]1
Reactant: CC(C)[C@H](C)c1nc(Cl)ccc1C(N)=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
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: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)C)cn1
Temperature: 90 °C

Procedure:
6-Chloro-[(S)-(+)-3-methyl-2-butyl]nicotinamide (Intermediate 20, 100 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 6, 100 mg), tetrakis(triphenylphosphine)palladium (10 mg) and aqueous sodium hydrogen carbonate (4 ml) were mixed in propan-2-ol (8 ml) and heated at 90° C. under nitrogen for 18 hrs. The solvents were evaporated from the cooled reaction under vacuum and the residue dissolved as far as possible in ethylacetate. The solution was applied to an SPE (SCX, 10 g) and washed with ethyl acetate. The product was eluted from the column with methanol/0.880 ammonia, and the solvents evaporated in vacuo. The residue was redissolved in ethyl acetate and filtered through an SPE (silica, 0.5 g). The filtrate was reduced to dryness under vacuum and triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2-dimethylpropyl]-3-pyridinecarboxamide.
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].N(C([O:25][CH2:26][CH3:27])=O)=NC(OCC)=O>C(OCC)C.C1C=CC=CC=1>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[S:1][S:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:26]([C:27]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1)=[O:25])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(c1ccccc1)c1ccccc1S
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccccc1SSc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.7 %

Procedure:
To a solution of 2-mercaptobenzophenone (2.3 g, 7.4 mmol) in diethyl ether (10 mL) was added dropwise diethyl azodicarboxylate (0.65 g, 3.7 mmol). The solution was stirred for 5 minutes at room temperature, then diluted with benzene (40 mL) and refluxed for 16 hours. The solution was cooled and concentrated in vacuo leaving a yellow liquid. The crude product was purified using silica gel chromatography (75% hexane/25% ethyl acetate) to give the title compound as a yellow foam (0.8 g, 50%);