Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[BrH:3].[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH2:13][C:14]([O:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:5]1>C(O)(=O)C.O>[BrH:1].[Br:3][CH:13]([C:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:4][N:5]=1)[C:14]([O:16][CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)=[O:15]
Reactant: BrBr
Reactant: CN1CCC(OC(=O)Cc2noc3ccccc23)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CN1CCC(OC(=O)C(Br)c2noc3ccccc23)CC1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 87.3 %

Procedure:
A solution of bromine (1.48 g) in glacial acetic acid (3 ml) was added dropwise with stirring to a solution of 1-methyl-4-piperidyl 1,2-benzisoxazole-3-acetate hydrobromide (3.0 g) in glacial acetic acid (6 ml). After the reaction mixture was stirred for 40 minutes at 60° C., it was diluted with water (100 ml) and extracted with two 100-ml portions of chloroform. The chloroform solution was dried over anhydrous sodium sulfate and evaporated to give crude 1-methyl-4-piperidyl 2-bromo-2-(1,2-benzisoxazol-3-yl)acetate hydrobromide (3.2 g). The hydrobromide thus obtained was dissolved in chloroform (15 ml) and thereto was added heptamethyleneimine (4.5 ml). The resulting mixture was stirred overnight at room temperature and evaporated in vacuo to give a residue, to which water (50 ml) was added. The resulting mixture was extracted with two 100-ml portions of toluene. The toluene layer was extracted with 5% hydrochloric acid (70 ml). The aqueous layer was made alkaline with aqueous ammonia solution and extracted with toluene. The toluene layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give an oily residue (2.25 g). The residue and oxalic acid (0.74 g) were dissolved in ethanol (10 ml). The solution was concentrated in vacuo to about a half volume. To the residue was added diethyl ether until it became turbid. The crystals precipitated were collected by filtration and recrystallized from ethanol-diethyl ether to give 1-methyl-4-piperidyl 2-heptamethyleneimino-2-(1,2-benzisoxazol-3-yl)acetate oxalate (2.41 g), m.p. 170°-173° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:12])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1([CH2:23][CH2:24]Br)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[Mg].C1COCC1>CCOCC.[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][C@H:9]([C@@H:10]([OH:11])[CH2:24][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C=O)OCc1ccccc1
Reactant: BrCCc1cccc2ccccc12
Agent: [Br-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](OCc1ccccc1)[C@@H](O)CCc1cccc2ccccc12
Temperature: 4 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A solution of (S)-2-(benzyloxy)propanal (Bull. Chem. Soc. Jpn. (1989) 62, 3038, 16.25 g) in ether (200 ml) was added to a suspension of zinc bromide (26.75 g) in ether (50 ml) below 6° C. and then an ethereal solution of 2-(1-naphthyl)ethylmagnasium bromide, prepared from 2-(1-naphthyl)ethyl bromide (46.55 g) and magnesium turnings (9.63 g) in ether (300 ml), was added below 8° C. The mixture was stirred at 4° C. for 1 h and then THF (200 ml) was added. The final mixture was stirred overnight at room temperature. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution (200 ml) and insoluble material was filtered. The filtrate was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated in vacuo. Flash chromatography (hexane:ethyl acetate =9:1) gave (2S,3S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol (9.78 g, 30.8%) as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[CH:3]1.[C:23](OC=C)(=[O:25])[CH3:24]>CC(CC(C)C)=O>[C:23]([O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[CH:3]1)(=[O:25])[CH3:24]
Reactant: O=C1CC(O)C=C1Cc1cccc(OCc2ccccc2)c1
Reactant: C=COC(C)=O
Solvent: CC(=O)CC(C)C
Product: CC(=O)O[C@H]1C=C(Cc2cccc(OCc3ccccc3)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
4-Hydroxy-2-(3-Benzyloxybenzyl)cyclopent-2-enone (5.73 g, 19.48 mmol) was dissolved in isobutyl methyl ketone (60 mL), and vinyl acetate (11.2 g, 13.01 mmol) and Lipase derived from Alculigenese spp (0.6 g) was added to the solution, and the mixture was stirred at room temperature for 1 day. The reaction mixture was filtered to remove Lipase and the filtrate was evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the (R)-3-(3-benzyloxybenzyl)-4-oxocyclopent-2-enyl acetate as yellow oil: 2.51 g (yield: 38%, 96% ee by HPLC using a chiral column) and (S)-4-hydroxy-2-(3-(benzyloxy)benzyl)cyclopent-2-enone as yellow oil: 2.68 g (yield: 47%, >99% ee by HPLC using a chiral column)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(NC(C)C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[N:11]=1)=[O:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2onc(-c3ccc(Cl)cc3)c2c1O
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2onc(-c3ccc(Cl)cc3)c2c1O
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A mixture of 7-bromo-3-(4-chloro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (150 mg, 0.38 mmol), tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.04 mmol), copper (I) iodide (14 mg, 0.08 mmol), trimethylsilylacetylene (107 μl, 0.76 mmol), diisopropylamine (321 μl, 2.27 mmol), and tetrahydrofuran (3.8 ml) was refluxed for eighteen hours before it was cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of hexanes and dichloromethane to give the title compound as a yellow solid (55 mg); MS (m/z): 415.34 (M+H+); 413.37 (M−H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CON(C)C(=O)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CON(C)C(=O)c1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide (2.76 g), 4-chlorophenylboronic acid (2.113 g), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.920 g), sodium carbonate (3.58 g), toluene (43.3 mL) and water (13 mL) was stirred at 100° C. overnight. To the reaction mixture was added water at room temperature, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was fractionated by HPLC(C18, mobile phase: water/acetonitrile (10 mM ammonium hydrogencarbonate-containing system)), the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.242 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][OH:47])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:48]([C:50]1[O:54][N:53]=[C:52](O)[C:51]=1[F:56])[CH3:49]>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][O:47][C:52]4[C:51]([F:56])=[C:50]([CH2:48][CH3:49])[O:54][N:53]=4)[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:36][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1onc(O)c1F
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Product: CCc1onc(OCCCc2csc(C3=C(C(=O)N(Cc4cccc(Cl)c4Cl)C4CC4)C4CN(C(=O)OC(C)(C)C)CC(C3)N4C(=O)OC(C)(C)C)n2)c1F

Procedure:
This compound is prepared from compound E4 and 5-ethyl-4-fluoroisoxazol-3-ol, according to the above-described procedure A. LC-MS: tR=1.24 min, ES+: 820.35.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[CH3:12].ClS([N:17]=[C:18]=[O:19])(=O)=O.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[N:8]2[C:18]([NH2:17])=[O:19])=[CH:4][C:3]=1[CH3:12]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cc2c(cc1F)NC(=O)C2
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2c(cc1F)N(C(N)=O)C(=O)C2

Procedure:
Following the procedure of Example 2, the title compound was prepared from 6-fluoro-5-methyl-2-oxindole (1.0 g, 6.0 mmole), chlorosulfonyl isocyanate (1.03 g, 7.3 mmole), toluene (30 ml). Water (5 ml) was used for the hydrolysis step. Yield=0.58 g, 46%. M.P. 200°-203° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3([C:19]4[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=4)[C:16]4[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:18])=[N:9]3)[CH:3]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cccc(F)c21
Product: NC1=NC(c2ccncc2)(c2cccc(-c3cccc(Cl)c3)c2)c2cccc(F)c21
Yield: 38 %

Procedure:
The title compound was synthesized as described for Example 1 in 38% yield, starting from 1-(3-bromophenyl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine (80 mg, 0.21 mmol) and 3-chlorophenylboronic acid (39.3 mg, 0.25 mmol).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:19][C:17]([CH2:16][CH2:15][NH:14][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3])=[O:18]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCNS(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
It is obtained by reacting 4-chlorosulfonyl-benzoic acid (1 eq) with H-βAla-OMe×HCl in CH2Cl2 using diisopropylethylamine (2 eq) as base. After 30 minutes at room temperature the reaction mixture is extracted with water and the organic layer is dried over Na2SO4. Removal of the solvent gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=[C:7]2[N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[NH:25][C:26]([CH3:31])=[C:27]([Cl:30])[C:28]=2[Cl:29])=[O:23])[CH2:17][CH2:16]1.Cl.[CH3:33][O:34][NH2:35]>>[CH3:33][O:34][NH:35][C:12]([C:9]1[CH:8]=[C:7]([N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22]([C:24]3[NH:25][C:26]([CH3:31])=[C:27]([Cl:30])[C:28]=3[Cl:29])=[O:23])[CH2:19][CH2:20]2)[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1)=[O:14]
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc4c(F)cccc34)CC2)c(Cl)c1Cl
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c2cccc(F)c2n1

Procedure:
The title compound was prepared from 8-fluoro-4-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)quinoline-2-carboxylic acid (Example 280) and O-methylhydroxylamine hydrochloride via the procedure described for Example 8.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9](=O)[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1.CN.[C:19]([BH3-])#[N:20].[Na+]>O1CCCC1>[CH3:19][NH:20][CH:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(CN1CCCC1)c1cccnc1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(CN1CCCC1)c1cccnc1
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
9 g (34.22 mmoles) of 1-(3-pyridinyl)-2-(1-pyrrolidinyl) ethanone dihydrochloride were suspended in 110 ml of tetrahydrofuran containing 20% of monomethylamine. After 15 mins. of stirring, 3.6 g (57.32 mmoles) of sodium cyanoborohydride were added at room temperature. After 24 h the reaction mixture was evaporated in vacuo to dryness. The residue was taken up with conc. NaOH solution and exhaustively extracted with diethyl ether. The organic solution was dried and evaporated in vacuo to dryness. 4.2 g of the crude product were obtained and used, without further purification, in the following step.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].[CH:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27](O)[CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C>[N+:31]([C:30]1[CH:25]=[CH:26][C:27]([O:23][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]2[C:4]([CH3:12])=[CH:5][C:6]([O:10][CH3:11])=[C:7]([O:8][CH3:9])[C:2]=2[OH:1])=[CH:28][CH:29]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cc(C)c(CCCCCCCCCC(=O)O)c(O)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: COc1cc(C)c(CCCCCCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)c(O)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10-(2-Hydroxy-3,4-dimethoxy-6-methylphenyl)decanoic acid (236.9 mg, 0.7 mmol) and p-nitrophenol (107.1 mg, 0.77 mmol) were dissolved in acetonitrile (2 ml). To this solution was added DCC (158.9 mg, 0.77 mmol) under ice-cooling. The solution was stirred at room temperature for 16 hours. The insoluble material was removed by filtration and the solvent was evaporated under reduced pressure. The residue was chromatographed on a silica gel column with chloroform as eluent to obtain about 5 m mol of 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decanoic acid p-nitrophenyl ester. The ester was dissolved in DMF (1.5 ml). To this solution was added methyl 1-α-O-benzyl-N-acetylmuramyl-L-valyl-D-isoglutaminate (0.15 g, 0.25 mmol), HoBt(0.14 g, 1 mmol) and NEM (128 μl, 1 mmol) and the reaction mixture was stirred at room temperature for four days. After evaporation, the residue was purified by the chromatography on a silica gel column with chloroform/acetone/methanol (10:3:1, v/v) as eluent and precipitated as a gel from ethanol/ether to obtain methyl 1-α-O-benzyl-6-O-{10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decanoyl}-N-acetylmuramyl-L-valyl-D-isoglutaminate (0.13 g). [α]D22 +71.8° (C 0.5, DMF). Rf4 =0.70.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:15]3[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: c1cc(NC2CCSCC2)ccc1CN1CCOCC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=CN(c1ccc(CN2CCOCC2)cc1)C1CCSCC1)C(=O)OCC
Temperature: 160 °C

Procedure:
A flask containing N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-thiopyran-4-amine (0.44 g) is treated with diethyl ethoxymethylenemalonate (0.35 mL). The flask is tightly capped and heated to 160° C. for 2 hours. The reaction is cooled to room temperature, treated with diethyl ethoxymethylenemalonate (0.35 mL) and pyridine (0.35 mL) and heated to 150° C. for 1 hour in a tightly sealed flask. The reaction is cooled to room temperature and azeotroped under reduced pressure with toluene (3×). The residue is flash column chromatographed on silica gel eluting with ethyl acetate. The product-containing fractions are evaporated to give 0.59 g of diethyl 2-{[4-(4-morpholinylmethyl)(tetrahydro-2H-thiopyran-4-yl)anilino]methylene}malonate as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H][H]>[Pd].CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: [H][H]
Reactant: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1C#N
Yield: 99.7 %

Procedure:
A mixture of 5.0 g (20.6 mmol) of tert-butyl 3-(3-methyl-4-cyanophenyl)acrylate (from Step A) and 500 mg of 10% palladium on carbon in 200 mL of EtOAc was stirred under 1 atm of hydrogen at rt for 16 h. The catalyst was removed by filtration. The filtrate was concentrated to afford 5.04 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 2.53 (s, 3H), 2.55 (t, J=7.6, 2H), 2.93 (t, J=7.6, 2H), 7.12 (d, J=7.8, 1H), 7.17 (s, 1H), 7.51 (d, J=7.8, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[C:25]2[O:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([C:25]5[O:26][C:27]([CH3:30])=[CH:28][CH:29]=5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1ccc(-c2cccc3c2C(C)NCC3)o1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1ccc(-c2cccc3c2C(C)N(C(=O)c2cc4ncc(Br)cn4n2)CC3)o1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[C:13]([CH3:23])=[C:14]([CH:19]=[C:20]([Cl:22])[CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:24](=O)[CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:22][C:20]1[CH:21]=[C:12]([N:11]([CH2:24][CH3:25])[CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[C:13]([CH3:23])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCC3(CC2)OCCO3)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a stirred solution of methyl 3-(1,4-dioxaspiro[4.5]decan-8-ylamino)-5-chloro-2-methylbenzoate (6.6 g, 19 mmol) and acetaldehyde (2.56 g, 58.4 mmol) in dichloroethane (70 mL) was added acetic acid (7.0 g, 120 mmol) and the reaction mixture stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (12 g, 57 mmol) was added at 0° C. and the reaction stirred overnight at room temperature. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (4.0 g, 56%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([O:20][CH3:21])[CH2:18][C:17]2[CH:22]=[CH:23][C:14]([CH3:13])=[CH:15][CH:16]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(C)cc1
Product: CON(Cc1ccc(C)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 78 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-methylbenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (78% yield): mp 108-110° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.92 (6H, s, CH3), 2.5 (3H, s, CH3), 3.84 (3H, s, OCH3), 4.97 (2H, s, NCH2), 6.57 (1H, s, CH), 7.31 (2H, d, J=8.1 Hz, aromatics), 7.42 (2H, d, J=8.1 Hz, aromatics). Anal. calcd for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C, 63.14; H, 5.93; N, 4.34.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[N:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2].C(O)(=O)C.[Br:19]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:19][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[N:13][C:12]([NH2:14])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: CCOc1cc2cccnc2c(N)n1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1nc(N)c2ncccc2c1Br
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a 250 mL round bottom flask was added 6-ethoxy-1,7-naphthyridin-8-amine (0.65 g, 3.43 mmol), glacial acetic acid (20 mL), followed by the dropwise addition of bromine (0.60 g, 3.78 mmol) dissolved in carbontetrachloride (40 mL). After addition was complete, the mixture was stirred for 2 h then neutralized with saturated NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The resultant residue was purified by silica gel to yield 5-bromo-6-ethoxy-1,7-naphthyridin-8-amine as a pale yellow solid (0.6 g, 2.24 mmol, 65%). 1H NMR (400 MHz, CDCl3): δ ppm 8.53 (d, J=3.95 Hz, 1H), 8.22 (d, J=8.79 Hz, 1H), 7.50 (dd, J=8.57, 4.17 Hz, 1H), 5.87 (br. s., 2H), 4.48 (q, J=7.03 Hz, 2H), 1.44 (t, J=7.03 Hz, 3H). LC/MS m/z 270 [M+H].