Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C2CCCCO2)=[O:26])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10]1.Cl.C(O)C>CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10]1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCN(C(=O)CC3CCCCC3)C2)c(Cl)c1)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(C(=O)CC3CCCCC3)C2)c(Cl)c1)NO
Reaction time: 2 h
Yield: 126.1 %

Procedure:
A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (680 mg) and 2N HCl/Ethanol (13.8 ml) was stirred for 2 hrs. EtOAc (10 ml) and IPE (50 ml) was added and stirred. After 1 hr, precipitate was filtered and dried to give 387 mg (0.63%) of (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylacetyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-hydroxyacrylamide hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:35][CH2:34]1.C1CCN2C(=NCCC2)CC1>>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([C:33]2([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:35][CH2:34]2)=[O:16])[CH2:11][C@@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)C1CC1
Reactant: C=C[C@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(Cl)Cl
Product: C=C[C@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)C1(S(N)(=O)=O)CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
(1R,2R)-1-(tert-Butoxycarbonylamino)-2-vinyl-cyclopropane-1-carboxylic acid (1.72 g, 7.57 mmol., 1.0 eq.) and dichloroethane (38 mL) were charged into a 100 mL round bottom flask. 1,1′-Carbonyldiimidazole (1.72 g, 10.61 mmol., 1.4 eq.) was added portionwise and the reaction mixture stirred at 50° C. for 15 hours. Cyclopropanesulfonamide (2.47 g, 20.4 mmol., 2.7 eq.) was added portionwise followed by dropwise addition of DBU (3.11 g, 20.4 mmol., 2.7 eq.). Stirring was continued at 50° C. for a further 15 hours by when LCMS analysis of the reaction mixture showed full consumption of the starting material. The solvent was removed under vacuum. The residue was partitioned between dichloromethane (50 mL) and 0.5 M hydrochloric acid (20 mL). The organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash column chromatography using heptanes:ethyl acetate gradient (60:50 to 50:50) as eluent. After combining the relevant fractions and removing the solvent under vacuum, 1.12 g (45%) of the title compound was isolated as a yellow semi solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.71 (br. s, 1 H), 5.61 (br. s, 1 H), 5.32 (d, J=16.87 Hz, 1 H), 5.20-5.28 (m, 1 H), 5.18 (d, J=10.27 Hz, 1 H), 2.88-3.00 (m, 1 H), 2.16 (q, J=8.44 Hz, 1 H), 1.87-1.96 (m, 1 H), 1.51 (s, 9 H), 1.40-1.47 (m, 1 H), 1.24-1.36 (m, 2 H), 1.07-1.16 (m, 1 H), 0.99-1.07 (m, 1 H). LC-MS: purity 100% (ELS), tR 1.74 min, m/z [M−H]-329.10.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:3]=1.Br[C:26]1[C:27]([C:32]#[N:33])=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:7]=1)=[C:26]1[C:27](=[C:32]([NH2:33])[N:8]=2)[N:28]=[CH:29][CH:30]=[CH:31]1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: N#Cc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(N)c3ncccc3c2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from step 2) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% methanol in dichloromethane to give a semipure solid, which was then swirled in hot ethyl acetate, filtered, and dried to give a pure solid. 1H NMR (acetone d-6): δ 9.02 (d, 1H), 8.89 (d, 1H), 8.25 (s, 1H), 7.80-7.84 (dd, 1H), 7.52 (d, 1H), 7.40 (d, 1H), 6.5 (br, 2H), 2.48 (s, 3H). LRMS [M+H]=210.2
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:11][C:12]1[S:16][C:15]([CH2:17][C@H:18]2[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[O:24])[CH2:19]2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:21]2[CH2:22][C@H:18]([CH2:17][C:15]3[S:16][C:12]([Cl:11])=[CH:13][CH:14]=3)[CH2:19][C@H:20]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1C(=O)Cn1cncn1
Yield: 28 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4S)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 67, (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (23.1 mg, 28%). 1H-NMR (400 MHz, CDCl3): σ 9.01 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.42 (d, 2H), 7.00 (t, 2H), 6.95-6.90 (m, 4H), 6.75 (d, 1H), 6.63 (d, 1H), 5.03 (dd, 2H), 4.83 (d, 1H), 3.76 (dd, 1H), 3.27 (t, 1H), 3.06-2.93 (m, 2H), 2.85-2.79 (m, 1H), 2.71 (dd, 1H), 1.73-1.66 (m, 1H). MS (EI) for C26H23ClFN5O3S. found 540.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([CH:22]=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.O[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][C:2]1([CH3:24])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([CH2:22][O:23][C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(C=O)cc43)sc2C(=O)N1
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(N3CCOc4ccc(COc5cccnc5)cc43)sc2C(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
A mixture of Example 50 (0.050 g, 0.14 mmol), 3-hydroxypyridine (0.015 g, 0.14 mmol), and triphenylphosphine (0.042 g, 0.16 mmol) in THF (15 mL) was cooled to 0° C. Diethyl azodicarboxylate (0.03 mL, 0.16 mmol) was added, and the reaction mixture stirred for 30 minutes at 0° C., then at r.t. for 3 h. Further portions of 3-hydroxypyridine (0.015 g, 0.14 mmol) and triphenylphosphine (0.021 g, 0.08 mmol) were added, and stirring continued for 2 h. The mixture was concentrated in vacuo and the residue partitioned between DCM (50 mL) and water (50 mL). The organic fraction was washed with water (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 6) to give the title compound (0.0045 g, 8%) as a white solid. δH (CDCl3) 8.32 (2H, br. s), 8.06 (1H, d, J 1.7 Hz), 7.38-7.31 (2H, m), 7.13 (1H, dd, J 8.5 and J 1.9 Hz), 6.99 (1H, d, J 8.5 Hz), 5.07 (2H, s), 5.21 (1H, br. s), 4.38-4.32 (2H, m), 4.18-4.11 (2H, m), 2.88 (2H, s), 1.40 (6H, s). LCMS (ES+) 423.0 (M+H)+, RT 2.27 minutes (Method 1).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]#[C:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH:14]=2)=[CH:5][CH:4]=1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26](P(=O)(OCC)OCC)Cl)=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:1][C:3]2[S:7][C:6]([C:8]#[C:9][C:10]3[S:11][C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[CH:14]=3)=[CH:5][CH:4]=2)=[CH:22][CH:21]=1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(C#Cc2cc3ccccc3s2)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(C#Cc2ccc(C#Cc3cc4ccccc4s3)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
A stirred solution of 0.75 gram (0.0028 mole) of 2-(5-formylthien-2-ylethynyl)benzothiophene and 0.83 gram (0.0028 mole) of diethyl (4-chlorophenyl)chloromethylphosphonate in 10 ml of dimethylformamide was cooled to 0° C., and 0.94 gram (0.0084 mole) of potassium tertbutoxide was added. Upon completion of addition, the reaction mixture was stirred at 0° C. for 30 minutes and then was allowed to warm to ambient temperature where it was stirred for 18 hours. After this time the reaction mixture was subjected to column chromatography on silica gel. Elution was accomplished using hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.20 gram of 2-[5-(4-chlorophenylethynyl)thien-2-ylethynyl]benzothiophene; m.p. 189°-191° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O>CO.[Pd]>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:10]=[CH:11][C:12]=1[NH2:13]
Reactant: COc1cc(CCN2CCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(CCN2CCCC2)ccc1N
Yield: 91.8 %

Procedure:
0.41 g of palladium-on-charcoal and 4.1 g (64.32 mmol) of ammonium formate are added to a solution of 3.2 g (12.86 mmol) of the product prepared in step 24.2 in 120 mL of methanol, under argon, and the mixture is refluxed for 2 hours. After filtration, the filtrate is concentrated to dryness to give 2.6 g of the expected product in the form of a light-brown solid, which is used as obtained in the following step. Yield=92%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=N[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CN[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
trans-4-[(4-tert-Butylcyclohexylimino)methyl]benzoic acid methyl ester (21.0 g, 69.2 mmol) was suspended in methanol (300 mL), and acetic acid (50 mL) was added. To the resulting clear solution was added sodium cyanoborohydride (3.5 g, 55.5 mmol), and the mixture was stirred at ambient temperature for 30 min. The reaction volume was then reduced to one third by rotary evaporation, and ethyl acetate (500 mL) was added. The organic phase was washed with sodium carbonate solution (5%, 500 mL), and dried with sodium sulphate. The solvent was removed by rotary evaporation to leave the title material as a white crystalline solid sufficiently pure for further reactions. Yield: 21.1 g (100%).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:17]([NH2:19])=[O:18])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.C(OC(=O)[NH:46][C@@H:47]1[C@H:52]([NH2:53])[CH2:51][CH2:50][O:49][CH2:48]1)(C)(C)C>CN1C(=O)CCC1.CCOC(C)=O>[NH2:46][C@@H:47]1[C@H:52]([NH:53][C:3]2[N:4]=[N:5][C:6]([C:17]([NH2:19])=[O:18])=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:8]=2)[CH2:51][CH2:50][O:49][CH2:48]1
Reactant: CSc1nnc(C(N)=O)c(Nc2ccc(C)cc2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
3-(Methylthio)-5-(p-tolylamino)-1,2,4-triazine-6-carboxamide (26 mg, 0.095 mmol) was dissolved in 4 mL NMP. To it was added mCPBA (77%) (86 mg, 0.38 mmol). The mixture was stirred at RT for 1 h. To it was added DIEA (0.17 mL, 0.95 mmol) and tert-butyl((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate (41 mg, 0.19 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was diluted with 100 mL EtOAc, washed with 1N NaOH and brine, dried, concentrated in vacuo. It was then treated with neat TFA for 1 h at RT. The mixture was diluted with water and subjected to reverse phase preparative HPLC to isolate the title compound (27 mg) as HCl salt. MS found for C16H21N7O2 as (M+H)+ 344.4. UV: λ=235, 273 nm. Proton NMR: (CD3OD) δ 7.56 (2H, d, J=6.8 Hz), 7.31 (2H, d, J=7.6 Hz), 4.36 (1H, dt, J=11.6; 5.2 Hz), 4.10 (1H, dd, J=11.6; 4.8 Hz), 3.99 (1H, d, J=13.2 Hz), 3.74 (1H, s), 3.67-3.61 (2H, m), 2.38 (3H, s), 2.16 (1H, m), 1.91 (1H, m) ppm.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])([CH3:3])[CH3:2].[CH2:15]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[CH:1]([N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[S:11](=[O:13])(=[O:12])[NH:14][CH2:15]1)([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)Nc1ccncc1S(N)(=O)=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)N1CNS(=O)(=O)c2cnccc21

Procedure:
A mixture of 1 g of 4-isopropylaminopyridine-3- sulfonamide (Preparation 3) and 1 g of paraformaldehyde in 20 cm3 of isopropanol to which 10 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 3 hours. After cooling, the crystalline precipitate is filtered and washed with isopropanol. The precipitate is dissolved in 150 cm3 of hot methanol. The possible insoluble material is filtered. The filtrate is concentrated to dryness and the residue is taken up in 30 cm3 of water. The aqueous suspension is adjusted to a pH of 7-7.5 (NaHCO3) and the precipitate corresponding to the title compound is filtered, washed with water and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[C:34]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:35]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([C:34]([N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)=[O:35])[CH:29]=1
Reactant: NCc1ccc(F)cc1C(=O)N1CCOCC1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)N1CCOCC1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 44, (2-(aminomethyl)-5-fluorophenyl)(morpholino)methanone. 1H NMR (CDCl3, 500 MHz) δ ppm: 1.59 (6H, s), 3.29 (2H, brs), 3.57 (2H, m), 3.74 (4H, s), 3.98 (4H, m), 5.26 (2H, s), 6.88 (1H, dd, 3=8.2, 2.7 Hz), 7.03 (1H, dt, J=8.5, 2.5 Hz), 7.24–7.33 (3H, m), 7.42 (2H, dd, J=8.6, 5.3 Hz), 7.47 (2H, dd, J=7.5, 2.0 Hz), 8.18 (1H, t, J=6.4 Hz); LC/MS m/z 551 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][OH:28]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:26][CH2:27][OH:28])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: OCCCBr
Reactant: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCOc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine prepared above is dissolved in N,N-dimethylformamide, and the solution is supplemented with potassium carbonate and 3-bromo-1-propanol and stirred at room temperature for overnight to obtain 6-bromo-2-[4′-(3″-hydroxypropoxy)phenyl]imidazo[1,2-a]pyridine. This is dissolved in pyridine, supplemented with p-toluenesulfonylchloride under an ice bath and then reacted at room temperature to obtain 6-bromo-2-[4′-(3″-p-toluenesulfonyloxypropoxy)phenyl]imidazo[1,2-a]pyridine as a target compound. The amount of the p-toluenesulfonylchloride to be used in this instance may be excessive relative to the reaction substrate, and is typically about double the reaction substrate 6-bromo-2-[4′-(3″-hydroxypropoxy)phenyl]imidazo[1,2-a]pyridine in molar ratio.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([CH:11]=O)[C:5]=1[F:13].[NH2:15][OH:16]>C(O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([CH:11]=[N:15][OH:16])[C:5]=1[F:13]
Reactant: NO
Reactant: COC(=O)c1c(Cl)ccc(C=O)c1F
Solvent: CCO
Product: COC(=O)c1c(Cl)ccc(C=NO)c1F
Reaction time: 16 h

Procedure:
To a solution of methyl-6-chloro-2-fluoro-3-formylbenzoate (930 mg, 4294 μmol) in ethanol (14.5 ml) at RT was added hydroxylamine (50 wt. % aqueous solution) (1316 μl, 21469 μmol) and the solution was stirred for 16 hrs. The volatiles were removed under reduced pressure, and the residue was diluted with water, which caused a solid to precipitate. The solid was collected by filtration and washed with water and dried in vacuo to give an off-white solid.
Reaction SMILES: [C:1]([C:3]([CH:20]([CH3:22])[CH3:21])([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)[CH2:4][CH2:5][CH:6]=O)#[N:2].[N+:23]([C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][NH2:32])([O-:25])=[O:24].[BH4-].[Na+]>CO>[CH:20]([C:3]([C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)([CH2:4][CH2:5][CH2:6][NH:32][CH2:31][CH2:30][CH2:29][O:28][C:27]1[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=1[N+:23]([O-:25])=[O:24])[C:1]#[N:2])([CH3:21])[CH3:22]
Reactant: COc1cc(C(C#N)(CCC=O)C(C)C)cc(OC)c1OC
Reactant: NCCCOc1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(C#N)(CCCNCCCOc2ccccc2[N+](=O)[O-])C(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
A solution of 8.09 g of 4-cyano-4-isopropyl-4-(3,4,5-trimethoxyphenyl)butyraldehyde and 4.96 g of 3-(2-nitrophenoxy)-propylamine in 100 ml of methanol was refluxed for 3 hours. After cooling, to the solution was added 0.50 g of sodium borohydride and the solution was stirred overnight at room temperature. The solvent was removed and to the residue was added water. The solution was extracted with chloroform and the extract was washed with water, dried, and evaporated. The residue was chromatographed on silica gel using 10% methanol-chloroform as an eluent to give 6.48 g of the desired compound as a pale yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:29])[O:12][C:13]2C(C=1)=CC=C(N1CCN(CCO)CC1)C=2.C(N(C(C)C)CC)(C)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:12][C:11](=[O:29])[CH2:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: O=c1oc2cc(N3CCN(CCO)CC3)ccc2cc1-c1nc2ccccc2s1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10 mg (0.025 mmol) 3-benzothiazol-2-yl-7-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-chromen-2-one are dissolved in 3 mL dichloromethane with 2.5 mg (0.8 eq.) 4-dimethylaminopyridine and 0.013 mL (3 eq.) diisopropylethylamine, and cooled to 0° C. 5.7 mg (1.2 eq.) tosyl chloride are added and the reaction mixture stirred for one hour before being allowed to reach room temperature. After an additional two hours stirring, the reaction mixture is evaporated, the residue taken up in tetrahydrofurane and treated with 0.2 mL tetrabutylammonium fluoride (1M in THF). After stirring for 30 minutes, the solution is evaporated and the desired product obtained as a yellow powder.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:10]C(C)=O>>[CH3:10][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CC(C)=O
Agent: [K]
Product: Cn1cc(Cl)cnc1=O
Yield: 50 %

Procedure:
1-Methyl-5-chloropyrimid-2-one was prepared as above from the potassium salt of 5-chloropyrimid-2-one (prepared as described in Crosby, G. D. and Berthold, V. R. J. Org. Chem. 25 (1960) 1916) in 50% yield, m.p. 210° C. (acetone). (Found: C, 41.61; H, 3.65; Calc. for C5H5ClN2O: C, 41.54; H, 3.48)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[C:23]4[C:29]([C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:28][N:27](COCC[Si](C)(C)C)[C:24]4=[N:25][CH:26]=3)=[CH:16][CH:15]=2)[C:11]#[N:12])=[O:9])[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10](=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:22]=[C:23]4[C:29]([C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:28][NH:27][C:24]4=[N:25][CH:26]=3)=[CH:18][CH:19]=2)[C:11]#[N:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)C(C#N)=Cc2ccc(Nc3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C(=O)C(C#N)=Cc2ccc(Nc3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)cc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
To a 35 ml vial, 2-(4-methylpiperazine-1-carbonyl)-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylonitrile (0.100 g, 0.0001 mole) was taken in CH2Cl2 (8 ml) and cooled to 0° C. under N2 atm. TFA (2 ml, 0.0238 mole) was added drop wise at 0° C. and stirred for 16 h at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure from the reaction mixture and saturated NaHCO3 solution was added dropwise to make pH basic. The solid which precipitated out was filtered and washed with water and pentane. The solid (0.050 g) was taken in ethanol (20 ml), NaOAc.3H2O (0.226 g, 0.0016 mole) was added and the reaction mixture and stirred at room temperature for 32 hr. Ethanol was evaporated under reduced pressure from the reaction mixture and obtained solid material was washed with water and pentane. The crude compound was purified by triturating with pentane to yield 0.017 g of 2-(4-methylpiperazine-1-carbonyl)-3-(4-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylonitrile.