Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[O:22][CH2:21]1>CCOC(C)=O>[N+:9]([C:5]1[CH:4]=[N:3][C:2]2[NH:1][CH:20]([CH2:21][OH:22])[CH2:19][O:8][C:7]=2[CH:6]=1)([O-:11])=[O:10]
Reactant: Nc1ncc([N+](=O)[O-])cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc2c(c1)OCC(CO)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
Into a 75 mL sealed tube were combined 2-amino-3-hydroxy-5-nitropyridine (0.138 g, 0.000890 mol), N,N-dimethylfonnamide (4.1 mL) and potassium carbonate (0.39 g, 0.0028 mol). The mixture was allowed to stir at room temperature for 10 minutes then 1-bromo-2,3-epoxypropane (0.12 g, 0.00089 mol) was added in one portion. The flask was sealed, then heated to 110° C. and stirred overnight. After allowing to cool, the mixture was concentrated under vacuum to give a crude solid which was dissolved in EtOAc (75 mL), washed with water and brine, then dried (Na2SO4), filtered and concentrated under vacuum to leave a crude residue. The residue was purified by column chromatography on silica gel using MeOH/CH2Cl2 (0-10% gradient) as eluent to give a solid (0.092 g, 46%). LC-MS 1.92 min. M/Z=212.0 (M+1). 1H NMR (d6-DMSO) δ 8.8 (d, 1 H), 7.8 (d, 1 H), 5.1 (t, 1H),4.2 (m, 1 H), 4.0 (m, 1H), 3.62 (m, 1H), 3.45 (m, 1H), 3.21 (m, 1H).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([N:24]([CH3:26])[CH3:25])=[CH:18][CH:19]=3)[N:14]=2)[CH:12]=1)=[O:7])C.C(OC(C1C=NN(C2NC(=O)C3C(=CC=CC=3N(C)C)N=2)C=1)=O)C.CN(C)C1C=C2C(C(=O)NC(N3C=C(C(O)=O)C=N3)=N2)=CC=1>C1COCC1>[CH3:25][N:24]([CH3:26])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]2[C:16]=1[C:21](=[O:23])[NH:22][C:13]([N:11]1[CH:12]=[C:8]([C:6]([OH:5])=[O:7])[CH:9]=[N:10]1)=[N:14]2
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N(C)C)ccc3c(=O)[nH]2)c1
Agent: CCOC(=O)c1cnn(-c2nc3cccc(N(C)C)c3c(=O)[nH]2)c1
Agent: CN(C)c1ccc2c(=O)[nH]c(-n3cc(C(=O)O)cn3)nc2c1
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)c1cccc2nc(-n3cc(C(=O)O)cn3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous 1M KOH (3.8 mL, 3.8 mmol) was added to a 3:2 mixture of 1-(7-dimethylamino-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester and 1-(5-dimethylamino-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.415 g, 1.27 mmol) in THF (3.8 mL). The reaction mixture was allowed to stir at room temperature for 18 h and was then concentrated. The residue was re-dissolved in water (10 mL) and acidified with aqueous HCl (1 M, 3 mL). The resulting precipitate was collected by filtration to yield a mixture of the titled compound and 1-(7-dimethylamino-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The collected precipitate was triturated from DMSO and rinsed with ethanol to yield pure 1-(7-dimethylamino-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid. The filtrate from the trituration was purified by reverse-phase HPLC to yield the titled compound (49.7 mg, 13% yield). MS (ESI/Cl): mass calcd. for C14H13N5O3, 299.1; m/z found, 300.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.99 (s, 2H), 8.96 (d, J=0.6 Hz, 1H), 8.25 (s, 1H), 7.84 (t, J=8.1 Hz, 1H), 7.67-7.48 (m, 2H), 3.12 (s, 6H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][P:10](=[O:17])([O:14]CC)[O:11]CC)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:18][Si:19](Br)([CH3:21])[CH3:20]>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][CH2:9][P:10](=[O:17])([O:14][Si:19]([CH3:21])([CH3:20])[CH3:18])[O:11][Si:19]([CH3:21])([CH3:20])[CH3:18])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCCP(=O)(OCC)OCC
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCP(=O)(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
To a solution of diethyl 3-methacryloyloxypropylphosphonate (28.2 g; 0.107 moles) in CH2Cl2 (60 g) is added dropwise a solution of trimethylsilyl bromide (34.4 g; 0.225 moles) in CH2Cl2 (22 g) at room temperature. The mixture is refluxed for 5 hours. The solvent is evaporated under vacuum to give di(trimethylsilyl) 3-methacryloyloxypropylphosphonate as a clear, colorless liquid (37.9 g). 1H NMR (CDCl3, δ ppm) 0.01 (s, 9H, CH3—Si), 1.41-1.55 (m, 2H, CH2—P), 1.59-1.73 (m, 2H, CH2—CH2—P), 1.66 (d, 3H, CH3), 3.90 (t, 2H, CH2—O), 5.28 (s, 1H, CH═), 5.82 (s, 1H, CH═). 31P NMR (CDCl3, δ ppm) 13.6.
Reaction SMILES: [CH2:1]([C:4]1([O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:24](O)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:5])[CH:2]=[CH2:3].S(Cl)([Cl:40])(=O)=O.ClCCl>N1C=CC=CC=1>[CH2:1]([C:4]1([O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:24]([Cl:40])[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:5])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: C=CCC1(O)O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC1(O)O[C@H](COCc2ccccc2)[C@H](Cl)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 15 h

Procedure:
Allyl-2,3,6-tri-O-benzyl-glucopyranose (as per Example 14) (960 mg) was dissolved in dry pyridine and added 65 μL of sulfuryl chloride at 0° C. dropwise. The reaction mixture was stirred at this temperature for 15 hours. Dichloromethane (150 mL) was added and the resulting solution was washed with sodium bicarbonate (2×150 mL) and water (2×150 mL). Solvent removal left the residue which was purified by chromatography on silica gel using hexane-ethyl acetate (5:1) as eluent to provide compound allyl 4-chloro-4-deoxy-2,3,6-tri-O-benzyl-galactopyranose (550 mg).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23](=[O:39])[CH:24]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:22].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:34]([O:33][C:32](=[O:38])[NH:31][CH:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:23]([NH:21][NH:22][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])=[O:39])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NN)c1ccccc1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl (2-hydrazinyl-2-oxo-1-phenylethyl)carbamate 249 (0.360 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g. 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 250 (0.40 g, 84%) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:19](=[O:26])[C:20](=[O:25])[C:21]=4OCC)=[CH:13][CH:12]=3)=[C:9]([CH2:27][CH3:28])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>C(O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:19](=[O:26])[C:20](=[O:25])[C:21]=4[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([CH3:29])[CH:31]=4)=[CH:13][CH:12]=3)=[C:9]([CH2:27][CH3:28])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cccc(N)c1
Reactant: CCOc1c(Nc2ccc(-c3c(CC)sc4ncnc(N)c34)cc2)c(=O)c1=O
Solvent: CCO
Product: CCc1sc2ncnc(N)c2c1-c1ccc(Nc2c(Nc3cccc(C)c3)c(=O)c2=O)cc1
Yield: 2.6 %

Procedure:
A mixture of Example 344A (0.027 g, 0.068 mol) and 3-methylaniline (0.073 mL, 0.68 mmol) in ethanol (2 mL) was stirred at reflux for 48 hours and concentrated. The residue was purified by silica gel chromatography with 5% methanol/dichloromethane to provide 8 mg of the desired product. MS (ESI(+)) m/e 346 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, J=7.46 Hz, 3H); 2.32 (s, 3H); 2.66 (q, J=7.12 Hz, 2H); 6.80-7.00 (m, 2H); 7.20-7.50 (m, 4H); 7.67 (d, J=8.48 Hz, 2H); 8.28 (s, 1H); 10.11 (s, 1H); 10.30 (s, 1H).
Reaction SMILES: [CH2:1]([O:4]C(=O)NC1CC(=O)OC1OC1CCCC1)[CH:2]=C.[O:20]=[C:21]1[O:25][CH:24]([O:26][CH2:27][CH2:28][C:29]2C=CC=[CH:31][CH:30]=2)[CH:23]([NH:35][C:36]([CH:38]2[CH2:42][CH2:41][CH2:40][N:39]2[C:43](=[O:57])[CH:44]([NH:46][C:47](=[O:56])[C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[C:50]([Cl:55])[CH:49]=2)[CH3:45])=[O:37])[CH2:22]1>>[CH:27]1([O:26][CH:24]2[CH:23]([NH:35][C:36]([CH:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43](=[O:57])[CH:44]([NH:46][C:47](=[O:56])[C:48]3[CH:53]=[CH:52][C:51]([NH:54][C:1](=[O:4])[CH3:2])=[C:50]([Cl:55])[CH:49]=3)[CH3:45])=[O:37])[CH2:22][C:21](=[O:20])[O:25]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OC1CCCC1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(=O)Nc1ccc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OC2CCCC2)cc1Cl
Yield: 69 %

Procedure:
Prepared from 97b and (2-cyclopentyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 215 mg of title compound (69% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.35-1.90 (m, 11H), 1.90-2.35 (m, 4H), 2.24 (s, 3H), 2.40-3.10 (m, 2H), 3.50-3.95 (m, 3H), 4.15-4.90 (m, 3H), 5.44 (s, 0.55H), 5.56 (s, 0.15H), 5.64 (d, 0.22H), 5.71 (d, 0.08H), 7.70-8.25 (m, 3H). Analytical HPLC: 12.13 min. LC-MS (ES+): m/e=549.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[O:19]1[C:18]2[CH:23]=[CH:24][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]3)=[CH:16][C:17]=2[O:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 100 mL of an ethyl acetate solution containing 3.62 g of tert-butyl(1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-yl)carbamate, 30 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and the mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, the residue thus obtained was added with ethyl acetate, and a solid substance was collected by filtration. The solid substance thus obtained was purified by silica gel column chromatography [silica gel; Chromatorex-NH, manufactured by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=5:1] to obtain 1.35 g of a pale yellow oily substance, 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamine.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([N+:20]([O-])=O)=[C:18]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=3[F:34])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].NCl>C1COCC1.O.[Zn]>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:14]2[C:19]([NH2:20])=[C:18]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=3[F:34])[N:17]=[CH:16][N:15]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2[N+](=O)[O-])CC1
Agent: NCl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2N)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 71.3 %

Procedure:
Mixture of 4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (197 mg, 0.3 mmole), Zn Dust (2.4 mmole, 8 eq) and 1 mL of Sat NH2Cl solution in 2 mL THF and 2 mL H2O was stirred at room temperature for 25 minutes. Zn Dust was filtered off by celite and washed with ethyl acetate. Crude was purified by column chromatography (Hexane/Ethyl Acetate=1/2, Rf=0.44) to give compound A120 as a yellow oil (100 mg, 71%). 1H NMR (DMSO-d6, 400 MHz) δ 1.19 (d, 6H), 1.62-1.68 (m, 2H), 1.88-1.93 (m, 2H), 3.23 (s, 3H), 3.33-3.39 (m, 2H), 3.64-3.70 (m, 2H), 4.77 (sep, 1H), 5.28-5.29 (m, 1H), 7.68 (d, 1H), 7.77 (d, 1H), 7.88 (s, 1H), 8.06 (t, 1H), 8.41 (sb, NH). Exact mass calculated for C20H26FN5O5S 467.2, found 468.5 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[N:4]=1.[OH:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[N:4]=[C:3]([CH2:2][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=2)[O:7][N:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1noc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCc2nc(CCc3nc(-c4ccccc4)oc3C)no2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.3 %

Procedure:
To a mixture of 5-chloromethyl-3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazole (0.61 g), methyl 2-(3-hydroxyphenyl)acetate (0.30 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.37 g, 43%) of methyl 2-[3-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8]([CH2:10]P(=O)(OCC)OCC)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][O:22][CH2:23][O:24][C:25]1[C:29]([CH:30]=O)=[CH:28][N:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=1.O>O1CCCC1>[C:1]([C:5]1[O:6][CH:7]=[C:8](/[CH:10]=[CH:30]\[C:29]2[C:25]([O:24][CH2:23][O:22][CH3:21])=[N:26][N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(Cc1coc(C(C)(C)C)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C\c1coc(C(C)(C)C)n1
Reaction time: 0.5 h
Yield: 0.7 %

Procedure:
To a solution of diethyl [(2-tert-butyl-1,3-oxazol-4-yl)methyl]phosphonate (2.32 g) in tetrahydrofuran (30 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (3.30 g) was added to the reaction mixture, and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:20-1:3, v/v) to give 2-tert-butyl-4-{(Z)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole as a pale-yellow oil (0.02 g, yield 0.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10](=[O:26])[N:11]([CH2:24][CH3:25])[N:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]=2[CH:15](O)[CH3:16])[CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1.OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10](=[O:26])[N:11]([CH2:24][CH3:25])[N:12]=[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:14]=2[CH:15]=[CH2:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CCn1nc(-c2ccccc2)c(C(C)O)c(Nc2cccc(Cl)c2)c1=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=Cc1c(-c2ccccc2)nn(CC)c(=O)c1Nc1cccc(Cl)c1
Yield: 63 %

Procedure:
To a solution of the title compound of example 1 (185 mg, 0.5 mmol) in toluene (8 mL), H2SO4 adsorbed on silica gel (Chavetz et al., Synthetic Communications, 24, 2325, 1884) (400 mg) was added portionwise during 4 h at 80° C. Then silica gel was filtered off and the residue was thoroughly washed with acetone. Solvent was removed under reduced pressure and the residue was treated with ice water. The final product precipitated and was isolated by filtration (63% yield).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:20][OH:21]>CO.C(OCC)(=O)C>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:20][OH:21])[CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: ON=C1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 146 %

Procedure:
To a solution of 4-chromanone (10 g, 67.6 mmol) in methanol (150 mL) was added triethylamine (15 mL, 108.1 mmol) and hydroxylamine hydrochloride (7.5 g, 108.1 mmol). The mixture was stirred at rt for 16 hrs. The solvent was evaporated giving a residue which was dissolved in ethyl acetate and extracted with water. The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation of the filtrate afforded chroman-4-one oxime (16.1 g, 100%) as a white crystalline solid. MS: 164.0 (M+H)+; tR=1.99 min (method 1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH:45]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:45][C:41]1[NH:40][CH:44]=[CH:43][N:42]=1
Reactant: CCCN(CCC)CCc1ccc(OCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCc1ccc(OCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
The compound (67.0 mg) obtained in Example 79-3 was dissolved in anhydrous methanol (1.5 ml) and then added with sodium cyanoborohydride (20.0 mg), acetic acid (1.50 ml), and 2-imidazole carboxaldehyde (23.0 mg), followed by stirring under a nitrogen atmosphere at 60° C. for 2 days. After completion of the reaction, the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (47.1 mg) of the subject compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(Br)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 2-bromo-3′-bromoacetophenone.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].[N:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[NH:14][NH2:15]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:5])[N:14]([C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:8]=2)[N:15]=1
Reactant: NNc1ncccn1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C)n(-c2ncccn2)n1
Reaction time: 69 h
Yield: 97.5 %

Procedure:
Dissolve 2,4-pentanedione (0.81 mL, 7.85 mmol) and pyrimidin-2-yl-hydrazine (1.037 g, 9.42 mmol) in acetic acid (10 mL). Stir the mixture for 69 hr. at room temperature then concentrate. Dilute the residue with saturated aqueous sodium bicarbonate, extract 3 times with DCM, dry (sodium sulfate), filter and concentrate to give 2-(3,5-dimethylpyrazol-1-yl)-pyrimidine as a white solid (1.333 g, 97%). MS (ES): m/z=175 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C1C[O:16][CH2:15][CH2:14]1>C(OCC)C.O.[Zn+2].[Br-].[Br-].[Cl-].[Cl-].[Zn+2]>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:14][CH:15]=[O:16]
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [Br-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: O
Product: O=CC=Cc1ccccc1C(F)(F)F
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of 2-trifluoromethylbenzaldehyde (260 mg) in 5 mL THF was added 200 mg of ZnBr2. With stirring, 400 mg of α,α-bis(trimethylsilyl)-t-butylacetaldimine (7) was added, and stirring was continued overnight. The solution was cooled to 10° C., then hydrolyzed by the addition of a solution of ZnCl2 (200 mg) in diethyl ether/water (3 mL each), followed by stirring at room temperature for 1 h. The solids were removed by filtration through Celite and the filtrate extracted with diethyl ether (2×). The combined ether extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide the crude title compound as an oil. The product was purified via silica gel column chromatography to afford a white powder (130 mg): 1H NMR (CDCl3) δ 6.70 (dd, 1 H, J=9.6, 4.5 Hz), 7.55 (t, 1 H, J=4.5 Hz), 7.63 (t, 1 H, J=4.5 Hz), 7.76 (d, 2 H, J=4.8 Hz), 7.88 (br d, 1 H, J=9.6 Hz), 9.77 (d, 1 H, J=4.8 Hz).
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:36][CH3:37])[C:27]([NH:29][C:30]1([CH:34]=O)[CH2:33][CH2:32][CH2:31]1)=[O:28])=[CH:20][CH:19]=2)#[CH:14].C(=O)([O-])[O-].[K+].[K+]>CO.[Cl-].[Na+].O>[C:34]([C:30]1([NH:29][C:27](=[O:28])[CH:26]([O:25][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:13]#[CH:14])=[CH:24]3)[S:36][CH3:37])[CH2:33][CH2:32][CH2:31]1)#[CH:1]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(C=O)CCC3)cc2c1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(C#C)CCC3)cc2c1
Reaction time: 8 h

Procedure:
Bestmann's reagent ((1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester) (123 mg) was added to a solution of 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-formyl-cyclobutyl)-2-methylsulfanyl-acetamide (180 mg) from Step 2 above in MeOH (15 ml) under nitrogen atmosphere. After cooling to 0° C. potassium carbonate (114 mg) was added and the mixture was stirred overnight at temperature from 0° C. to room temperature, then poured into brine and extracted with ethyl acetate (2×). The combined organic layers were washed with water, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/CH2Cl2, 1/1/3) to give N-(1-ethynyl-cyclobutyl)-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide (106 mg) as white solid.