Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH3:27])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[I-].[Na+].[C:31]([O:34][CH:35](Br)[CH2:36][CH3:37])(=[O:33])[CH3:32].C(OC(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH3:27])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH:35]([O:34][C:31](=[O:33])[CH3:32])[CH2:36][CH3:37])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Reactant: CCC(Br)OC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: C=CC1=C(C(=O)OC(CC)OC(C)=O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 26.2 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g) in N,N-dimethylformamide (40 ml) was added sodium iodide (0.8 g) and 1-bromopropyl acetate (0.9 g) under ice-cooling with stirring, and the stirring was continued at the same temperature for half an hour. The reaction mixture was poured into a mixture of water and ethyl acetate, and the separated organic solution was washed twice with a saturated aqueous sodium chloride and twice with water, followed by drying over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether and then chromatographed on silica gel eluting with a mixed solvent of ethyl acetate and chloroform (4:6 to 6:4 by volume), and fractions containing a desired compound were collected. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether and then collected by filtration to obtain 1-acetoxypropyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (0.62 g), mp 97°-101° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:10])=[O:9].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21].C(N(CC)CC)C>CN(C=O)C>[CH3:19][O:18][C:15]1[N:14]=[CH:13][C:12]([N:11]2[C:20](=[O:21])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:9])=[O:10])=[CH:17][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2N)cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)Nc3ccccc3S2(=O)=O)cn1
Yield: 62.7 %

Procedure:
The title compound (143 mg, 0.47 mmol) was prepared from 2-amino-N-(6-methoxypyridin-3-yl)benzenesulfonamide (209 mg, 0.75 mmol), 1,1′-carbonyldiimidazole (486 mg, 3.0 mmol) and triethylamine (0.28 mL, 1.5 mmol) in DMF (3.75 mL) using the methods of (IntA14), step 3.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][C:15](=[O:22])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:13])([CH3:12])[CH3:11].[BH4-].[Na+]>CO>[C:10]([O:14][C:15](=[O:22])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cc1cccnc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccnc1CNCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
Using General Procedure B, 3-methyl-pyridine-2-carbaldehyde (2.87 g, 23.7 mmol) in dry MeOH (10 mL) was added to a solution (4-amino-butyl)-carbamic acid tert-butyl ester (4.47 g, 23.7 mmol) (Krapcho, A. et al. Synth. Commun. 1990, 20, 2559-2564) in dry MeOH (50 mL) and warmed to 50° C. under N2 for 17 h. The mixture was cooled to ambient temperature and NaBH4 (1.35 g, 35.7 mmol) was added, resulting in bubbling. The mixture was stirred for 90 min. under N2 when the bubbling subsided. A solution of saturated NaHCO3 (50 mL) and CH2Cl2 (150 mL) were added to the MeOH solution and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3×100 mL), dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography on silica gel (130 g) with CH2Cl2/MeOH (96:4) to CH2Cl2/MeOH/NH4OH (88:8:4) afforded the title compound (6.05 g, 87%) as an orange oil which solidified on standing. 1H NMR (CDCl3) δ 1.35-1.50 (m, 4H), 1.43 (s, 9H), 2.05 (bs, 1H), 2.30 (s, 3H), 2.72 (t, 2H, J=6.5 Hz), 3.00-3.20 (m, 2H), 3.86 (s, 2H), 4.76 (bs, 1H), 7.07 (dd, 1H, 7.5, 4.5 Hz), 7.42 (d, 1H, J=7.5 Hz), 8.38 (d, 1H, J=4.5 Hz); 13C NMR (CDCl3) δ 18.06, 27.45, 27.89, 28.43, 40.48, 49.54, 52.18, 78.89, 121.78, 130.84, 137.52, 146.41, 156.03, 157.25; ES-MS m/z 194 (M+H). Anal Calcd. For C16H27N3O2.0.2(H2O): C, 64.70; H, 9.30; N, 14.15. Found: C, 65.07; H, 9.35; N, 14.29.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[OH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[CH2:26][CH2:25]1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccc(CN3CCC(O)CC3)cc2)cc1
Temperature: 60 °C
Reaction time: 21 h
Yield: 99.9 %

Procedure:
A mixture of methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (0.6 g, 1.88 mmol), 4-hydroxypiperidine (0.29 g, 2.82 mmol), potassium carbonate (0.39 g, 2.82 mmol) and N,N-dimethylformamide (12 mL) was stirred at 60° C. for 21 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.72 g, yield 99%) as a beige powder. MS (ESI+): 384 (M+H).
Reaction SMILES: II.[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1I.[B:12](OC)([O:15]C)[O:13]C.Cl>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[B:12]([OH:15])[OH:13]
Reactant: Fc1ccc(I)c(Cl)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)cc1Cl

Procedure:
To 1.05 g Mg in THF (20 mL) was added catalytic I2 and then a 1 mL portion of the 2-Chloro-4-fluoro-iodobenzene (10 g total, 39 mmol) was added. The mixture was stirred, slowly warmed, and an exothermic reaction began. The remainder of the 2-Chloro-4-fluoro-iodobenzene was added at a rate to maintain the exotherm and then the reaction was heated to THF reflux for 2.5 h, then cooled to 23°. The resulting mixture was added with rapid stirring to a −70° solution of trimethyl borate (4.53 mL, 40 mmol) in THF (40 mL). The reaction was stirred at <0° for 20 min and at 23° for 16 h, then poured into 2N HCl (150 mL), stirred 2 h, and the THF was removed under vacuum. The residual aqueous solution was extracted with Et2O (3×200 mL) and the combined extracts were dried (Na2SO4) and concentrated to afford a red solid. Trituration with hexane and drying afforded the title compound as a tan solid. (1.89 g, 28%). 1H-NMR CD3OD δ 7.09 (m, 1H), 7.21 (m, 1H), 7.38 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCN(CC(=O)N(C)C)CC2
Yield: 60.7 %

Procedure:
Following a procedure analogous to Example 113, 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide (47 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (47 mgs) were converted to the title compound (51 mgs) as a white foam. 1H-NMR (CDCl3): δ 10.16 (s, 1H), 8.53 (d, J=7.4 Hz, 1H), 8.06 (s, 2H), 7.85 (d, J=14.4 Hz, 2H), 7.48 (s, 1H), 7.40-7.34 (m, 2H), 7.20 (t, J=7.6 Hz, 1H), 6.65 (s, 1H), 6.52 (s, 1H), 3.88 (s, 3H), 3.30 (s, 2H), 3.17 (s, 3H), 3.00 (s, 3H), 2.90-2.70 (complex m 7H). LC/MS, found 547.18 (M+H)+; MP: 66-67° C.;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C([O-])([O-])=O.[K+].[K+].[NH2:37][C:38]1[N:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:41]3[CH:40]=[N:39][C:38]([NH2:37])=[N:43][CH:42]=3)[C:3]=12
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnc(N)nc2)c2c(N)ncnc21
Temperature: 120 °C
Yield: 28.8 %

Procedure:
3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (Intermediate D2a, 60 mg, 0.118 mmol), K2CO3 (32.6 mg, 0.236 mmol), 2-aminopyrimidin-5-ylboronic acid (32.7 mg, 0.236 mmol) and Pd(dppf)Cl2 (4.31 mg, 5.89 μmol) were reacted in 2 ml of dioxane, purged with argon and heated overnight at 120° C. The reaction was quenched by the addition of 1M HClaqueous (2 ml) and the resulting mixture was straightforward purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile (prior to drying 2 ml of 1M HClaqueous were added) to give the title compound (16.2 mg, 28.9%) as a yellow solid.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[O-:15][C:16]#[N:17].[Na+]>O1CCCC1>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[N:17]=[C:16]=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: N#C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1N=C=O
Reaction time: 8 h
Yield: 90 %

Procedure:
In an argon atmosphere, 7.69 g (33.0 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 30 mL of tetrahydrofuran and after adding 2.58 g (purity: 90%, 35.7 mmol) of sodium cyanate, the mixture was stirred for 8 hours under heating and refluxing. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 85° C./3.3×102 Pa) to obtain 1,3-di-tert-butyl-2-isocyanato-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NCO) as a colorless liquid (yielded amount: 7.09 g, yield: 90%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][C:31](OCC)=[O:32])[CH:28]=2)[NH:23][CH:22]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Cl.C(CC1C=CC(NN)=CC=1)(OCC)=O>>[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][CH2:31][OH:32])[CH:28]=2)[NH:23][CH:22]=1)=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: CCOC(=O)Cc1ccc2[nH]cc(CCNC(=O)OC(C)(C)C)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)Cc1ccc(NN)cc1
Agent: Cl
Product: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(CCO)cc12

Procedure:
Diisobutylaluminium hydride reduction of ethyl 3-[2-(N-tert-butyloxycarbonylamino)ethyl]-1H-indole-5-acetate using the conditions described for Intermediate 1 (Step 4) afforded the title compound as a colourless thick oil, after purification by flash chromatography (silica gel, diethyl ether); δH (250 MHz, CDCl3) 8.03 (1H, br s, indole N--H), 7.44 (1H, s, Ar--H), 7.32 (1H, d, J=8.3 Hz, Ar--H), 7.07 (1H, dd, J=8.3 and 1.6 Hz, Ar--H), 7.02 (1H, d, J=2.2 Hz, Ar--H), 4.60 (1H, br s, --NH--), 3.89 (2H, t, J=6.5 Hz, --CH2OH), 3.45 (2H, m, --CH2N--), 2.97 (2H, t, J=6.5 Hz, --CH2CH2OH), 2.93 (2H, t, J=6.8 Hz, --CH2 -- ), 1.43 (9H, s, t--Bu); m/z (CI) 303 (M+ -1). (Found: m/z 304.1759. C17H24N2O requires: m/z 304.1787).
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)/[C:8](NC2SC=CN=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=[O:28])C>>[CH:1]1(/[CH:6]=[C:7](\[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)/[C:8]([OH:9])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
A solution of the isomeric mixture of 3-cyclopentyl-2-(4-meth-anesulfonyl-phenyl)-acrylic acid ethyl ester [65.02 g, 0.202 mol, (E):(Z)=1.63:1] in methanol (504 mL) was treated with a 1N aqueous sodium hydroxide solution (423 mL, 0.423 mol). The reaction mixture was stirred at 25° C. for 20 h, at which time, thin layer chromatography indicated the presence of starting material. The reaction mixture was then concentrated in vacuo to remove some of the methanol (300 mL). The resulting reaction mixture was heated under reflux for 1 h, at which time, thin layer indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove methanol. The remaining aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×1 L). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-acrylic acid (62.58 g) as a cream solid consisting of a 16.2:1 mixture of (E):(Z) isomers. The cream solid was treated with ethyl acetate (200 mL), and the resulting slurry was heated to a boil. The resulting white solid surrounded by a light yellow liquid of ethyl acetate was allowed to cool to 25° C. The solid was filtered to afford pure (E)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-acrylic acid (41.18 g, 69%) as a white solid: mp 200-202° C.; EL-HRMS m/e calcd for C15H18O4S (M+) 294.0926, found 294.0921.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].CCCP(=O)=O.O>CN(C)C=O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1ccc(F)cc1
Agent: CCCP(=O)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccc(F)cc1)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.1 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (250 mg, 0.62 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(4-fluoro-benzyl)-amine (8k) (210 mg, 0.74 mmol) in dimethylformamide (5 mL) was added propylphosphonic anhydride (50 wt % in ethyl acetate) (1.3 g, 1.85 mmol) at 0° C. After stirring at room temperature for 20 h, water (20 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to yield 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(4-fluoro-benzyl)-amide (312) (96 mg, 23.18%) as a colourless sticky solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22](I)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].C[O:44][C:45](=[O:48])[CH2:46][SH:47].C(O)CO.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.[Cu](I)I.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([S:47][CH2:46][C:45]([OH:48])=[O:44])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(I)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: COC(=O)CS
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(SCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-iodopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (400 mg) is dissolved in isopropyl alcohol (2 ml), then thereto are added thioglycolic acid methyl ester (120 μl), copper iodide (20 mg), ethylene glycol (62 μl) and potassium carbonate (156 mg), and the mixture is stirred at 80° C. under nitrogen flow overnight. After allowing to cool to room temperature, water is added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer is washed with a saturated brine twice, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in methanol (6 ml), then thereto are added 1M-aqueous sodium hydroxide solution (3 ml) and tetrahydrofuran (6 ml), and the mixture is stirred at room temperature for 10 minutes. Ten % aqueous citric acid solution is added to the reaction mixture and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine twice, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1→1:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxymethylsulfanyl-pyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (153 mg).MS (m/z): 674 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=[N+]([O-])c1c[nH]nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1cc([N+](=O)[O-])c(Cl)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of 3-chloro-4-nitro-1H-pyrazole (1.0 g, 6.8 mmol) in DMF (30 mL) was added ethyl 2-bromo-2-methylpropanoate (2.00 g, 10.2 mmol) and Cs2CO3 (4.40 g, 13.6 mmol). The mixture was stirred at 100° C. for 2 h. After filtration, the solution was poured into water and extracted with ethyl acetate for 3 times. The organic layers were combined and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography to afford the title compound (1.2 g, 68%) as yellowish oil. LC-MS (ESI): m/z=262.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH3:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.[Cl-].[Na+]>CN(C)C=O.C(N(CC)CC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=3)=[CH:30][CH:29]=2)[C:10]([CH3:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])c1ccc(-c2ccncc2)cc1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccncc3)cc2)C(C)(C)C1
Temperature: 60 °C
Reaction time: 120 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3,3-dimethylpiperazine (173 mg) in a mixture of N,N-dimethylformamide (2.5 ml) and triethylamine (1.0 ml) was added (4-nirophenyl) 4-(4-pyridyl)benzoate (330 mg). The resulting mixture was stirred at 60° C. for 5 days. The reaction mixture was diluted with methylene chloride and then added with a saturated aqueous solution of sodium chloride to form two layers. The organic layer obtained by separation was washed with a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crudely purified product was purified by chromatography on a silica gel column (methylene chloride:methanol=50:1), whereby the title compound (199 mg) was obtained as colorless amorphous.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C@@:7]1(C)[C@H:13]2[C@H:11]([O:12]2)[CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].[N-:19]=[N+:20]=[N-:21].[Na+]>CO.O>[N:19]([C@H:11]1[CH2:10][CH2:9][CH2:8][C@@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:16])[CH3:15])[C@@H:13]1[OH:12])=[N+:20]=[N-:21]
Reactant: CC(C)(C)[Si](C)(C)O[C@]1(C)CCC[C@H]2O[C@H]21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCC[C@H](N=[N+]=[N-])[C@H]1O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a stirred solution of tert-butyl-dimethyl-[[(1R,5R,6R)-5-methyl-7-oxabicyclo[4.1.0]heptan-5-yl]oxy]silane, 50c, (0.05 g, 2.15 mmol) in methanol (5 mL) and H2O (0.6 mL) was added NH4Cl (0.23 g, 0.15 mL, 4.30 mmol), followed by portion wise addition of sodium azide (0.42 g, 1.26 mL, 6.45 mmol). The resulting reaction mixture was warmed to 60° C., stirred for 12 h, at which point TLC-analysis revealed traces of the starting material. The reaction mixture was cooled to ambient temperature, quenched with H2O (2 mL), concentrated under reduced pressure to remove methanol, extracted with ethyl acetate (3×15 mL), washed with brine (10 mL), dried over MgSO4, filter and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2.5-10% ethyl ether in hexanes gradient) to afford 254 mg of (1R,2S,6R)-2-azido-6-[tert-butyl(dimethyl)silyl]oxy-cyclohexanol, 50d, as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH:6]=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[CH:19]([C:20]([OH:22])=[O:21])[CH2:18][C:17](=[O:23])[N:7]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(C=Nc2ccccc2)c1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1C
Product: COc1cccc(C2C(C(=O)O)CC(=O)N2c2ccccc2)c1

Procedure:
A solution of 42.3 gm. of 3-methoxybenzylidenaniline, 20 gm. of succinic anhydride and 200 ml. of xylene was refluxed for 16 hours. The crude product was obtained as a solid via the same workup used for example 1B. Recrystallization from ethyl acetate followed by a second recrystallization from acetonitrile provided 21.0 gm. of colorless crystals, m.p. 145°-149°.