Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32]>C(#N)C.CN(C)C1C=CN=CC=1>[Si:35]([O:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:7]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(-c2cc(CNCCO)ccn2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
N-(2-Hydroxyethyl)-N-[[2-(3,4,5-trimethoxyphenyl)-pyridin-4-yl]methyl]amine (5.0 g) was dissolved in acetonitrile (100 mL), and to the solution triethylamine (2.22 g) and 4-(dimethylamino)pyridine (250 mg) were added, and tert-butylchlorodimethylsilane (3.08 g) was then added. The mixture was stirred at 50° C. for 4 hours. The reaction, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([CH2:27][CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:11][C@@H:10]([C:40](=[O:60])[N:41]([CH:57]2[CH2:59][CH2:58]2)[CH2:42][C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:44]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CS.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][CH2:27][CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:11][C@@H:10]([C:40](=[O:60])[N:41]([CH:57]2[CH2:59][CH2:58]2)[CH2:42][C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:44]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N(CCN3C(=O)c4ccccc4C3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Agent: O=C(O)CS
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCCN3C(=O)c4ccccc4C3=O)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Reaction time: 2.5 h

Procedure:
To a solution of (3R*,5S*)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-[[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-(2-nitro-benzenesulfonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.3 mmol) in DMF (1 mL) are added thioglycolic acid (104 uL, 1.5 mmol) and DBU (224 uL, 1.5 mmol) at room temperature. After 2.5 h, the reaction mixture is quenched by H2O (20 mL) and extracted with CH2Cl2 (50 mL). The organic phase is successively washed with H2O and brine, then dried over Na2SO4 and concentrated in reduced pressure. The residue is purified by silica gel column chromatography to afford the title compound. MS: 658 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.60 min.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[CH2:15](O)[CH3:16]>>[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([O:13][CH2:15][CH3:16])=[O:12]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 82 %

Procedure:
20 ml (27 mmol) of thionyl chloride are added dropwise, at room temperature, to a solution of 10 g (49 mmol) of 5-bromonicotinic acid in 250 ml of ethanol. The reaction medium is stirred at room temperature for 4 days and then evaporated under vacuum. The residue is taken up in dichloromethane and washed with aqueous sodium carbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 9 g (82%) of ethyl 5-bromonicotinate are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:21]=[C:20]3[C:15]([C:16](=[O:27])[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][NH:19]3)=[CH:14][C:13]=2[F:28])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[CH2:36][OH:37]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:21]=[C:20]3[C:15]([C:16](=[O:27])[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:19]3[CH2:35][CH2:36][OH:37])=[CH:14][C:13]=2[F:28])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCO)c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Temperature: 100 °C
Yield: 87.3 %

Procedure:
A mixture of ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (10.5 g), dimethylformamide (100 ml), and potassium carbonate (7.4 g) was heated at 100° C. for 15 minutes. To the solution was added a solution of 10.1 g of ethylene bromohydrin in dimethylformamide (10 ml), and the mixture was heated at 100° C. for 45 minutes with stirring. After removal of the resulting inorganic substance by filtration, the filtrate was concentrated to dryness under reduced pressure. Water (80 ml) was added to the residue, and the resulting crystals were collected by filtration and recrystallized from ethanol to give 10.2 g of ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1-(2-hydroxyethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (mp 215°-217° C.). Thionyl chloride (5.0 g) was added to the solution of the resulting hydroxyethyl derivative (4.6 g) in chloroform (50 ml), and the mixture was refluxed under heating for 30 minutes. After cooling, the solution was treated with 30 ml of water and neutralized with a saturated sodium bicarbonate solution. The chloroform layer was separated, washed with water, and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was chromatographed on silica gel with chloroform and the crystals resulting from the main fraction were recrystallized from ethyl acetate to give 4.7 g of ethyl 1-(2-chloroethyl)-7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (mp 143°-144° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>CN(C=O)C.O>[Br:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:8][C:9]([C:11]2[N:15]([CH2:24][CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH:14]=[CH:13][N:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: Cc1c(Br)cccc1NC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(Cn1ccnc1C(=O)Nc1cccc(Br)c1C)OCC
Temperature: 100 °C
Yield: 81.8 %

Procedure:
Step 2 A solution of N-(3-bromo-2-methylphenyl)-1H-imidazole-2-carboxamide (0.70 g, 2.499 mmol) in DMF (12.5 mL) was treated with potassium carbonate (0.794 g, 5.75 mmol) and 2-bromo-1,1-diethoxyethane (0.395 mL, 2.62 mmol). The suspension was heated at 100° C. overnight. The mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 85:15 to 20:80 hexane-EtOAc) to provide N-(3-bromo-2-methylphenyl)-1-(2,2-diethoxyethyl)-1H-imidazole-2-carboxamide as a white solid (0.81 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 10.17 (1H, s), 7.51 (1H, d, J=2.6 Hz), 7.49 (1H, d, J=2.6 Hz), 7.44 (1H, d, J=1.1 Hz), 7.18 (1H, t, J=8.0 Hz), 7.10 (1H, d, J=1.1 Hz), 4.75 (1H, t, J=5.4 Hz), 4.52 (2H, d, J=5.3 Hz), 3.63 (2H, dq, J=9.7, 7.0 Hz), 3.35-3.44 (2H, m), 2.31 (3H, s), 1.05 (6H, t, J=7.0 Hz). Mass spectrum m/z 396, 398 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH:16]([C:20]([NH:22][C:23]4[CH:24]=[C:25]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=4)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:21])[CH2:17]3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].[N+:48]([CH2:50]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:49]>CO>[O:2]1[C:1]([C:3]2[CH:8]=[C:7]([O:9][C:10]3[CH:19]=[C:18]4[C:13]([CH2:14][CH2:15][CH:16]([C:20]([NH:22][C:23]5[CH:24]=[C:25]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=5)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:21])[CH2:17]4)=[CH:12][CH:11]=3)[CH:6]=[CH:5][N:4]=2)=[CH:50][N:48]=[CH:49]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C=O)c4)cc3C2)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5cnco5)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 74.3 %

Procedure:
To a solution of tert-butyl [3-[({7-[(2-formylpyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)amino]-5-(trifluoromethyl)benzyl]carbamate (120 mg, 0.21 mmol) in MeOH (2 mL), was added potassium carbonate (116 mg, 0.84 mmol) and 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene (45.2 mg, 0.23 mmol). The reaction mixture was heated at 70° C. for 30 min. and then allowed to cool to rt and the solvents were evaporated. The residue was dissolved in DCM, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl [3-{[(7-{[2-(1,3-oxazol-5-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalen-2-yl)carbonyl]amino}-5-(trifluoromethyl)benzyl]carbamate (95.0 mg, 74.1%). LCMS: (FA) ES+ 609.3, ES− 607.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH3:12])[CH2:18][CH2:19]2)[CH:28]=[CH:27][CH:26]=1)(=[O:32])[CH3:31]
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 95 was prepared from 2-(4-chlorophenyl) propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.31–7.25 (m, 6H), 6.98–6.93 (m, 2H), 3.51–3.48 (m, 1H), 3.35–3.31 (m, 2H), 3.03 (d, 1H, J=11.6 Hz), 2.93 (d, 1H, J=11.2 Hz), 2.50 (m, 1H), 2.42–2.38 (m, 2H), 2.19 (s, 3H), 2.05–1.96 (m, 2H), 1.90–1.80 (m, 2H), 1.70–1.59 (m, 4H), 1.51 (d, 3H, J=7.2 Hz); ESMS m/e: 442.2 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)[C:12]([O:15][CH3:16])=[N:13][CH:14]=1>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([C@H:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)[C:12]([O:15][CH3:16])=[N:13][CH:14]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(F)cc1[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A DCM (12 mL) solution of TFA (11.3 mL, 146 mmol) was added to (R)-tert-butyl 2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylate (4.33 g, 14.6 mmol) and stirred at ambient temperature for 1 hour. The reaction was then concentrated, taken up in EtOAc, then washed with NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and concentrated, and the crude material was purified by silica column chromatography eluting with a 1-2% 7 N NH3-MeOH/DCM to afford (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine as a liquid (1.40 g, 49% yield).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].CN(C)[CH2:10][C:11]1C=CC=CC=1.[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:20]=1[NH2:21].C(=O)C>C(Cl)Cl>[CH:10](=[N:21][C:20]1[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:19]=1[CH3:18])[CH3:11]
Reactant: CN(C)Cc1ccccc1
Reactant: Cc1cccc(C)c1N
Agent: CC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC=Nc1c(C)cccc1C
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
180 g (3 mols) of sodium sulphate and 3 ml of dimethylbenzylamine were added to 121 g (1 mol) of 2,6-dimethylaniline in 200 ml of methylene chloride. 88 g (2 mols) of acetaldehyde were added to the mixture at 0° C. The mixture was stirred at 0° C. for 4 hours and was filtered, and the filtrate was concentrated in vacuo at a maximum bath temperature of 20° C. 140 g (95.2% of theory) of N-ethylidene-2,6-dimethylaniline were obtained as a reddish oil.
Reaction SMILES: Cl[O-:2].[K+].[OH-].[K+].[Cl:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14](=[O:16])C)=[C:9]([F:17])[CH:8]=1>[Cl-]>[Cl:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14]([OH:16])=[O:2])=[C:9]([F:17])[CH:8]=1
Reactant: [O-]Cl
Reactant: CC(=O)c1cc(F)c(Cl)cc1F
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(F)c(Cl)cc1F
Temperature: 40 °C

Procedure:
A 3.6 liter aqueous solution containing 500 g (5.5 mole) of potassium hypochlorite and 115 g potassium hydroxide, was taken in a 5 liter, 3-necked round-bottomed flask equipped with a Trubore stirrer, a thermometer, an addition funnel and a water condenser. 228.5 g (1.2 mole) of 4'-chloro-2',5'-difluoroacetophenone was dissolved in 550 ml of chloride and the solution was slowly added to the flask via the addition funnel. The temperature was not allowed to exceed 40° C. After the addition was complete, the heterogeneous mixture was stirred vigorously at reflux (40° C.) for 18 hours.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:33]([NH:35][CH2:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:39][C:38]([CH3:41])([CH3:40])[CH2:37][CH2:36][N:35]([CH2:33][CH3:34])[C:11](=[O:13])[CH2:10][C:9]1[C:8]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=2[O:6][C:5]=1[C:3](=[O:4])[C:2]([CH3:1])([CH3:21])[CH3:20]
Reactant: CCNCCC(C)(C)C
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCC(C)(C)C)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 45 °C

Procedure:
To a mixture of 7.7 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1, 6.1 mg HOBt, and 10.2 mg EDC was added 0.5 mL dry DMF. Add 6.6 N-ethyl-3,3-dimethylbutan-1-amine hydrochloride from the Step A above followed by 16 μL DIEA. This solution was heated at 45° C. over night. It was purified directly on RP-HPLC using 65-80% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.38 min. (m/Z=424.3, 318.2, 402.3).
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:23]=[C:22]([C:24]2[C:33]3[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[S:36][C:32]=3[C:31]([Br:41])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)[CH:21]=[C:20]([Br:42])[C:7]=1[O:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([NH2:12])=O.C[Si]([N:47]=[N+:48]=[N-:49])(C)C.O>CCOCC>[Br:42][C:20]1[CH:21]=[C:22]([C:24]2[C:33]3[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[S:36][C:32]=3[C:31]([Br:41])=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[CH:29]3)[CH:23]=[C:6]([Br:5])[C:7]=1[O:8][C@@H:9]([C:10]1[NH:49][N:48]=[N:47][N:12]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Al](C)C
Solvent: CCOCC
Solvent: O
Product: Brc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1O[C@H](Cc1ccccc1)c1nnn[nH]1
Temperature: 85 °C
Yield: 56.5 %

Procedure:
Trimethylaluminum (7.24 mL, 14.4 mmol, 2.0 M solution in toluene) was added to (R)-2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenoxy ]-3-phenyl-propionamide (1.33 g, 1.93 mmol) under a dry nitrogen atmosphere. Trimethylsilyl azide (1.92 mL, 14.4 mmol) was then added and the solution was heated in a 85° C. oil bath. After 7 h the reaction mixture was cooled to room temperature and diluted with ether. Water was cautiously added and after bubbling subsided, the mixture was partitioned between dilute aqueous HCl and ether. The ether phase was concentrated and triturated with petroleum ether, a small amount of methanol, a small amount of ether and finally petroleum ether to provide the title compound as a white solid (0.802 g, 57%): mp 238-239° C.: NMR (DMSO-d6); δ8.28 (d, J=8 Hz, 1 H), 8.07 (d, J=8 Hz, 1 H), 7.81-7.74 (m, 3 H), 7.62 (ddd, 8, 7, 1 Hz, 1 H), 7.57-7.53 (m, 2 H), 7.44 (ddd, 8, 7, 1 Hz, 1 H), 7.38-7.22 (m, 5 H), 6.60 (d, J=8 Hz, 1 H), 5.87 (dd, J=9, 7 Hz, 1 H), 3.90 (dd, J=13, 7, 1H), 3.80 (dd, J=13, 8, 1H); MS (-ESI): [M-H], 3 bromine isotope pattern, 731 (60%), 733 (90%) 735 (100%) 737 (60%); Anal. Calc. for C31H19Br3N40S: C, 50.64, H, 2.61, N, 7.62. Found: C, 49.65, H, 2.434, N, 7.16.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[H-].[Na+].[CH2:41]([O:44][P:45]([O:51][CH2:52][C:53]1[C:61]([CH3:62])=[CH:60][CH:59]=[CH:58][C:54]=1[C:55](Cl)=[O:56])([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:42]=[CH2:43]>O1CCCC1>[CH2:48]([O:47][P:45]([O:51][CH2:52][C:53]1[C:61]([CH3:62])=[CH:60][CH:59]=[CH:58][C:54]=1[C:55]([O:38][C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11])=[O:56])([O:44][CH2:41][CH:42]=[CH2:43])=[O:46])[CH:49]=[CH2:50]
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Yield: 69 %

Procedure:
According to a similar procedure to that described in Example 1-(12), 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (976.6 mg, 1.80 mmol) described in Reference example 1, sodium hydride (55% dispersion in mineral oil; 94.2 mg, 1.96 mmol), and 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoyl chloride obtained above were reacted in tetrahydrofuran (10 ml), and the reaction mixture was worked up to afford, after extraction, the title compound as a crude oil. The crude oil was subjected to chromatography on a silica gel (100 g) column (eluent; ethyl acetate:hexane=3:2˜4:1) to afford the title compound (1.0641 g, 69% yield) as a pale yellow amorphous solid.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=C1)=[O:2].[NH2:13][C:14]1[N:23]=[C:22]([C:24]([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[CH2:43][OH:44])[CH:20]=2)[N:15]=1.C(NCCN)(OC(C)(C)C)=O.Cl.C(=O)(O)[O-]>N1C=CC=CC=1>[NH2:5][CH2:6][CH2:7][NH:3][C:1](=[O:2])[O:44][CH2:43][C:36]1[CH:37]=[C:38]([F:42])[C:39]([F:41])=[CH:40][C:35]=1[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:13])[N:23]=[C:22]2[C:24]([N:26]1[CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34]1)=[O:25]
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(C)(C)OC(=O)NCCN
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: NCCNC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
400 mg of 1,1′-carbonyldiimidazole are dissolved in 10 ml of pyridine and cooled to 0° C. A solution of 1.0 g of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone dissolved in 10 ml of pyridine is added. The mixture is subsequently stirred at 0° C. for 2 h and at 25° C. for 2 h. 400 mg of N-Boc-ethylenediamine are then added, and the mixture is stirred at 25° C. for a further 18 h. The mixture is added to 250 ml of 1 N HCl and stirred at 25° C. for 3 h, neutralised using bicarbonate solution and washed 3 times with 150 ml of dichloromethane each time. The organic phases are washed twice with 50 ml of water each time, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[O:14][CH:13]2[N:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([O:18]CC1C=CC([N+]([O-])=O)=CC=1)=[O:17])([CH3:7])[CH3:6])=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd].O>[NH2:1][CH2:4][C:5]([C:8]1[O:14][CH:13]2[N:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([OH:18])=[O:17])([CH3:7])[CH3:6]
Reactant: [H][H]
Reactant: CC(C)(CN=[N+]=[N-])C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)CC2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CN)C1=C(C(=O)O)N2C(=O)CC2O1

Procedure:
A solution of 21 mg (0.054 mmol) of p-nitrobenzyl 3-(2-azido-1,1-dimethylethyl)-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in 1 ml of ethyl acetate is added via a syringe through a septum stopper to a prehydrogenated mixture, at 0° C., of 60 mg of palladium on charcoal (10%) in 1 ml of ethyl acetate and 0.7 ml of water. After a reaction time of 20 minutes, 5.7 ml of hydrogen have been taken up (theoretical amount 4.9 ml). The reaction mixture is filtered at 0° C., and the aqueous phase is washed twice with 2 ml of pre-cooled ethyl acetate. The aqueous phase contains 8.96 mg of the title compound. UV spectrum in H2O: λmax =271 nm (ε=5000)
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:20][C:21]1[C:22]([O:36][CH2:37][CH3:38])=[N:23][O:24][C:25]=1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.[ClH:39]>C(OCC)C>[ClH:39].[NH2:8][CH:9]([CH2:20][C:21]1[C:22]([O:36][CH2:37][CH3:38])=[N:23][O:24][C:25]=1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CCOc1noc(C(=O)OCc2ccccc2)c1CC(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOc1noc(C(=O)OCc2ccccc2)c1CC(N)C(=O)OCc1ccccc1

Procedure:
A mixture of benzyl (RS)-2-[(tert-butoxycarbonyl)amino]-3-(5-benzyloxycarbonyl-3-ethoxyisoxazol-4-yl)propionate (1.9 g, 3.6 mmol) and a saturated solution of HCl in dietyl ether (40 mL) was boiled under reflux for 2 h. The formed crystals were collected by filtration, stirred with ethyl acetate, and collected by filtration (0.53 g, 32%): mp 142-144° C.; 1H NMR (DMSO-d6) δ1.32 (t, 3 H), 3.17 (dd, 1 H), 3.25 (dd, 1 H), 4.17-4.32 (m, 3 H), 5.09 (dd, 2 H), 5.39 (s, 2 H), 7.24-7.53 (m, 10 H); MS ((M+H)+) m/z 425. Anal. calcd, C, 59.93; H, 5.48; N, 6.08; found, C, 59.70; H, 5.49; N, 6.26.