Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24]C)=[O:23])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:15]([O:14][C:12]([N:10]1[CH2:11][C@@:7]([C:4]2[CH:3]=[CH:2][C:1]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:6][CH:5]=2)([S:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH2:8][C@H:9]1[C:22]([OH:24])=[O:23])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H]1C[C@@](SC[Si](C)(C)C)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.2 %

Procedure:
To a solution of (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-((trimethylsilyl)methylthio)pyrrolidine-1,2-dicarboxylate (472 mg, 0.884 mmol) in THF (10 mL) and MeOH (10 mL) was added premade solution of Lithium hydroxide monohydrate (74.2 mg, 1.769 mmol) in Water (10 mL). The formed white slurry was stirred at room temperature for 3 days. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated to afford the desired product (2S,4R)-1-(benzyloxycarbonyl)-4-(biphenyl-4-yl)-4-((trimethylsilyl)methylthio)pyrrolidine-2-carboxylic acid (460 mg, 0.797 mmol, 90% yield) as a wax. This product was used for the next reaction without further purification. LC-MS (retention time: 3.43 min, method B), MS m/z 520 (M+H).
Reaction SMILES: CN(C)C=[C:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=1)[C:5](OCC)=[O:6].[CH3:23][C:24]([NH:34][NH:35][C:36](OC(C)(C)C)=O)([CH3:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1>C(O)(=O)C.C(OCC)C>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([C:4]2[CH:36]=[N:35][N:34]([C:24]([CH3:23])([CH3:33])[CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:5]=2[OH:6])=[CH:15][CH:14]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCc1ccc(C(=CN(C)C)C(=O)OCC)cc1
Reactant: Cc1ccc(CC(C)(C)NNC(=O)OC(C)(C)C)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCc1ccc(-c2cnn(C(C)(C)Cc3ccc(C)cc3)c2O)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Ethyl 3-(dimethylamino)-2-(4-hexylphenyl)acrylate and 0.50 g (1.8 mmol) of tert-butyl 2-(2-methyl-1-(p-tolyl)propan-2-yl)hydrazinecarboxylate were dissolved in 2 mL of acetic acid and stirred at 90° C. for 24 hours. After the stirring, the reaction mixture was mixed with 0.5 mL of acetic acid and stirred for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with diethyl ether and washed with distilled water, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 30 g, ethyl acetate:hexane=0:100 to 35:65). The resulting solid was washed with isopropyl ether to give 164 mg of the desired product as a white solid.
Reaction SMILES: FC1C=CC=C(F)C=1C(NC1C=CC(C2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:16]C=2C)=CC=1)=O.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.CCO>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:15](=[S:16])[NH2:14]
Reactant: Cc1sc(-c2ccccn2)nc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=S)c1ccccn1
Yield: 100.6 %

Procedure:
The solution of 2 (0.5 g, 1.73 mmol) in THF (100 mL) with phenyltrimethylammonium tribromide (0.68 g, 1.8 mmol) was heated at 60° C. for 2 hr. Then the solution was quenched with water and extracted with EtOAc (3×50 mL). The combined EtOAc solution was concentrated to give the crude product, which could be used directly for the next step without further purification. The solution of resulting crude product with pyridine-2-carbothioamide (0.24 g, 1.74 mmol) in EtOH was heated at 70° C. overnight. The solution was diluted with water and extracted with EtOAc. Column chromatography (Hexanes/EtOAc=1/1) afforded compound 2 in 51% overall yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH3:12][CH:13]([OH:16])[CH:14]=[CH2:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH2:15][CH2:14][C:13](=[O:16])[CH3:12])=[CH:6][CH:5]=1
Reactant: C=CC(C)O
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)c1ccc(CCC(C)=O)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of methyl-4-bromobenzoate (1.0 g, 4.65 mmol) in triethylamine (13 mL) was added 3-buten-2-ol (1 mL, 11.63 mmol), palladium (II) acetate (0.104 g, 0.465 mmol), and then triphenylphosphine (0.244 g, 0.93 mmol). The reaction was stirred in a 75° C. oil bath overnight under nitrogen atmosphere. Monitoring by TLC (3:1 hexane:ethyl acetate) showed the product and aryl bromide. The reaction was cooled to room temperature and then concentrated. Water was then added followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (5:1 to 3:1 hexane:ethyl acetate) to obtain the product (250 mg, 26% yield). 1H NMR (600 MHz, CDCl3): δ 7.95 (d, 2H, J=8.4 Hz), 7.25 (d, 2H, J=8.4 Hz), 3.90 (s, 3H), 2.95 (t, 2H, J=7.45 Hz), 2.77 (t, 2H, J=7.68 Hz), 2.14 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.FC(F)(F)C(O)=[O:24].OO.S(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=2[S:5](=[O:24])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a solution of 3-bromo-6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene (4 g, 11.45 mmol) in DCM (20.02 mL) at room temperature was added trifluoroacetic acid (20.02 mL) dropwise, the reaction went from orange to dark brown in color. Upon addition the resulting mixture was stirred at room temp for 10 min and then hydrogen peroxide (30% wt. aq) (1.583 mL, 16.47 mmol) was added dropwise. After 90 min at room temperature the reaction mixture was quenched with sodium bisulfite (1.714 g, 16.47 mmol) (vigorous bubbling was observed) followed by 3.0 mL of water. The resulting suspension was stirred vigorously for 15 min and then concentrated in vacuo to remove DCM and most of the TFA. The residue was partitioned between DCM (40 mL) and sat. aq. NaHCO3 solution (40 mL) and separated. The organic layer was collected (phase separator) and concentrated in vacuo to afford the crude product, which was purified by column chromatography (SiO2, 1-40% EtOAc/Heptane) to afford 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (4.6 g, 10.08 mmol, 88% yield) as an orange solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.51-7.65 (m, 2H), 7.37-7.51 (m, 2H), 7.08 (dd, J=2.27, 8.34 Hz, 1H), 6.79-6.96 (m, 2H), 3.74 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][C:18](=[O:24])[NH:19]2.N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])[NH:19][C:18]1=[O:24]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 51.9 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 74 mg 4-methyl-2-oxindole, and 75 μL, piperidin in ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 80 mg (52%) of the title compound as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:38]=[CH:39][CH:40]=1)[O:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=1[CH2:44][NH2:45].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:38]=[CH:39][CH:40]=1)[O:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C:22](=[O:28])[CH2:23][CH2:24][C:25]([NH:45][CH2:44][C:43]1[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=1[F:41])=[O:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1F
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(Cl)c(Cl)c2)C(=O)CCC(=O)O)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(Cl)c(Cl)c2)C(=O)CCC(=O)NCc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A mixture of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(3,4-dichlorobenzyl)succinamic acid (0.91 g, 1.5 mmols), 2-fluorobenzylamine (0.23 g, 1.8 mmols), diethyl cyanophosphate (0.25 ml, 1.8 mmols), triethylamine (0.25 ml, 1.8 mmols) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an amorphous solid of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(3,4-dichlorobenzyl)-N′-(2-fluorobenzyl)succinamide (0.61 g, 57%).
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.[OH-].[Li+]>CO.O>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3.5 h
Yield: 90.5 %

Procedure:
To a stirred solution of N-Cbz-L-Leu-L-Leu-OCH3 (6.0 g, 14.6 mmol) in MeOH/H2O (3:1) (60 mL) at R. T. was added lithium hydroxide monohydrate (LiOH.H2O) (1.0 g, 43.9 mmol) and hydrogen peroxide H2O2 (30% weight in H2O) (4.5 mL, 43.9 mmol). The reaction mixture was stirred for 3.5 h and then quenched with 10% HCl. The resulting mixture was extracted with EA (3×20 mL). The combined organic extracted were washed with sat. NaCl (2×10 mL), dried (MgSO4) and concentrated in vacuo to afford N-Cbz-L-Leu-L-Leu-OH as a white solid (5.0 g, 90.5%): 1H NMR (CDCl3, 300 MHz) δ 0.89-0.92 (t, 12H, J=3.0 Hz), 1.48-1.71 (m, 6H), 4.11-4.13 (m, 1H), 4.55-4.62 (m, 1H), 5.09 (s, 2H), 5.64 (d, 1H, J=9.0 Hz), 6.83 (d, 1H, J=9.0 Hz), 7.33-7.40 (m, 5H) ppm.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N+:21]([O-])=O)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>O1CCCC1.C(O)C.O>[NH2:21][C:20]1[C:14]2[O:13][CH2:12][CH2:11][N:10]3[C:16](=[C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:8]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][C:9]=43)[C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c-3cccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(N)cccc1-3
Temperature: 100 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of methyl 12-cyclohexyl-4-nitro-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (9.94 g, 23.6 mmol) in tetrahydrofuran (85 ml), ethanol (170 ml) and water (42.5 ml) were added ammonium chloride (6.31 g, 118 mmol) and reduced iron (6.60 g, 118 mmol), and the mixture was stirred at 100° C. for 2 hr. After filtration of the reaction solution, saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure to give a solid. The obtained solid was washed with a mixed solvent (hexane:ethyl acetate-20:1). The solid was collected by filtration to give methyl 4-amino-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (8.62 g, yield 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([NH:19][C:20]2[C:25]([NH:26][C:27](=[O:44])/[CH:28]=[CH:29]/[CH:30]=[CH:31]/[C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=3)=[CH:24][CH:23]=[CH:22][C:21]=2[O:45]C(=O)/C=C/C=C/C2C=C(OC)C(OC)=C(OC)C=2)=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([NH:19][C:20]2[C:25]([NH:26][C:27](=[O:44])/[CH:28]=[CH:29]/[CH:30]=[CH:31]/[C:32]3[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=3)=[CH:24][CH:23]=[CH:22][C:21]=2[OH:45])=[O:18])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(/C=C/C=C/C(=O)Nc2cccc(OC(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)c2NC(=O)/C=C/C=C/c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(/C=C/C=C/C(=O)Nc2cccc(O)c2NC(=O)/C=C/C=C/c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 196 mg (0.23 mmol) of N,N′,O-tri[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2,3-diaminophenol synthesized by the process described above in anhydrous methanol-tetrahydrofuran (3 ml-3 ml) was cooled in an ice bath. To the solution was added 19 mg (0.14 mmol) of potassium carbonate. The ice bath was removed, and the mixture was stirred for 1 hour at room temperature. Added to the reaction mixture were 0.5 ml of 1N hydrochloric acid and 5 ml of a saturated saline solution to conduct extraction with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil (515 mg) was purified by column chromatography on silica gel, thereby obtaining 126 mg (yield: 90%) of crude crystals of the title compound. The crude crystals thus obtained were recrystallized from ethanol-ether, thereby obtaining a pale yellow crystalline powder.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](O)=[O:7])=[N+:2]=[N-:3].S(Cl)([Cl:13])=O>ClCCCl>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([Cl:13])=[O:7])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CC(=O)O)N=[N+]=[N-]
Solvent: ClCCCl
Product: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Temperature: 50 °C

Procedure:
To a stirred solution of 3-azido-3-methylbutanoic acid (10 g, 69.8 mmol) in anhydrous 1,2-dichloroethane (50 mL) was added thionyl chloride (10.0 mL, 140 mmol). The flask was fitted with a condenser and the reaction was heated in a 50° C. oil bath for 2 hours. The reaction was concentrated to a brownish-black suspension. The residue was vacuum distilled through a short path distillation apparatus. The forerun was discarded and the major fraction distilled at 66° C. at 18 mbar as a pale yellow liquid (9.66 g, 59.7 mmol, 85.6%). 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2H). 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 6H), 3.10 (s, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[C:25](=[O:34])[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29].CC(O[Na])=O.[NH2:40]O.Cl.Cl>C1COCC1.C(O)C.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[C:25]1[O:34][N:40]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:26]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1c(OCOC)cc(OCOC)cc1Oc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2c(OCOC)cc(OCOC)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Reaction time: 24 h
Yield: 49.5 %

Procedure:
To a stirred solution of ethyl 4-[2,4-bis(methoxymethoxy)-6-(4-nitrophenoxy)phenyl]-2,4-dioxobutanoate (71 g, 149 mmol) in THF (250 mL) and ethanol (500 mL) is added CH3COONa (24.4 g, 298 mmol) and NH2OH.HCl (22.8 g, 328 mmol) at room temperature. After the conversion to the oximes is complete, 6 M HCl solution was added dropwise to reach pH 2 to promote the cyclization. After stirring for 24 hours, Na2HPO4 was added to reach pH 6 and the suspension taken up in ethyl acetate was thoroughly washed with brine and dried over Na2SO4. The solvent was removed and the residue was crystallized from a mixture of MTBE (240 mL) and hexane (180 mL), to provide the title compound (35 g, 49% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:24])=[C:6]([C:17]2[CH:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16].[CH3:25][O-:26].[Na+].CO>O>[Cl:23][C:20]1[N:19]=[CH:18][C:17]([C:6]2[C:7]([C:8]3[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=3[F:16])=[C:2]([O:26][CH3:25])[N:3]=[N:4][C:5]=2[CH3:24])=[CH:22][CH:21]=1
Reactant: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nnc(C)c(-c2ccc(Cl)nc2)c1-c1c(F)cc(F)cc1F

Procedure:
A mixture of 3-chloro-5-(6-chloro-pyridin-3-yl)-6-methyl-4-(2,4,6-trifluorophenyl)-pyridazine (Compound No. I.a.11, 700 mg), sodium methoxide (30% solution in methanol, 750 mg) and 10 ml of methanol is heated for 6 h to 60° C. Subsequently the reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The combined organic layer is washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The remainder is purified by chromatography on silica gel, using a mixture of heptane/ethyl acetate 3:1 as eluent to obtain 4-(6-chloro-pyridin-3-yl)-6-methoxy-3-methyl-5-(2,4,6-trifluoro-phenyl)-pyridazine (Compound I.a.12), m.p. 123-124° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[F:21][CH2:22][C:23](OCC)=[O:24]>O1CCCC1.CCOCC>[F:21][CH2:22][C:23](=[O:24])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CF
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CF
Temperature: -78 °C

Procedure:
A solution containing 12.6 g (125 mmol) of diisopropylamine in 90 ml of dry tetrahydrofuran was cooled to -78° C. and 52.4 ml of 2.5M n-butyllithium (131 mmol) was added. A solution of 14.5 g (125 mmol) of t-butyl acetate in 10 ml of tetrahydrofuran was then added dropwise over a 30 min period with stirring and allowed to react for another 30 min at -78° C. A solution of 6.00 g (56.6 mmol) of ethyl fluoroacetate in tetrahydrofuran was added dropwise with stirring to the resultant pale yellow solution and the mixture allowed to react for another 30 min at -78° C. and then allowed to stir and warm to ambient temperature over one hour. The resulting pale yellow solution was diluted with 250 ml of ether and the ethereal solution was extracted with 250 ml of 1N HCl, 250 ml of water, and 250 ml of saturated aqueous sodium bicarbonate. The solution was then dried over magnesium sulfate and distilled at atmospheric pressure to remove the solvents. The residue was fractionally distilled under reduced pressure from a based-washed and oven-dried flask containing a few potassium bicarbonate crystals to obtain 7.00 g (70 percent of theory) of the desired product as a colorless oil boiling at 72°-74° C. at 10 torr. The proton and fluorine nmr spectra were consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[C:6]([Br:13])[C:3]=1[CH2:4][NH2:5].C([O-])([O-])=O.[Na+].[Na+].[C:20](ON1C(=O)CCC1=O)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21]>O1CCOCC1>[C:20]([NH:5][CH2:4][C:3]1[C:2]([Br:1])=[CH:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=1[Br:13])([O:22][CH2:23][CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21]
Reactant: NCc1c(Br)cc(C(=O)O)cc1Br
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1c(Br)cc(C(=O)O)cc1Br)OCC1c2ccccc2-c2ccccc21
Yield: 88.2 %

Procedure:
To a solution of 2,6-dibromo-4-carboxybenzylamine (20 g, 0.064 mol) in dioxane (500 mL), was added an aqueous solution of Na2CO3 (10%, 410 mL) with stirring. After stirring at 26° C. for 15 min was added Fmoc-OSu (30.5 g, 0.09 mol) in portions for 2 h and allowed to stir at ambient temperature for 24 h. The solid precipitate was filtered off and washed with diethyl ether (3×200 mL), followed by methanol (3×200 mL). The solid salt was acidified with an aqueous solution of HCl (3 N, 100 mL) to pH=2. The precipitate was filtered under suction and dried. The crude solid was recrystalised from methanol/diethyl ether to give N-(Fmoc)-2,6-dibromo-4-carboxybenzylamine (30 g, 87%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=1[Cl:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cc(Cl)ccc1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 46.6 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 650 mg, 4.45 mmol), 2,5-dichlorophenylboronic acid (Aldrich; 831 mg, 4.36 mmol), copper(II) acetate (807 mg, 4.45 mmol) and triethylamine (623 μL, 4.45 mmol) in 1,2-dichloroethane (4.5 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(2,5-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (592 mg, 46%) as a yellow oil that solidified on standing.