Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([C:23]4([O:28][CH3:29])[CH2:27][CH2:26][NH:25][CH2:24]4)=[O:22])[CH:18]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[C:42]([F:52])[CH:41]=2)[CH2:36][CH2:35]1)=[O:33].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([C:23]4([O:28][CH3:29])[CH2:27][CH2:26][N:25]([CH2:31][C:32]([N:34]5[CH2:39][CH2:38][N:37]([C:40]6[CH:45]=[CH:44][C:43]([C:46]7[N:47]=[CH:48][CH:49]=[CH:50][N:51]=7)=[C:42]([F:52])[CH:41]=6)[CH2:36][CH2:35]5)=[O:33])[CH2:24]4)=[O:22])[CH:18]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(OC(C)C)cc4)c3c2)CCNC1
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(OC(C)C)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-pyrrolidine-3-carboxylic acid [3-(4-isopropoxy-phenyl)-1H-indazol-5-yl]-amide (8AB) (40 mg, 0.086 mmol, 1 equiv) and 2-Chloro-1-[4-(3-fluoro-4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (7AB) (35 mg, 0.103 mmol, 1.2 equiv) were weighed out in a flask, and to it was added N,N-dimethylformamide (3 mL) and diisopropylethylamine (22 mg, 30 uL, 0.172 mmol, 2 equiv). The reaction content was stirred at room temperature, overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Nc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(Cl)c2)c1-c1ccccc1

Procedure:
m-Chloroaniline (5 mmol, 0.6 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. Upon completion of the reaction, the crude solid was recrystallized from ethanol to provide the named product (m.p. 93.2° C.-94.6° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH2:19]C)([N:7]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])C)[CH3:2].[CH:22]([N:35]1[CH2:38][C:37](OS(C)(=O)=O)([CH3:39])[CH2:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:17][C:37]3([CH3:39])[CH2:38][N:35]([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:36]3)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])[CH3:19])[CH3:2]
Reactant: CCOC(=O)C(C)(CC)N1C(=O)COc2ccc(O)cc21
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3(C)CN(C(c4ccccc4)c4ccccc4)C3)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
A mixture of ethyl 2-(6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (Example #65, Step C, 0.200 g, 0.754 mmol), methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (0.275 g, 0.829 mmol) and Cs2CO3 (0.491 g, 1.508 mmol) in DMF (8 mL) was stirred at 90° C. for 3 h. The reaction mixture was cooled to ambient temperature and poured into water (150 mL). The aqueous mixture was extracted with EtOAc (3×20 mL) and the combined organic phase was washed with brine (3×20 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% to 10% EtOAc in petroleum ether) to give 2-[6-(1-benzhydryl-3-methyl-azetidin-3-yloxy)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propionic acid ethyl ester as a white solid (0.300 g, 79%). 1H NMR (CDCl3, 400 MHz): δ 7.44 (m, 4H), 7.30 (m, 3H), 7.29 (m, 1H), 7.28 (m, 2H), 6.87 (d, J=8.8 Hz, 1H), 6.28 (d, J=8.8 Hz, 1H), 6.22 (s, 1H), 5.32 (q, J=7.2 Hz, 1H), 4.55 (d, J=17.6 Hz, 2H), 4.42 (s, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.38 (m, 2H), 3.19 (m, 2H), 1.59 (m, 6H), 1.16 (t, J=7.2 Hz, 3H).
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][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:6][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
Under argon condition, 4-bromobenzoic acid methyl ester (500 mg, 2.33 mmol), bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2; 86.1 mg, 0.116 mmol), triphenylphosphine (PPh3; 18.3 mg, 0.0698 mmol), trimethylsilyl acetylene (TMS acetylene; 493 μL, 3.49 mmol), and triethylamine (Et3N; 486 μL, 3.49 mmol) were dissolved in 10 mL of dry THF and the reaction mixture was stirred for 20 minutes at room temperature. To this cuprous iodide (CuI; 8.86 mg, 0.0465 mmol) was again added and the mixture was stirred for 15 hours at room temperature. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure and then 20 mL of n-pentane was added to the residue. The mixture was filtered through celite pad to remove the precipitate. The resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 503 mg (2.16 mmol, 93%) of the desired compound.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([O:9][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:8]
Reactant: C=C(C)C
Reactant: CC(C)(Br)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)C(C)(C)Br

Procedure:
Isobutene is condensed into a solution of 2-bromo-2-methylpropanoic acid (10 mmol) and trifluoroacetic acid (1 mmol) in 100 mL of CH2Cl2 until the starting material is consumed, as observed by TLC. The volatile components are evaporated in vacuo, and the residue is filtered through a pad of neutral alumina using 50% ether/hexane. The filtrate is concentrated in vacuo and used without further purification.
Reaction SMILES: Cl[O-:2].[Na+].[C:4]([C:7]1[C:8]([CH3:22])=[C:9]2[C:14](=[CH:15][CH:16]=1)[S:13](=[O:18])(=[O:17])[CH2:12][C:11]([CH3:20])([CH3:19])[C:10]2=[O:21])(=[O:6])C>O1CCOCC1.O>[C:4]([C:7]1[C:8]([CH3:22])=[C:9]2[C:14](=[CH:15][CH:16]=1)[S:13](=[O:17])(=[O:18])[CH2:12][C:11]([CH3:20])([CH3:19])[C:10]2=[O:21])([OH:6])=[O:2]
Reactant: CC(=O)c1ccc2c(c1C)C(=O)C(C)(C)CS2(=O)=O
Reactant: [O-]Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)ccc2c1C(=O)C(C)(C)CS2(=O)=O
Temperature: 28 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
11.6 Grams (about 9.8 mmol) of a 6.3 wt % sodium hypochlorite aqueous solution was placed in a 50-ml three-necked round-bottomed flask, and cooled to 15~20° C., and then a solution of 0.83 g (2.96 mmol) of 6-acetyl-3,3,5-trimethylthiochroman-4-one-1,1-dioxide in 5 ml of dioxane was gradually added. The mixture was stirred at 15~20° C. for 30 minutes, and then stirred at room temperature (temperature-increased to 28° C.) for 3 hours, and the reaction mixture was diluted with about 50 ml of water and washed with chloroform twice. A sodium sulfite aqueous solution was added to an aqueous layer to decompose excess hypochlorite, and then the mixture was neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution to give a white solid. The solid was extracted with ethyl acetate, and an organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, to give 0.68 g (yield 81%) of 6-carboxy-3,3,5-trimethylthiochroman-4-one-1,1-dioxide in the form of a white solid.
Reaction SMILES: Cl.CO.C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:36]4[CH:35]=[CH:34][S:33][C:32]=4[CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[C:13]([O:37][CH3:38])[CH:12]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[S:33]1[CH:34]=[CH:35][C:36]2[C:28]([N:25]3[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][O:18][C:14]4[C:15]([CH3:17])=[CH:16][C:11]([NH2:10])=[CH:12][C:13]=4[O:37][CH3:38])[CH2:27][CH2:26]3)=[CH:29][CH:30]=[CH:31][C:32]1=2
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc(C)c1OCCCN1CCN(c2cccc3sccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)cc(C)c1OCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
6N-hydrochloric acid (3 ml) was added to a methanol solution (10 ml) of {4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}-carbamic acid tert-butyl ester (2.18 g, 4.3 mmol) and the mixture was stirred at room temperature overnight. After stirred at 60° C. for 15 minutes, the mixture was cooled to room temperature and a 6N aqueous sodium hydroxide solution was added thereto to neutralize it. Dichloromethane was added to the reaction mixture, and the substance extracted with dichloromethane was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2→ethyl acetate). The purified product was concentrated to dryness under reduced pressure to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylaniline (1.26 g) as light yellow solid
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][CH2:37][CH2:38]O)=[CH:31][CH:30]=1>C(Cl)Cl.[Al]>[Br:1][CH2:38][CH2:37][O:36][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=1
Reactant: OCCOCc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(COCCBr)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solution of 2-{[(4-chlorophenyl)methyl]oxy}ethanol (129 mg, 0.691 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vial was capped, wrapped in aluminum foil, and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (98 mg, 57%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[C:14]1([C:20]2[C:28]3[C:27]([N:29]4[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]4)=[N:26][CH:25]=[N:24][C:23]=3[S:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:13][CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH:2]([OH:1])[CH2:3][NH:35][CH:32]1[CH2:33][CH2:34][N:29]([C:27]2[C:28]3[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:21][S:22][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:30][CH2:31]1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reactant: OCc1cccc(OCC2CO2)c1
Product: OCc1cccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)c1
Yield: 64 %

Procedure:
Synthesis followed SP6 (4 h), using 150 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 64% yield upon purification by prep. HPLC (reversed phase).
Reaction SMILES: [C@@H:1]12[C:7](=[O:8])[NH:6][C@@H:5]1[CH2:4][CH2:3][NH:2]2.[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[O:8]=[C:7]1[C@@H:1]2[C@@H:5]([CH2:4][CH2:3][N:2]2[C:16](=[O:17])[NH:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1N[C@@H]2CCN[C@H]12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1N[C@@H]2CCN(C(=O)Nc3ccccc3)[C@H]12

Procedure:
100 mg (0.89 mmol) of (1S,5R)-2,6-diazabicyclo[3.2.0]heptan-7-one were dissolved in 5 ml of chloroform and heated to boiling under reflux. Phenyl isocyanate (0.1 ml, 0.89 mmol) and 1 drop of triethylamine were added. thereto and the mixture was left to react at the boiling temperature for 1 hour. After concentration the residue was chromatographed over silica gel (0.063-0.2 mm particle size) with ethyl acetate:ethanol=3:2.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:38][C:39]([Si:42]([CH3:78])([CH3:77])[O:43][C@H:44]([C@@H:55]([CH3:76])[CH2:56]/[C:57](/[CH3:75])=[CH:58]\[C@H:59]([CH3:74])[C@@H:60]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[C@@H:61]([CH3:65])[CH2:62][NH:63][CH3:64])[C@H:45]([CH3:54])[C@@H:46]([OH:53])[C@@H:47]([CH3:52])/[CH:48]=[CH:49]\[CH:50]=[CH2:51])([CH3:41])[CH3:40].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:71][C:70]([Si:67]([CH3:68])([CH3:69])[O:66][C@H:60]([C@@H:59]([CH3:74])/[CH:58]=[C:57](/[CH3:75])\[CH2:56][C@H:55]([CH3:76])[C@@H:44]([O:43][Si:42]([C:39]([CH3:41])([CH3:40])[CH3:38])([CH3:78])[CH3:77])[C@H:45]([CH3:54])[C@@H:46]([OH:53])[C@@H:47]([CH3:52])/[CH:48]=[CH:49]\[CH:50]=[CH2:51])[C@@H:61]([CH3:65])[CH2:62][N:63]([CH3:64])[C:8](=[O:10])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([CH3:73])[CH3:72]
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CNC
Reactant: O=C(O)CC1CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CN(C)C(=O)CC1CCCCC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A DMF (2 mL) solution of cyclohexaneacetic acid (30.2 mg, 0.222 mmol) and BOP (131 mg, 0.296 mmol) is added to the stirred DMF (3 mL) solution of (3Z,5S,6S,7R,8R,9S,11Z,13S,14R,15S)-8,14-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5,7,9,11,13,15-hexamethyl-16-(methylamino)-1,3,11-hexadecatrien-6-ol (90 mg, 0.148 mmol) and DIEA (77 μL, 0.444 mmol) dropwise at 0° C. The solution is warmed up to 23° C. and stirred for an additional 1 hour. DMF is removed in vacuo and the residue is dissolved in EtOAc (10 mL). The organic solution is washed with H2O (1×10 mL) and brine (1×10 mL). The aqueous layer is extracted with Et2O (3×20 mL) and the combined extracts are dried (Na2SO4) and concentrated. Chromatography (SiO2, 0–30% EtOAc-hexanes gradient elution) provided the desired compound (70 mg, 65%). HRMS: ESI m/z 734.5906 (M+H+), Calcd. 734.5939.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:5][C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7].FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1)[CH2:5][C:6]([NH:8][NH2:9])=[O:7]
Reactant: CC(C)(C)OC(=O)NNC(=O)CC(CCBr)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)CC(CCBr)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl N′-[5-bromo-3-(3-trifluoromethylphenyl)pentanoyl]hydrazinecarboxylate (1.6 g) was dissolved in methylene chloride (8 mL), and trifluoroacetic acid (10 mL) was added at 0° C. The mixture was stirred at room temperature for two hours and then concentrated under reduced pressure. The resulting oil was diluted with ethyl acetate, and then washed with 1 N sodium hydroxide aqueous solution and brine and dried over magnesium sulfate. The oil after concentration under reduced pressure (990 mg) was used directly for the next reaction as a crude product.
Reaction SMILES: [CH:1](OC)([O:4][CH3:5])[O:2][CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:20][C:21]1[N:26]=[CH:25][C:24](C=O)=[CH:23][CH:22]=1>CO>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH:1]([O:4][CH3:5])[O:2][CH3:3])=[CH:25][N:26]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(OC)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
Trimethyl orthoformate (643 μl, 5.9 mmol) and p-toluene sulphonic acid monohydrate (102 mg, 0.54 mmol) were added to 6-bromo-pyridine-3-carbaldehyde (1 g, 5.37 mmol) dissolved in MeOH (40 ml). The mixture was stirred for 24 h at room temperature and then partitioned between water and Et2O. The organic extract was washed with water, 5% Na2CO3, dried over Na2SO4 and evaporated under vacuo to give 1.2 g of 2-bromo-5-dimethoxymethyl-pyridine as a brown oil.
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[CH2:9]([N:13]1[C:17](S)=[N:16][N:15]=[C:14]1[CH2:19][OH:20])[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:9]([N:13]1[CH:17]=[N:16][N:15]=[C:14]1[CH2:19][OH:20])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1c(S)nnc1CO
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCCCn1cnnc1CO
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To a mixture of 90% nitric acid (17 ml) and water (25 ml) was added sodium nitrite (0.07 g) and then 4-n-butyl-3-hydroxymethyl-5-mercapto-4H-1,2,4-triazole (10.0 g) was slowly added for 0.5 hours at 45° C. After cooling to room temperature, sodium carbonate was slowly added thereto to adjust pH to 7 at 0° C. The reaction mixure was concentrated under reduced pressure, methanol was added to the residue, and the precipitates were removed by filtration. The mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:9), to give 4-n-butyl-3-hydroxymethyl-4H-1,2,4-triazole (6.78 g) as orange oil. To 4-n-butyl-3-hydroxymethyl-4H-1,2,4-triazole (6.78 g) was slowly added thionyl chloride (44 ml) at 0° C. The mixture was heated to reflux for 1 hour, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate, to give 4-n-butyl-3-chloromethyl-4H-1,2,4-triazole hydrochloride (7.03 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9]([Mg]Br)[CH3:10]>C1COCC1>[CH2:9]([CH:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[OH:8])[CH3:10]
Reactant: CC[Mg]Br
Reactant: Cc1ccc(C=O)s1
Solvent: C1CCOC1
Product: CCC(O)c1ccc(C)s1
Temperature: -78 °C

Procedure:
5-Methyl-2-thiophenecarboxaldehyde (10.0 g) is dissolved in THF and cooled to -78° C. To that solution is added ethyl magnesium bromide (1M in hexane; 80 cc) dropwise over several minutes. The cooling bath is removed and the reaction allowed to equilbrate to room temperature. The reaction is quenched by adding a saturated solution of NH4Cl. The reaction is extracted with ether, dried and evaporated to yield the title product as an almost colorless oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16]>>[Br:1][CH2:2][CH2:3][O:5][N:6]1[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]2[C:10]1=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCCBr
Product: O=C1c2ccccc2C(=O)N1OCCBr

Procedure:
The compound N-(2-bromoethoxy)phtalimide was prepared analogously from 1,2-dibromoethane and N-hydroxyphtalimide.
Reaction SMILES: O.[C:2]([O:6][C:7](=[O:14])[N:8]([N:12]=O)[CH:9]1[CH2:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].[Cl-].[NH4+]>CO.[Zn]>[C:2]([O:6][C:7]([N:8]([CH:9]1[CH2:10][CH2:11]1)[NH2:12])=[O:14])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(N=O)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(N)C1CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
Water (24 mL) was added over 1 min to a mixture of N-nitroso-N-cyclopropyl-carbamic acid tert-butyl ester (2.01 g, 10.8 mmol), zinc powder (7.2 g, 110 mmol) and ammonium chloride (8.8 g, 165 mmol) in methanol (48 mL). An exotherm and gas evolution were noted. The mixture was stirred at room temperature for 2.25 h and at 50° C. for 2 h. The mixture was allowed to cool. It was filtered through Celite, and the Celite was washed well with methanol. The colvents were evaporated and dichloromethane (250 mL) was added. Salts were filtered off and the solution was dried (magnesium sulfate), filtered, and evaporated. The residue was passed through a cotton plug with a small amount of dichloromethane, the solvent was evaporated to give a clear oil. This was purified by chromatography using an ISCO 120 g column, eluting with 10-60% ethyl acetate/hexanes to give N-cyclopropyl-hydrazinecarboxylic acid tert-butyl ester (207 mg, 11%) as a pale yellow oil, along with a 36% yield of over-reduced cyclopropyl-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:8]2)(=[O:4])=[O:3].C1C(=O)N([Br:30])C(=O)C1>CC#N>[Br:30][C:11]1[C:12]2[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(S(C)(=O)=O)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2cc(S(C)(=O)=O)ccc2c1Br
Yield: 86 %

Procedure:
A mixture of 161 (4.47 g, 13.91 mmol) and NBS (2.72 g, 1528 mmol) in MeCN (80 mL) was stirred at reflux for 3 h, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and the solution was washed with 10% aqueous Na2SO3 and water, dried, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2Cl2, to give tert-butyl 1-bromo-6-(methylsulfonyl)-2-naphthylcarbamate (162) (4.79 g, 86%) as a white solid: mp (MeOH) 190° C.; 1H NMR [(CD3)2SO] δ 8.95 (s, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.08 (dd, J=9.0, 1.9 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 3.25 (after D2O exchange, s, 3H), 1.50 (s, 9H). Anal. (C16H18BrNO4S) C, H, N.