Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][N:9]=1>>[CH3:15][O:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: COc1cccnc1Br
Product: COc1cccnc1N1CCNCC1
Yield: 82 %

Procedure:
Anhydrous piperazine (45.6 g) and 2-bromo-3-methoxypyridine (10.0 g) were heated neat in an autoclave at 100° C. for 20 h. Upon cooling, the mixture was treated with 5% NaCO3 (20 mL) and extracted with CH2Cl2 (3×50 mL). The extracts were dried using anhydrous K2CO3, filtered, and concentrated under reduced pressure to yield 1-(3-methoxy-2pyridinyl)piperazine (III; 8.43 g; 82%) after silica gel chromatography (CH2Cl2/MeOH/NH4OH; 93:7:0.7).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20]([C:22]2[C:23]([S:28][CH3:29])=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:14][CH2:13]1>ClCCl>[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20]([C:22]2[C:23]([S:28]([CH3:29])=[O:6])=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:13][CH2:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncccc1C(=O)c1cnoc1C1CC1
Solvent: ClCCl
Product: CS(=O)c1ncccc1C(=O)c1cnoc1C1CC1
Temperature: -20 °C

Procedure:
3-Chloroperoxybenzoic acid, an oxidant (2.85 g), was added to a stirred solution of 5-cyclopropyl-4-(2-methylsulphenylpyridin-3-oyl)isoxazole (236 g) in dichloromethane at -20° C. A further quantity of the oxidant (0.14 g) was added after 5 minutes. The reaction mixture was stirred at -20° C. until analysis (by thin layer chromatography) indicated reaction was complete. The mixture was filtered and the filtrate was washed successively with aqueous sodium bicarbonate solution and aqueous sodium metabisulphite solution, dried (anhydrous magnesium sulphate), filtered and evaporated. The crude product was suspended in refluxing acetonitrile. The suspension was cooled to room temperature and filtered. The product was dried to yield 5-cyclopropyl-4-(2-methylsulphinylpyridin-3-oyl)isoxazole (compound 7, 2.0 g) as colourless crystals, m.p.148°-152.4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:20]2[CH2:19][CH2:18][CH:17]([CH2:16][O:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[O:12][CH3:11])[CH2:22][CH2:21]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CCl
Reactant: COc1ccccc1OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1OCC1CCN(Cc2cccnc2OC)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
200 mg of 2-methoxy-3-(chloromethyl)pyridine, 380 mg of 4-[(2-methoxyphenoxy)methyl]piperidine and 235 mg of potassium carbonate were added in 10 ml of acetonitrile, and the mixture were stirred at room temperature for 3 hours 15 minutes. After filtering the reaction solution, the solvent was evaporated, and the crude product was purified by silica gel column chromatography (hexane:ethyl acetate=3:2), to give 359 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][C:11]([Si](C(C)C)(C(C)C)C(C)C)=[N:10][CH:9]=2)[N:5]2[N:23]=[CH:24][C:25]([C:26]([N:28]3[CH2:33][C@@H:32]4[CH2:34][C@H:29]3[CH2:30][O:31]4)=[O:27])=[C:4]2[CH:3]=1.Cl.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)[N:5]2[N:23]=[CH:24][C:25]([C:26]([N:28]3[CH2:33][C@@H:32]4[CH2:34][C@H:29]3[CH2:30][O:31]4)=[O:27])=[C:4]2[CH:3]=1
Reactant: Cc1cc(-c2cnc([Si](C(C)C)(C(C)C)C(C)C)o2)n2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)c2c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(-c2cnco2)n2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl(7-iodo-5-methylpyrazolo[1,5-a]pyridin-3-yl)methanone (300 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (330 mg), tetrakis(triphenylphosphine)palladium(0) (90 mg) and 3N aqueous potassium carbonate solution (0.522 mL) in DME (3 mL) was stirred with microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give (5-methyl-7-(2-(triisopropylsilyl)-1,3-oxazol-5-yl)pyrazolo[1,5-a]pyridin-3-yl)((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methanone. The obtained (5-methyl-7-(2-(triisopropylsilyl)-1,3-oxazol-5-yl)pyrazolo[1,5-a]pyridin-3-yl)((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methanone was dissolved in THF (3 mL), and 1N hydrochloric acid was added thereto. The reaction mixture was stirred at room temperature for 30 min, saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (83 mg).
Reaction SMILES: [CH3:1][O:2]CC1NC(=O)C2C(=CC=CC=2)N=1.[N+:15]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([CH2:28]CC)[N:22]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[N:48]([C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:47]=[N:46][N:45]=3)=[CH:34][CH:33]=1)[C:21]2=[O:68])([O-:17])=[O:16]>>[CH3:1][O:2][CH2:28][C:23]1[N:22]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[N:48]([C:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[N:47]=[N:46][N:45]=3)=[CH:34][CH:33]=2)[C:21](=[O:68])[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[N:24]=1
Reactant: CCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COCc1nc2ccccc2c(=O)[nH]1
Product: COCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
2-methoxymethylquinazolin-4(3H)-one was alkylated in the same manner as described above for 6-nitro-2-n-propyl-3-[(2'-(N-triphenylmethyl-tetrazol-5-yl)-biphen-4-yl)-methyl]-quinazolin-4(3H)-one to give the title compound. 200 MHz-1H-NMR (CDCl3):3.43 (s, 3H), 4.36 (s, 2H), 5.46 (bs, 2H), 6.90 (m, 6H), 7.00 (d, 2H, J=8.2 Hz), 7.12 (d, 2H, J=8.2 H ), 7.19-7.38 (m, 10H), 7.48 (m, 2H), 7.84(d, 1H, J=8.9 Hz), 7.92 (m, 1H), 8.56 (dd, 1H, J=2.7, 9.01 Hz), 9.20 (d, 1H, J=2.6 Hz).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:20][O:21][CH2:22][CH2:23][C:24](Cl)=O.O.[NH2:28][NH2:29]>C1(C)C=CC=CC=1.C(O)C>[CH3:20][O:21][CH2:22][CH2:23][C:24]1[NH:29][N:28]=[CH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCc1ccccc1
Reactant: NN
Reactant: COCCC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCc1[nH]ncc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
To a solution of 2-phenylacetaldehyde (4.0 g, 33.3 mmol) in toluene (10 mL), were added LiHMDS (33.3 mL, 33.3 mmol) at 0° C. After stirring for 10 min, 3-methoxypropanoyl chloride (4.08 g, 33.3 mmol) was added and continued stirring for 30 min at 0° C. The reaction was quenched with acetic acid (glacial, 2 mL), diluted with ethanol (75 mL), and hydrazine hydrate (5.00 g, 100 mmol) was added. The reaction was brought to reflux for 4 hrs. After cooling to room temperature, the reaction was concentrated and extracted with EtOAc, dried over MgSO4, and purified by column chromatography to give the title compound as yellowish oil (2.5 g). LCMS m/z 203.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.85 (t, J=6.69 Hz, 2H), 3.17 (s, 3H), 3.48 (t, J=6.63 Hz, 2H), 5.75 (s, 1H), 7.31-7.38 (m, 3H), 7.41-7.47 (m, 2H), 13.08 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:27]=1)#[N:2].[SH2:28]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:27]=1)(=[S:28])[NH2:2]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(NC(=O)c2cc3cc(C(N)=S)ccc3o2)cc1
Reaction time: 16 h

Procedure:
Ethyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate (1.49 g, 4.09 mmol) was dissolved in a mixed solvent of pyridine (50 ml) and triethylamine (5 ml). A hydrogen sulfide gas was blown in for 10 minutes at room temperature and the mixture was stirred for 16 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give ethyl 4-[(5-thiocarbamoyl-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. Acetone (100 ml) and iodomethane (10 ml) were added to this solid, and the mixture was refluxed under heating for 2 hours. The reaction mixture was heated to room temperature. The resulting precipitate was collected by filtration to give ethyl 4-[[5-[(1-methylthio)iminomethyl]-2-benzofuranyl]carbonylamino]phenoxyacetate as a yellow solid. To this solid was added ethanol (50 ml) and benzylamine (0.5 ml, 4.6 mmol), and the mixture was refluxed under heating for 2 hours. The reaction mixture was concentrated to about 10 ml under reduced pressure, and diethyl ether (40 ml) was added. The resulting precipitate was collected by filtration to give 1.70 g of hydriodide of compound (1) as a yellow solid (69% in three steps).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C:17](=[O:21])[C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH-].[Na+].CC(OC)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([OH:21])[C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(CC(=O)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCc1cc(C[C@@H](O)C(=O)O)cc(C)c1OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.08 h

Procedure:
Under an argon atmosphere a solution of 9.59 g (30.7 mmol) 3-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-2-oxo-propionic acid in 25 mL THF was combined with 4.26 mL (31.0 mmol) triethylamine, stirred for 5 min and cooled to −30° C. (internal temperature). A solution of 19.7 g (61.0 mmol) (1R)-B-chlorodiisopinocampheylborane in 35 mL THF was added dropwise and after the end of the addition the reaction solution was stirred for 30 min without cooling. 15 mL 4 N NaOH was added (temperature rose to 20° C.), the mixture was stirred for 5 min, cooled to 0° C., combined with 50 mL MTBE and stirred for 20 min. The organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was further reacted without purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:19]2[CH2:28][CH2:27][C:22]3(OCC[O:23]3)[CH2:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:19]2[CH2:28][CH2:27][C:22](=[O:23])[CH2:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1cc(C2=CCC3(CC2)OCCO3)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C2=CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 68 %

Procedure:
A solution of 20% TFA in DCM (25 mL) was added to 8-[3-(methyloxy)-4-nitrophenyl]-1,4-dioxaspiro[4.5]dec-7-ene (900 mg, 3.09 mmol) and the mixture was stirred at rt for approximately 14 h. The reaction was then concentrated under vacuum. The residue was dissolved in EtOAc and aqueous (saturated) NaHCO3. The organic layer was separated, washed with H2O, dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step D (520 mg, 2.10 mmol, 68%) as a tan solid. MS (ESI): 248 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.ClC(Cl)(Cl)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.CCN(C(C)C)C(C)C>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(CC(F)(F)F)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.17 g, 0.34 mmol) in DMF (1.5 mL) was added 2,2,2-trifluoroethyl trichloromethanesulfonate (0.19 g, 0.68 mmol), followed by iPr2NEt (0.24 mL, 1.36 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was poured into brine and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) afforded the desired product, 3a, as a white solid.
Reaction SMILES: Cl.[C:2]([NH2:8])(=[NH:7])[C:3]([CH3:6])([CH3:5])[CH3:4].C[O-].[Na+].C[O:13][CH:14]=[C:15]([C:20](OC)=O)[C:16]([O:18][CH3:19])=[O:17]>CO>[C:3]([C:2]1[N:8]=[C:14]([OH:13])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][N:7]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)C(=N)N
Reactant: COC=C(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(C(C)(C)C)nc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
Pivalamidine hydrochloride (5.00 g, 37 mmol) dissolved in methanol (80 mL) was treated with NaOMe (2.0 g, 37 mmol) and stirred at RT for 15 min. To this was added dimethyl 2-(methoxymethylene)malonate (6.4 g, 37 mmol) and the solution stirred at RT overnight. The solution was heated at reflux for 1 h, then cooled to RT and concentrated. The oily mass was dissolved in H2O (125 mL) and the pH adjusted to ˜3 (wet litmus) with AcOH. The precipitated solids were collected by filtration, washed with H2O (50 mL) and dried to yield methyl 2-t-butyl-4-hydroxypyrimidine-5-carboxylate (3.50 g, 45%). 1H NMR (400 MHz, DMSO-d6): δ 1.29 (s, 9H), 2.97 (s, 3H), 8.47 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:11]Br>>[Br:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: BrBr
Product: BrC12CC3CC(CC(C3)C1)C2

Procedure:
The reaction was conducted in accordance with the method of The Japanese Patent Publication No. 61980/1995 (JP-B-7-61980) to obtain an adamantane monoaclylate, namely, 15 mole of anhydrousbromine and 1.6 mole of adamantane were reacted at the reflux temperature of bromine for 7 hours, surplus bromine was distilled off under reduced pressure, and after the addition of 200 ml of carbon tetrachloride (IV), the residual bromine was resolved with sodium sulfite. A white powderly 1-bromoadamantane was provided by removing organic layer, and recrystallizing the obtained crude products from methanol.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])([CH3:5])[CH2:3]N.C=O.[C:21](O)(=O)C.[C:25]([BH3-])#[N:26].[Na+]>CO.O.ClCCl>[CH3:21][N:26]([CH3:25])[CH2:1][C:2]([CH3:5])([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH3:3]
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: CC(C)(CN)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CN(C)CC(C)(C)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-Methyl-2-(2-nitro-4-trifluoromethyl-phenyl)-propylamine (0.76 g, 2.9 mmol) in methanol (29 mL) at 0 degrees C. was added formaldehyde (0.60 mL of a 37 wt % solution in water, excess), acetic acid (0.83 mL, 14.5 mmol), and sodium cyanoborohydride (0.36 g, 5.8 mmol). The homogeneous yellow solution was allowed to warm to room temperature and was stirred overnight. After approximately 12 h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate until basic. The mixture was concentrated in vacuo, and the resulting material was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed once with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow oil which contained solid material. The oil was dissolved in dichloromethane and filtered through a plug of cotton. Purification by flash chromatography provided the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8](Br)[C:7]1=[O:13])[CH3:2].Cl.[N:16]([CH2:19][C@@H:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:17]=[N-:18].C(OC(N[C@@H](CC1C=CC=CC=1)CO)=O)(C)(C)C.C(N(CC)CC)C>CCO>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:28][C@H:20]([CH2:19][N:16]=[N+:17]=[N-:18])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]1=[O:13])[CH3:2]
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)Cn1ccnc(Br)c1=O
Agent: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1ccnc(N[C@H](CN=[N+]=[N-])Cc2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 72 h

Procedure:
To a solution of (3-bromo-2-oxo-2H-pyrazin-1-yl)-acetic acid ethyl ester (8.75 g, 33.5 mmol, preparation described in example 17, step J) in EtOH (60 ml) was added (S)-1-azidomethyl-2-phenyl-ethylamine hydrochloride (7.5 g, 35.3 mmol, prepared from (S)-(−)-2-(tertbutoxycarbonylamino)-3-phenyl-1-propanol following the procedure of Horwell et al (J. Med. Chem. 1991, 34, 404–414) and Boc removal under standard HCl(g) conditions) and triethylamine (10.8 ml, 77.6 mmol). The pressure flask was flushed with argon, sealed and the reaction mixture was stirred at 110° C. for 3 days. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 20% EtOAc in hexane to 40%) to give (S)-[3-(1-azidomethyl-2-phenylethylamino)-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester as a brown syrup. 1H NMR (CDCl3, 400 MHz): δ 7.36–7.20 (m, 5H); 6.85 (d, J=4.4 Hz, 1H); 6.41 (d, J=4.4 Hz, 1H); 6.20 (bd, J=8 Hz, 1H); 4.58 (A of AB, d, J=17.5 Hz, 1H));); 4.52 (B of AB, d, J=17.5 Hz, 1H)); 4.43–4.33 (m, 1H); 4.25 (q, J=7.3 Hz, 2H); 3.52 (A of ABX, dd, J=12.5, 5 Hz, 1H); 3.40 (B of ABX, dd, J=12.5, 5 Hz, 1H); 3.00 (A of ABX, dd, J=14, 6.7 Hz, 1H); 2.92 (B of ABX, dd, J=14, 7.9 Hz, 1H); 1.29 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(=S)=S>[C:19]1([CH2:25][C:26]([C:4]2[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:2][CH:3]=2)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CCCCc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
To a solution of 5.12 g of methyl 5-phenylvalerate in 25 ml of carbon disulfide, 7.10 g of anhydrous aluminium chloride was added under ice-cooling, and then 4.11 g of phenylacetyl chloride was added dropwise and stirring was continued at room temperature for 6 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride layer was washed successively with water, aqueous potassium carbonate solution and water, dried, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride:n-hexane=2:1) to afford 5.45 g of colorless crystals. Recrystallization from isopropyl ether gave colorless flakes, mp 53.5°~54° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:38])[C:30]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:37])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:37])[C:30]=1[C:29](=[O:38])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Reactant: Cc1cccc(C)c1C(=O)NC(C)(C)C
Product: Cc1cccc(CC(=O)[C@@H](Cc2ccccc2F)NC(=O)OC(C)(C)C)c1C(=O)NC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (2.65 g, 8.1 mmol) and N-tert-butyl-2,6-dimethyl-benzamide (5.0 g, 24 mmol), followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[N:6]=[C:5]2[CH3:11]
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn(COCC[Si](C)(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of 5-bromo-3-methylindazole 104 (2 g, 9.48 mmol) in anhydrous DMF (20 mL), cooled in ice bath, was added-sodium hydride (60% w/w, 0.57 g, 14.25 mmol) and (2-trimethylsilylethoxy)methyl chloride (2.5 mL, 14.16 mmol) in a dropwise manner. The reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. Ethyl acetate (200 mL) was added. The organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-bromo-3-methyl-N-(2-trimethylsilanylethoxymethyl)indazole 116 (2.95 g, 8.65 mmol) as a mixture of the 1H- and 2H-indazole regioisomers.