Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:15])[CH2:10][CH2:11][N:12]([CH3:14])C.[Br:16][C:17]1[CH:18]=C([CH:21]=[CH:22][CH:23]=1)N>C(O)C.O>[Br:16][C:17]1[CH:18]=[C:14]([NH:12][CH2:11][CH2:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])=[O:15])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Br)c1
Reactant: CN(C)CCC(=O)c1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(CCNc1cccc(Br)c1)c1ccccc1Cl
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 1-(2-chlorophenyl)-3-(dimethylamino)propan-1-one HCl salt (5.17 g, 20.85 mmol) and 3-bromoaniline (2.27 mL, 1 equiv) in 1:1 ethanol/water (21 mL, 1.0M) was heated at reflux overnight. LC-MS found the starting material was gone. The reaction mixture was cooled to rt. The ethanol was removed in vacuo. The residue was partitioned between EtOAc and water. The organic layer was washed with 1% aq HCl (2×30 mL), satd aq NaHCO3 solution (20 mL), brine (20 mL), and dried over Na2SO4. After filtration and concentration, the residue (6.08 g) was purified by chromatography on a 120-g silica cartridge to afford 3-(3-bromophenylamino)-1-(2-chlorophenyl)propan-1-one (2.75 g, 40% yield) as an orange oil. LC-MS (3 min) tR=2.03 min, m/z=340, 341(M+1); 1H NMR (CDCl3) δ 7.47(d, 1H), 7.44-7.38 (m, 2H), 7.33 (td, 1H), 7.00 (m, 1H), 6.84 (m, 1H), 6.77 (s, 1H), 6.56 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20](Cl)=[O:21])=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[NH:24][C:25](=[NH:28])[CH2:26][CH3:27].CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH2:26]([C:25]1[N:28]=[C:20]([C:18]2[CH:17]=[N:16][C:12]3[O:13][CH2:14][CH2:15][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[C:11]=3[CH:19]=2)[O:21][N:24]=1)[CH3:27]
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Reactant: CCC(=N)NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1noc(-c2cnc3c(c2)N(S(=O)(=O)c2ccccc2)CCO3)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a solution of 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (40 mg, 0.118 mmol; Example 1, Step 1) in DCM (2 mL) was added N-hydroxypropionimidamide (20.81 mg, 0.236 mmol) and DIPEA (50 μL, 0.286 mmol). The reaction was stirred at room temperature for 16 hours. LCMS analysis of the reaction mixture indicated consumption of starting material. The reaction mixture was treated with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (3×10 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was diluted with THF (5 mL) and TBAF in THF (118 μL, 0.118 mmol) was added. The reaction was then stirred overnight. The reaction mixture was concentrated in vacuo and the resulting paste was purified by flash column chromatography using a gradient elution of hexanes with 30-100% EtOAc to provide 7-(3-ethyl-1,2,4-oxadiazol-5-yl)-1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (29.7 mg, 0.076 mmol, 64.2% yield) as a white solid. LCMS (+ESI) m/z=373.0 [M+H]+; 1H-NMR (CDCl3) δ 8.87 (d, 1H), 8.77 (d, 1H), 7.71 (m, 2H), 7.63 (tt, 1H) 7.51 (m, 2H), 4.01 (m, 2H), 3.92 (m, 2H), 2.84 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[CH2:20][NH2:21].Cl.C1(C2N=NC(CN)=CC=2)C=CC=CC=1>>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[CH2:20][NH:21][S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NCc1cc2ccccc2o1
Agent: Cl
Agent: NCc1ccc(-c2ccccc2)nn1
Product: O=S(=O)(NCc1cc2ccccc2o1)c1cccnc1
Yield: 95.6 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 2-(d) except for using 3-pyridylsulfonyl chloride (154 mg, 0.867 mmol), and using (benzofuran-2-ylmethyl)amine (128 mg, 0.870 mmol) obtained in Reference Example 10-(b) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride to afford the title compound (239 mg) as a white solid. (Yield: 96%)
Reaction SMILES: [C:1]1([CH:7]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:17])CO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.[CH3:26]N(C=O)C>>[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[CH:26]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10]2=[O:17])=[CH:20][CH:19]=1
Reactant: NCc1ccncc1
Reactant: O=C1COC(c2ccccc2)c2ncccc21
Reactant: CN(C)C=O
Product: O=c1c2cccnc2c(-c2ccccc2)cn1Cc1ccncc1
Yield: 48 %

Procedure:
To a solution of 8 -phenylpyrano [3,4-b]pyridin-5-one (102 mg, 0.46 mmoles) in 2 ml DMF was added 4-picolylamine (0.055 ml, 0.55 mmoles) under nitrogen. The reaction mixture was heated overnight to 80° C., cooled and then concentrated under vacuum to give 0,335 g crude product which was chromatographed eluting with 1:1 ethyl acetate/hexanes to give 69 mg (48% yield) of the desired 6-(4-pyridylmethyl)-8-phenyl-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 199.5°-200.5° C.; 1H NMR (CDCl3,300 MHz) δ5.30 (s, 2H), 7.26 (d, 2H, J=6), 7.34-7.59 (m, 7H), 8.6 (d, 2H, J=6), 8.78 (dd, 1H, J=8.04, 2.00), 8.99 (dd, 1H, J=4.39, 1.83); 13C NMR (75 MHz, CDCl3) δ161.90, 154.52, 152.09, 150.08, 145.44, 136.72, 134.77, 133.67, 129.96, 128.40, 127.92, 122.44, 122.16, 121.90, 121.81, 51.18; IR (KBr) vmax 3445, 1655, 1624, 1599, 1437, 1421, 1373, 1169, 1099, 993,922, 868, 794, 763, 727, 707, 677, 607, 598, 522 cm-1 ; mass spectrum (EI), m/e 313. Anal. (C20H15N3O 3/4 H2O) Calcd.: C, 73.49; H, 5.09; N, 12.86. Found: C, 73.73; H, 4.99; N, 12.36.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[CH2:12]([Mg]Br)[CH3:13].O.Cl>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1)[CH3:13]
Reactant: CC[Mg]Br
Reactant: Cc1cn2nc(Cl)ccc2n1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCc1ccc2nc(C)cn2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
6-Chloro-2-methylimidazo[1,2-b]pyridazine (5.00 g, 29.8 mmol) and [1,3-bis(diphenylphosphino)propane]nickel (II) dichloride (0.08 g, 0.15 mmol) were suspended in dry ether (40 ml)-dry THF (20 ml) and then stirred under ice-cooling, during which a solution of ethylmagnesium bromide in ether (3 M, 15 ml, 45 mmol) was added dropwise thereto over 5 minutes (internal temperature 10° C. or less). The temperature of the reaction solution was increased to room temperature, and the mixture was stirred at the same temperature for 2 hours and under reflux with heating for 3 hours. The reaction solution, while being stirred, was left and cooled to room temperature, and water (30 ml) was added little by little. Further, the reaction mixture was stirred at room temperature and adjusted to about pH 5 to 6 with conc. hydrochloric acid. The organic layer and the aqueous layer were separated from each other, and the aqueous layer was extracted with ethyl acetate (70 ml×2). The organic layers were combined and washed with water (250 ml×3). The organic layer was dried over magnesium sulfate and concentrated, and the residues were purified by silica gel column chromatography (chloroform:ethyl acetate=2:1→1:1), and the resulting crude oil was further purified by silica gel column chromatography (ethyl acetate), and the title compound was obtained as pale red oil. The yield was 1.32 g (27.4%).
Reaction SMILES: Cl.C1(P(=CC(C=NN)=[O:23])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.N([O-])=[O:28].[Na+].[O:31]1C[CH2:34][CH2:33][CH2:32]1>O>[OH2:23].[CH:15]1([CH2:34][C:33]([CH:32]=[O:31])=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=N[O-]
Reactant: NN=CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=CC(=O)CC1CCCCC1
Temperature: 0 °C

Procedure:
77 ml of 2N hydrochloric acid are added slowly, with stirring and cooling to 10°-13° (ice-water bath), to a mixture of 15 g of 1-cyclohexyl-3-(triphenylphosphoranylidene-hydrazono-acetone and 7.37 g of sodium nitrite in 120 ml of tetrahydrofuran and 42 ml of water. After another 30 minutes at room temperature the organic solution is separated and the aqueous phase is extracted with methylene chloride. The combined organic solutions are dried over sodium sulphate and evaporated under reduced pressure. The syrupy residue is treated with ether, the resulting triphenyl phosphinoxide is filtered off and the filtrate is evaporated. The residue is chromatographed on a column of 120 g of acid-washed silica gel, elution being carried out with about 3000 ml of a 97:3-mixture of hexane and ethyl acetate to yield the cyclohexylmethyl-glyoxal hydrate as a syrupy product; infra-red absorption spectrum (in methylene chloride): characteristic bands at 2.90-4.1μ (broad); 3.47μ, 3.53μ and 5.80μ; the product is further processed without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[CH:24]12[O:31][CH:28]([CH2:29][CH2:30]1)[CH2:27][NH:26][CH2:25]2.C(N(CC)CC)C>C(O)C>[CH:20]([N:17]1[C:4]2=[N:5][C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[N:7][C:2]([N:26]3[CH2:25][CH:24]4[O:31][CH:28]([CH2:29][CH2:30]4)[CH2:27]3)=[C:3]2[CH:19]=[N:18]1)([CH3:22])[CH3:21]
Reactant: C1CC2CNCC1O2
Reactant: CC(C)n1ncc2c(Cl)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Temperature: 140 °C

Procedure:
A suspension of crude 4-chloro-1-isopropyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidine (2.5 mmol maximum) and 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (0.47 g, 3.1 mmol) in ethanol (12 mL) was treated with triethylamine (1.1 mL) and then heated for 20 minutes in the microwave reactor at 140° C. At the completion of the reaction, the mixture was refrigerated overnight before collection of the precipitate via Buchner filtration. The solid was washed with methanol and dried under house vacuum to provide 3-(1-isopropyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane as a yellow powder (0.96 g, 97% over 2 steps). MS (ES+): 394.9, 396.0 (M+H)+
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C(O)(C)C>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:2]/[C:1]([C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cncnc1
Solvent: CC(C)O
Product: CN(C)/C=C/C(=O)c1cncnc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 68.8 %

Procedure:
5-Acetylpyrimidine (1 g, 8.2 mmol) and N,N-dimethylformamide dimethyl acetal (1.3 g, 11 mmol) were dissolved in 20 mL of isopropanol. The solution was stirred at 100° C. for 24 hours, cooled to room temperature, and concentrated under reduced pressure. Ethyl ether was then added to the residue. After being cooled in an ice bath for a couple of hours, the solid was collected by filtration, rinsed with cold ethyl ether, dried in vacuum to obtain 1 g (59% yield) of the title compound. MS (M+1)=178.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:13]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCC(=O)N2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C2CCCN2)c1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a solution of 5-(3-methoxyphenyl)-2-pyrrolidinone (7.0 g) in dry tetrahydrofuran (280 ml) was added lithium aluminum hydride (55 ml of 1.0 M soln.) dropwise at ambient temperature, under nitrogen. The reaction mixture was warmed under reflux for 2 hrs. After cooling to ambient temperature, the reaction was quenched with 10% aqueous tetrahydrofuran (60 ml) followed by 10% sodium hydroxide solution (50 ml). The suspension was filtered through a pad of celite and the filter cake was washed with dichloromethane. The combined filtrates were concentrated. The concentrate was dried over anhydrous potassium carbonate, and filtered. The filtrate was concentrated to give 6.3 g (96%) of 2-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH3:21])[C:11]([CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])(=[O:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH:26]=O>[OH-].[Na+].CO>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]([CH3:21])[C:11]([CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[O:12])=[O:3])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: CC(=O)c1ccccc1N(C)C(=O)CNC(=O)C(C)(C)C
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)CNC(=O)C(C)(C)C)c1ccccc1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Yield: 27.9 %

Procedure:
5 drops of 3M sodium hydroxide solution were added to a mixture of 160 mg (0.52 mmol) of N-[[N-(2-acetylphenyl)-N-methylcarbamoyl]methyl]pivalamide and 100 mg (0.57 mmol) of 3,4-dichlorobenzaldehyde in 3 ml of methanol. After 1 hr at room temperature the solvent was removed by evaporation and the residue chromatographed on silica gel using ethyl acetate/petrol (55:45) for the elution. There was obtained 65 mg of (E)-N-[[N-[2-[3-(3,4-dichlorophenyl)acryloyl]phenyl]-N-methylcarbamoyl]methyl]pivalamide as a yellow gum. MS: m/e 463 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[H][H].C1CCCCC=1>C(O)C.[Pd]>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[C:7]([NH2:8])=[CH:6][C:5]([NH2:11])=[CH:4][N:3]=2)[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CN1CCN(c2ncc(N)cc2N)CC1

Procedure:
2 g of 1-(3,5-dinitropyrid-2-yl)-4-methylpiperazine, obtained according to Protocol A from 2-chloro-3,5-dinitropyridine and 4-methylpiperazine, were reduced by hydrogen transfer in 50 ml of ethanol in the presence of palladium-on-charcoal and 5 ml of cyclohexene. 1.63 g of 2-(4-methylpiperazin-1-yl)pyridine-3,5-diamine were obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].N>C(O)C.[Ni]>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][NH2:9]
Reactant: N#Cc1ccccc1-c1ncc[nH]1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1ccccc1-c1ncc[nH]1

Procedure:
A solution of 2-(1H-imidazol-2-yl)-benzonitrile (50 mg, 0.30 mmol) in ethanol saturated with ammonia (5 ml) was stirred in the presence of Raney nickel (50% slurry in water, washed with ethanol, catalytic amount) under a hydrogen atmosphere for 2 h. The reaction mixture was filtered over celite and concentrated to give 2-(1H-imidazol-2-yl)-benzylamine; 1H NMR (CDCl3, 400 MHz) δ8.13 (d, 1H, J=7.5 Hz), 7.42 (m, 1H), 7.28 (m, 2H), 7.18 (bs, 2H), 3.96 (s, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:29]([C:30]([C:32]3[CH:49]=[CH:48][C:35]([CH2:36][NH:37][C:38](=[O:47])[CH2:39][CH2:40][CH:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[CH:34][C:33]=3[CH3:50])=[O:31])[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:51])[C:23]=3[NH:22][C:21]=2[CH:52]=1>ClCCl.C(N(CC)CC)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([N:44]2[CH2:45][CH2:46][CH:41]([CH2:40][CH2:39][C:38](=[O:47])[NH:37][CH2:36][C:35]3[CH:48]=[CH:49][C:32]([C:30]([N:29]4[CH2:28][C:27]5[CH:26]=[N:25][N:24]([CH3:51])[C:23]=5[NH:22][C:21]5[CH:52]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]4=5)=[O:31])=[C:33]([CH3:50])[CH:34]=3)[CH2:42][CH2:43]2)=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(CNC(=O)CCC2CCNCC2)ccc1C(=O)N1Cc2cnn(C)c2Nc2cc(Cl)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(CNC(=O)CCC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)ccc1C(=O)N1Cc2cnn(C)c2Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 1108) (2.97 mg, 0.005 mmol) in dichloro-methane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then sol-vents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=700.5, 702.5
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[N:12]O)[CH2:3]1)[CH2:9]2.[H][H]>CCO.[Rh]>[NH2:12][CH:5]1[CH:6]2[CH2:11][C:2]3([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]1[CH2:3]3)[CH2:7]2
Reactant: [H][H]
Reactant: ON=C1C2CC3CC1CC(O)(C3)C2
Agent: [Rh]
Solvent: CCO
Product: NC1C2CC3CC1CC(O)(C3)C2
Yield: 97.8 %

Procedure:
Rh/Al2O3 (2.3 g, 5 wt. %, 1.1 mmol) was added to a mixture of 5-hydroxy-admantane-2-one oxime (10 g, 55 mmol) in EtOH (100 mL) in a Parr hydrogenation bottle. The hydrogenation reaction was performed in a Parr hydrogenation instrument at 55 psi pressure of hydrogen at 50° C. for 48 hours. The disappearance of starting material and generation of the product were detected by LC-MS. The mixture was filtered through celite and concentrated under vacuum to dryness to give 4-amino-adamantan-1-ol (about 9 g, ˜98%) which was used for the next step without further purification. Mass spectrum: m/z: 168.1 (M+1).
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])=[C:10]([F:22])[C:9]([CH2:23]O)=[CH:8][CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[C:11]([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:16]#[N:17])=[C:10]([F:22])[C:9]([CH2:23][Br:2])=[CH:8][CH:7]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CO)c2F)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CBr)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of PBr3 (0.74 mL of a 1 M solution in DCM, 1.1 equiv) was added to a solution of 107 (0.24 g, 0.67 mmol) in DCM (5 mL). The mixture was stirred at RT for 1 h and then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3, and dried (MgSO4). Evaporation of the volatile materials afforded 0.17 g (60%) of 96.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]([NH:11]C(=O)OC(C)(C)C)=[N:9][CH:10]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][CH2:3][C:1]#[N:2])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(CCC#N)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCCc1cnc(N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 5-(2-cyanoethyl)pyrazin-2-ylcarbamate (25 mg, 0.101 mmol) in DCM (0.336 mL) was added TFA (0.1 mL, 1.298 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After quenched with sat. NaHCO3, the reaction mixture was extracted with DCM. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was used in next step reaction without purification. LCMS (m/z): 149.1 (MH+), 0.24 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][C:6]1([CH2:29][OH:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(N(CC)CC)C.C1COCC1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:35]([O:30][CH2:29][C:6]1([CH2:5][C:4]2[CH:31]=[CH:32][C:33]([F:34])=[C:2]([F:1])[CH:3]=2)[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(-c2nnc3n2CCCC3(CO)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2nnc3n2CCCC3(COC(C)=O)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A catalytic amount of 4-dimethylaminopyridine was added to a mixture of {8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methanol (80.0 mg), acetic anhydride (19.4 μL), triethylamine (28.6 μL) and THF (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and diluted with ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (72.5 mg).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:16])=[CH:18][CH:19]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc(C(C)(C)C)cc1
Yield: 105.5 %

Procedure:
30.95 g (347 mmol) of 2-amino-2-methyl-1-propanol was weighed into a 500 mL Erlenmeyer flask fitted with a stir bar and septum. Added 200 mL CH2Cl2. Established and maintained nitrogen atmosphere. Stirred the solution in an ice/water bath. Added 34 mL (174 mmol) of 4-tert-butylbenzoyl chloride dropwise over 30 min. A white precipitate formed. Stirred at room temperature overnight. Removed the solids by filtration and washed with CH2Cl2. Removed the solvent from the filtrate on rotavap and dried at 60°/4 torr to obtain 45.79 g of the title compound as a light yellow resin. MS (ESI) 248 (M−H)−.
Reaction SMILES: C(CP(=O)([O:8][CH2:9][CH3:10])OCC)#N.[H-].[Na+].[Cl:14][C:15]1[C:23]([CH:24]=O)=[C:19]2[CH:20]=[CH:21][O:22][C:18]2=[CH:17][CH:16]=1.ClC1C(C=O)=CC2[O:34][CH:33]=[CH:32]C=2C=1>COCCOC>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:22][CH2:21][CH:20]([O:8][CH2:9][CH3:10])[O:34][CH2:33][CH3:32])=[CH:19][C:23]=1[CH3:24]
Reactant: O=Cc1c(Cl)ccc2occc12
Reactant: O=Cc1cc2occc2cc1Cl
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(COc1ccc(Cl)c(C)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of diethyl cyanomethylphosphonate (11.5 ml) in dry ethylene glycol dimethyl ether (DME; 10 ml) was added dropwise to a suspension of sodium hydride (60%; 2.914 g) in DME (50 ml) at 0° under nitrogen. The mixture was stirred at 0° for 20 mins. Then a solution of 5-chloro-benzofuran-4-carbaldehyde mixture with 5-chloro-benzofuran-6-carbaldehyde (10.95 g) in DME (50 ml) was added in one portion. The mixture was heated at 60° for 2 h, cooled to room temperature and partitioned between water (150 ml) and ether (3×100 ml). The combined organic extracts were washed with brine (2×100 ml) and dried (MgSO4). The solvent was evaporated and the residue purified by column chromatography. Elution with cyclohexane/ethyl acetate 20:1 gave the title compound as a colourless solid (6.75 g)