Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8]C(=O)C)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:31]C(Cl)Cl>O>[ClH:1].[ClH:31].[CH3:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][N:22]([C:2]3[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=3)[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: ClC(Cl)Cl
Reactant: CC(=O)Nc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(N2CCN(c3ccc(N)nn3)CC2)c1
Product: Cl
Temperature: 160 °C
Reaction time: 7 h
Yield: 6.6 %

Procedure:
A mixture of 3.5 parts of N-(6--chloro-3-pyridazinyl)acetamide, 3.6 parts of 1-(3-methylphenyl)piperazine and 2.8 parts of potassium carbonate was stirred for 7 hours in an oil bath at 160° C. After cooling, trichloromethane and water were added. The layers were separated. The organic layer Was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2-propanone. The salt was filtered off and dried, yielding 0.5 parts (6.6%) of 6-[4-(3-methylphenyl)-1-piperazinyl]-3-pyridazinamine dihydrochloride; mp. 178.5° C. (compound 220).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:26])([CH3:25])[CH3:24])[N:18]=3)[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].Br[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH3:36])[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCCC>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:26])([CH3:24])[CH3:25])[N:18]=3)[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([CH3:36])[CH:35]=1
Reactant: Cc1cnc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)cc(O)c(Cl)c1=O
Reactant: Cc1cncc(CBr)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cncc(COc2cc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ncc3C)c(=O)c2Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
To the intermediate at Step F, a solution of 3-chloro-4-hydroxy-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (386 mg, 1.0 mmol) in N,N-dimethylformamide (1.7 mL) was added 3-(bromomethyl)-5-methylpyridine (205 mg, 1.1 mmol), potassium carbonate (0.35 g, 2.52 mmol) and 18-crown-6 (7 mg). The slurry was stirred at ambient temperature for 18 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo to provide a brown oil. Normal phase chromatography (ethyl acetate/heptane) provided 351 mg of the alkylated product MS (M+H) 493.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]#[N:9])#[N:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(#N)C>[CH2:10]([N:5]([CH2:6][CH2:7][C:8]#[N:9])[CH2:4][CH2:3][C:1]#[N:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: N#CCCNCCC#N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#CCCN(CCC#N)Cc1ccccc1
Yield: 81.3 %

Procedure:
A mixture of 50.0 g (0.406 mol) of bis(2-cyanoethyl)amine, 51.45 g (0.406 mol) of benzyl chloride, 1.0 g (6.7 mmol) of sodium iodide, 22.05 g (0.208 mol) of sodium carbonate and 150 mL of acetonitrile was stirred mechanically and heated at reflux under nitrogen for 5 h. The cooled reaction mixture was filtered and the solids were washed with acetonitrile (3×50 mL). The combined filtrates were concentrated by rotary evaporation. A solution of the residue in 100 mL of CH2Cl2 was washed with saturated aqueous Na2S2O3 (2×20 mL) and saturated aqueous NaCl (2×50 mL). The combined aqueous layers were extracted with CH2Cl2 (3×30 mL). The combined CH2CO2 solutions were dried over MgSO4, filtered and concentrated by rotary evaporation. The residual solvent was removed under vacuum (0.5 mm), yielding 70.4 g (89%) of product as a light yellow oil. 1H NMR (CDCl3/TMS) δ 7.34 (m, 5 H), 3.70 (s, 2 H), 2.88 (t, J=6.8 Hz, 4 H), 2.44 (t, J=6.8 Hz, 4 H). 13C NMR (CDCl3) δ137.5, 128.3, 127.4, 118.4, 57.7, 49.1, 16.4. IR (film, cm−1) 3070 (w), 3050 (m), 3020 (s), 2930 (s), 2830 (s), 2240 (s), 1595 (m), 1575 (w), 1485 (s), 1445 (s), 1415 (s), 1360 (br), 1250 (br), :1125 (s), 1070 (s), 1020 (s), 960 (s), 730 (s), 690 (s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:12]O)[O:9]2)=[CH:4][CH:3]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[S:24](Cl)(=[O:26])=[O:25].[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>N1C=CC=CC=1.O>[OH:32][CH2:31][CH2:30][CH2:29][NH:28][CH2:12][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][S:24]([C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=3)(=[O:26])=[O:25])=[CH:3][CH:4]=2)[O:9]1
Reactant: NCCCO
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Nc1ccc2c(c1)OC(CO)CC2
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1ccc2c(c1)OC(CNCCCO)CC2)c1ccc2ccccc2c1
Temperature: 80 °C

Procedure:
A solution of (7-amino-3,4-dihydro-2H-chromen-2-yl)methanol (25 mg, 140 μmol) in pyridine is treated with 2-naphthalenesulfonylchloride (70 mg, 308 μmol) at ambient temperature for 1 h, treated with 3-amino-1-propanol (3 mmol, 0.23 mL), heated at 80° C. for 3 h, diluted with water and extracted with ethyl acetate. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. The resultant residue is purified by reverse phase preparative HPLC to give the title product, M+H 427, retention time 7.92 min.
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1>[Zn].C(O)(=O)C>[Cl:1][C:2](=[CH2:3])[CH2:4][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:13]
Reactant: C=C(Cl)CCl
Reactant: O=Cc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=C(Cl)CC(O)c1ccccc1
Yield: 95.2 %

Procedure:
125.40 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 60.00 g of benzaldehyde, 180 g of toluene, 240 g of 5% acetic acid and 73.88 g of zinc powder at 45° C., and then the mixture was allowed to react at the same temperature of 3 hours. After the reaction was completed, zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution and dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 98.23 g of 2-chloroallylphenylcarbinol. The results were as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[NH:5][CH3:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:6])[CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNc1ccc(F)c(Cl)c1
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccc(F)c(Cl)c1
Yield: 53.5 %

Procedure:
3-chloro-4-fluoro-N-methylaniline (260 mg, 1.63 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (200 mg, 0.41 mmol, as described in Example 3.03), using an analgous procedure to that described in Example 3.00, to afford 8-(1-((3-chloro-4-fluorophenyl)(methyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (107 mg, 53.7%) as a white solid. Mass Spectrum: M+H+ 488. NMR Spectrum: (DMSOd6) 1.55 (d, 3H), 2.63 (s, 3H), 2.91 (s, 3H), 3.01 (s, 3H), 3.20-3.29 (m, 2H), 3.30-3.37 (m partially hidden by H2O, 2H), 3.42-3.49 (ms, 2H), 3.49-3.57 (m, 2H), 5.54 (s, 1H), 5.55 (q, 1H), 6.79 (dd, 1H), 6.98 (dd, 1H), 7.23 (dd, 1H), 7.68 (d, 1H), 7.87 (d, 1H).
Reaction SMILES: [C:1]([O:4][CH:5]([C@@H:7]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:10]2[NH:11][C:12](=O)[O:13][C@H:9]2[CH2:8]1)[CH3:6])(=[O:3])[CH3:2].F[B-](F)(F)F.C[O+](C)C.[CH3:42][NH:43][CH3:44]>C(Cl)Cl>[C:1]([O:4][CH:5]([C@@H:7]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:10]2[N:11]=[C:12]([N:43]([CH3:44])[CH3:42])[O:13][C@H:9]2[CH2:8]1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CNC
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC(=O)OC(C)[C@H]1C[C@@H]2OC(N(C)C)=N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 5 (0.90 g, 2.0 mmol), trimethyloxonium tetrafluoroborate (1.5 g, 10 mmol) and 4 Å Molecular sieves (0.5 g) in DCM (5 mL) was stirred overnight at room temperature, followed by addition of dimethylamine (20 mL, 1 M in THF, 20 mmol). The reaction mixture was stirred for 12 h at room temperature, then quenched with saturated aqueous NaHCO3 (20 mL), extracted with DCM (4×50 mL). The organic layer was washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give crude product 6, which was used in the next step directly. (ES, m/z): [M+H]+ 467.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=C(C(OCC)=O)[CH:7]=[CH:6][C:5]2=1.[CH3:23][Mg]Br.[CH3:26][C:27]([CH3:29])=[O:28]>C1COCC1>[Br:1][C:2]1[CH:14]=[C:13]([C:15]([NH2:16])=[O:17])[C:12]2[NH:11][C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][CH:7]=[C:26]([C:27]([OH:28])([CH3:23])[CH3:29])[CH:9]=3
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Br)cc12
Reactant: C[Mg]Br
Reactant: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
Ethyl 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (1.05 g, 2.471 mmol, Example 58C) was dissolved in THF (100 mL) in a 250-ml round bottom flask and cooled to 0° C. Methylmagnesium bromide (1.4 M solution in 25%THF+75%toluene) (26 mL, 36 4 mmol) was added and the mixture stirred at 0° C. for 1 hour, than the reaction was allowed to warm to room temperature during 1 hour. The reaction mixture was cooled to −78° C. and excess Grignard reagent quenched by the addition of acetone (5 mL, 68.1 mmol). The mixture was stirred for 30 minutes at -78° C., then quenched with sat. aq. NH4Cl solution (at −78° C.). The flask was transferred into a water/ice bath and stirred for 10 minutes. The reaction mixture was poured into a separating funnel loaded with water and ethyl acetate. The layers were separated, the aqueous extracted once more with EtOAc (pH of aqueous ˜9) The organic layer was washed once with water, once with brine, then dried over Na2SO4, filtered and concentrated in vacuum. (bath temp <30° C.). The crude product was purified by flash column chromatography on silica (25 g BIOTAGE® cartridge, eluent gradient from 5% EtOAc in DCM to 75% EtOAc in DCM during 96 fractions a 21 ml). Product eluted in fractions 57-80. Product containing fractions were combined and evaporated to give 395.5 mg 3-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide. 1H NMR (DMSO-d6) δ ppm 11.38 (s, 1H), 8.48 (d, 1H, J=1.8), 8.22 (b, 1H), 8.09-8.09 (m, 2H), 7.88 (d, 1H, J=1.0), 7.54 (b, 1H), 7.33 (dd, 1H, J=8.3, 1.5), 5.05 (s, 1H), 1.52 (s, 6H). MS (ESI) m/e+=347/349 (1 Br isotope pattern) consistent with [M+H]+ and m/e+=330/332 (1 Br isotope pattern) consistent with [M+H−NH3]+. HPLC retention time 9.89 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[NH:14])[NH2:13])=[CH:8][CH:7]=1)[CH3:3].[CH2:16]([C:23](=[CH:26]OCC)C=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:30]C[O-].[Na+]>CO>[CH2:2]([O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:23]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:26]=[CH:30][N:14]=2)=[CH:8][CH:7]=1)[CH3:3].[CH2:17]([C:16]1[CH:23]=[CH:26][N:13]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([C:5]([OH:4])=[O:15])=[CH:11][CH:10]=2)[N:14]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:30]
Reactant: CCOC(=O)c1ccc(C(=N)N)cc1
Reactant: CCCCCCCC(C=O)=COCC
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCCc1ccnc(-c2ccc(C(=O)O)cc2)n1
Product: CCCCCCCc1ccnc(-c2ccc(C(=O)OCC)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 0.1 mole of 4-amidino-benzoic acid ethyl ester hydrochloride, 0.1 mole of 2-n-heptyl-3-ethoxy-acrolein and 0.14 mole of sodium ethylate in 100 ml of methanol is stirred overnight at room temperature under an atmosphere of nitrogen. After the usual work up and separation into basic and acidic fractions, there is obtained 4-(4-n-heptylpyrimid-2-yl)-benzoic acid ethyl ester and 4-(4-n-heptylpyrimid-2-yl)-benzoic acid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][NH:14][C@H:15]([CH:23]([CH3:25])[CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O.NN>C(O)C>[NH2:3][CH2:12][CH2:13][NH:14][C@H:15]([CH:23]([CH3:25])[CH3:24])[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17]
Reactant: CC(C)[C@@H](NCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)[C@@H](NCCN)C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
t-Butyl (R)-2-(2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylamino)-3-methylbutyrate (6.60 g; 19.05 mmol) was dissolved in ethanol (100 ml). Hydrazine hydrate (4.62 ml; 95.25 mmol) was added, and the reaction mixture was heated under reflux for 2 h. The solid was filtered off with suction through kieselguhr and washed with ethanol (100 ml). The solvent was removed and the residue was partitioned between saturated NaHCO3 solution (150 ml) and CH2Cl2 (150 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×; 100 ml). The combined organic phases were dried over MgSO4. Removal of the solvent under reduced pressure resulted in t-butyl (R)-2-(2-aminoethylamino)-3-methylbutyrate (4.60 g; 19.05 mmol). MS: 217.25 (M+H); Rt: 0.69 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: CCN(CC)CC.[CH2:8]([O:15][C:16](=[O:36])[C:17]([C:22](=O)[CH2:23][O:24][C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2)=[CH:18]N(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[C:38]1([CH3:46])[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH:44][NH2:45]>CC#N>[CH2:8]([O:15][C:16]([C:17]1[C:22]([CH2:23][O:24][C:25]23[CH2:26][CH:27]4[CH2:33][CH:31]([CH2:30][CH:29]([CH2:28]4)[CH2:34]2)[CH2:32]3)=[N:45][N:44]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH3:46])[CH:18]=1)=[O:36])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=C(C(=O)COC12CC3CC(CC(C3)C1)C2)C(=O)OCc1ccccc1
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccccc1-n1cc(C(=O)OCc2ccccc2)c(COC23CC4CC(CC(C4)C2)C3)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
NEt3 (0.2 mL, 1.43 mmol) was added to a mixture of 2-[2-(adamantan-1-yloxy)-acetyl]-3-dimethylamino-acrylic acid benzyl ester (0.539 g, 1.4 mmol), and o-tolylhydrazine hydrochloride (0.222 g, 1.4 mmol) in MeCN (8 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 17 h. The precipitated solid was filtered off, washed with MeCN and dried to afford the product, (0.359 g, 56%).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44]>C(Cl)Cl.CO>[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:33][CH2:32][N:31]([CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:30][CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: Cc1noc(C)c1-c1ccc2nc(N3CCN(CC(=O)N(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
To a solution of (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-piperazin-1-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine trihydrochloride (10 mg, 0.03 mmol) in methylene chloride (1.0 mL), potassium carbonate (18 mg, 0.13 mmol) was added, followed by 2-chloro-N,N-dimethylacetamide (2.7 μL, 0.026 mmol) and the mixture was stirred for 5 min. The mixture was then heated at 60° C. overnight. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound, (3.7 mg, 30%). LCMS calc. for C27H32N7O3 (M+H)+: m/z=502.2. found: 502.3.
Reaction SMILES: Cl.[C:2](=[NH:11])(OC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:12][NH:13][NH2:14].Cl[C:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=O.N1C=CC=CC=1>CO.O>[CH3:12][N:13]1[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:11][C:16]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[N:14]1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CNN
Reactant: COC(=N)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3)n(C)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a solution (20 ml) of methyl benzimidate hydrochloride (2.00 g) in methanol was added methylhydrazine (0.540 g) at 0° C. This mixture was stirred at 0° C. for 1 hr., and at room temperature for 2 hrs., and concentrated. The residue was washed with ether to give colorless crystals. A mixture of these crystals, methyl 4-chloroformylbenzoate (2.32 g) and pyridine (30 ml) was heated under reflux for 1 hr. and poured into iced water. The crystals were collected by filtration and purified by silica gel column chromatography (hexane:ethyl acetate=2:1, volume ratio) to give methyl 4-(1-methyl-5-phenyl-1H-1,2,4-triazol-3-yl)benzoate (1.50 g, yield 44%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 167–168° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:19])([F:18])[C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([N:15]2[CH:14]=[C:13]([C:12]([F:19])([F:18])[F:11])[CH:17]=[N:16]2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(-n2cc(C(F)(F)F)cn2)nc1
Temperature: 80 °C
Yield: 47.9 %

Procedure:
A round bottom flask was charged with 2-chloro-5-nitropyrimidine (2.50 g, 15.7 mmol), 4-(trifluoromethyl)-1H-pyrazole (2.35 g, 17.2 mmol), K2CO3 (4.33 g, 31.3 mmol) and acetonitrile (39 mL). The reaction was heated at 80° C. for 2 hours. Potassium carbonate filtered off with a büchner funnel and acetonitrile removed under reduced pressure. The crude material was dissolved in ethyl acetate and transferred to a separatory funnel. Organics washed with water (3×), with brine (1×), dried over sodium sulfate, filtered and concentrated to afford the raw material. Purification by silica gel flash chromatography (ethyl acetate/heptane) provide 5-nitro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (1.95 g, 49%) as a yellow solid. MS (M+1): 259.2.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1.C[C@H]1CNCCN1>CO.C(Cl)(Cl)Cl>[CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1
Reactant: C[C@@H]1CN(c2ccccn2)CCN1
Agent: C[C@H]1CNCCN1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H]1CN(c2ccccn2)CCN1

Procedure:
The title compound was prepared following the protocol used for the preparation of Intermediate 3, but starting from (S)-2-methyl piperazine (43%). TLC-Chloroform/MeOH (8/2); Rf=0.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[OH:12].[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[NH2:8][C:6]1[C:5]([F:11])=[CH:4][C:3]([OH:12])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(O)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Zinc dust (10 g, 160 mmol) was added portion wise to a solution of 2-chloro-5-fluoro-4-nitro-phenol (3.0 g, 16 mmol) and NH4Cl (8.4 g, 160 mmol) in THF (150 mL) and MeOH (150 mL) and the mixture was stirred at RT for 0.5 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3×50 mL). The combined filtrate was washed with brine (3×100 mL), dried over Na2SO4 and concentrated to provide 4-amino-2-chloro-5-fluorophenol (2.5 g, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1 H), 6.76 (d, J=9.2 Hz, 1 H), 6.65 (d, J=12.4 Hz, 1 H), 4.70 (s, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:7]=1)[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][NH:33][C:32](=[O:35])[CH2:31]2)=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:33]2[CH2:34][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:31][C:32]2=[O:35])[CH:7]=1)[CH3:2]
Reactant: O=C1CC(c2ccc(Cl)cc2)CN1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CC(c3ccc(Cl)cc3)CC2=O)c1

Procedure:
Prepared according to the procedure described in Example 116, Step 1, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid ethyl ester and 4-(4-chloro-phenyl)-pyrrolidin-2-one.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:34])[C:22]([CH3:33])([CH3:32])[CH2:23]OS(C(F)(F)F)(=O)=O>C1COCC1>[CH3:19][O:20][C:21](=[O:34])[C:22]([CH3:33])([CH3:32])[CH2:23][F:1]
Reactant: COC(=O)C(C)(C)COS(=O)(=O)C(F)(F)F
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CF
Temperature: 0 °C
Reaction time: 6 h

Procedure:
27 mL of a 1 M solution of tetrabutylammonium fluoride in THF are added slowly and under ice cooling to a solution of 7.25 g (27.4 mmol) 2,2-dimethyl-3-trifluoromethanesulfonyloxy-propionic acid methyl ester in 150 mL of THF. The resulting solution is stirred 6 h at 0° C. and then 10 h at RT. The solvent is evaporated carefully and the residue partitioned between DCM and brine. The organic phase is washed with brine, dried with sodium sulfate and evaporated carefully. The brown oil is distilled in a Kugelrohr-oven (oven temperature 120 to 150° C.) to give the title compound as a colorless liquid.