Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:9]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: NC1CCCCC1
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Solvent: CC(=O)O
Product: COC(=O)c1cc(NC2CCCCC2)c(NC2CCCCC2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa- 1,4-diene- 1,2-dicarboxylic acid dimethyl ester (Example 1a) in 21.5 ml (188 mmol) of cyclohexylamine and 4.5 ml of glacial acetic acid is boiled under reflux for 3.5 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 100 ml of 2N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/hexane 5:12 and the product fractions are concentrated by evaporation and again chromatographed with ethyl acetate/hexane 1:4, yielding the title compound in the form of a yellow oil, FAB-MS: 388 [M+ ].
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[CH3:30][O:31][CH2:32][CH2:33][N:34]1[CH2:43][CH2:42][C:41]2[C:40]([C:44](O)=[O:45])=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]1=[O:47].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:44]([C:40]1[C:41]2[CH2:42][CH2:43][N:34]([CH2:33][CH2:32][O:31][CH3:30])[C:35](=[O:47])[C:36]=2[CH:37]=[CH:38][CH:39]=1)=[O:45])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: COCCN1CCc2c(C(=O)O)cccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCN1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Reaction time: 20 h
Yield: 30 %

Procedure:
Poured into a suspension of 242 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 104 mg of 2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 8 mg of hydroxybenzotriazole, 99 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 7 cm3 of dichloromethane is 0.28 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The reaction mixture is kept stirring for 20 h at a temperature close to 20° C. The suspension obtained is filtered and the precipitate is washed 3 times with 5 cm3 of ethyl ether, then dried under vacuum. 79 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white powder.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=12.Cl[C:18]([C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:19]>C(N(CC)CC)C>[CH3:28][O:27][C:25]([C:24]1[CH:29]=[C:20]([CH:21]=[CH:22][C:23]=1[N+:30]([O-:32])=[O:31])[C:18]([C:3]1[N:4]2[CH:9]=[C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]=[CH:6][C:5]2=[CH:1][N:2]=1)=[O:19])=[O:26]
Reactant: CC(C)(C)OC(=O)c1ccc2cncn2c1
Reactant: COC(=O)c1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)c2ncc3ccc(C(=O)OC(C)(C)C)cn23)ccc1[N+](=O)[O-]

Procedure:
This compound is obtained according to the same process as that described in example 9 by benzoylation of tert-butyl imidazo[1,5-a]pyridine-6-carboxylate with methyl 5-(chlorocarbonyl)-2-nitrobenzoate in the presence of triethylamine. A yellow solid is obtained. Melting point: 170° C.; 1H NMR (d6-DMSO): 1.63 (9H, s), 3.89 (3H, s), 7.76 (1H, d), 8.05 (1H, s), 8.12 (1H, d), 8.26 (1H, d), 8.70 (1H, d), 8.77 (1H, s), 10.25 (1H, s)
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:6]=1[CH2:7][OH:8].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:6]=1[CH2:7][O:8][C:14](=[O:16])[CH3:15]
Reactant: OCc1c(Cl)cccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1c(Cl)cccc1Cl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
Add 500 mL of dichloromethane to 100 g of 2,6-dichlorobenzyl alcohol followed by 117 mL of triethylamine. Cool the solution to 5° C. and add 65 mL of acetic anhydride. After 2.5 hr at room temperature, add another 10 mL of acetic anhydride, 20 mL of triethylamine and 0.5 g of 4-dimethylaminopyridine. Wash the organic layer with 1N HCl followed by saturated aqueous sodium bicarbonate and brine. Dry the organic layer (sodium sulfate) and evaporate to afford 131.5 g of the titled compound as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1>CCOC(C)=O.CCOCC.Cl.CCOCC>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1
Reactant: COCCOc1cccc(OCCOc2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCCOc1cccc(OCCOc2nccnc2N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
The product obtained in Step 1 above was dissolved in a mixture of EtOAc (18 mL) and ether (9 mL) and 5 M HCl/ether (9 mL) was added. The mixture was stirred at room temperature for 3 h. The precipitatated hydrochloride salt was filtered off and washed thoroughly with ether. The hydrochloride was dissolved in EtOAc/MeOH/Et3N (100:40:5) and purified by column chromatography on silica using NH3-satd. EtOAc/CH3OH (100:15) as eluent. The combined pure fractions were concentrated in vacuo and the resulting oil was dried (˜0.8 torr, room temperature) to give 0.36 g (69%) of the title product. HRMS m/z calcd for C19H26N4O4 (M)+ 374.1954, found 374.1947.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(C([Cl:16])=O)=O>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5,6-dichloro-nicotinic acid (7.0 g, 0.036 mol, Aldrich), (COCl)2 (50 mL, Aldrich) and DMF (2 drops) was stirred at room temperature for 4 h. The solution was evaporated in vacuo to give the title compound as an orange solid
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]2[C:17](=[O:18])[N:8]3[C:9]([C:14]([OH:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.O1[CH2:30][CH2:29][O:28][CH2:27]C1>O>[C:4]1(=[O:19])[N:5]([CH:6]2[C:17](=[O:18])[N:8]3[C:9]([C:14]([O:16][CH2:3][C:2]4[CH:1]=[CH:30][C:29]([O:28][CH3:27])=[CH:22][CH:23]=4)=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:1](=[O:24])[C:2]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:3]12
Reactant: CC1=C(C(=O)O)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Reactant: C1COCCO1
Solvent: O
Product: COc1ccc(COC(=O)C2=C(C)CS[C@@H]3C(N4C(=O)c5ccccc5C4=O)C(=O)N23)cc1
Reaction time: 2 h

Procedure:
To a suspension of 13.4 g. (38 mmol.) of 7-phthalimido-3-methyl-3-cephem-4-carboxylic acid in 20 ml. of dioxane and 10 ml. of water were slowly added 3.8 g. of KHCO3. The solution was evaporated to dryness, and 100 ml. of DMF and 8.8 g. of p-methoxybenzyl bromide were added to the potassium salt residue. The mixture was stirred for 2 hrs. and then poured onto 200 g. of ice. The resulting mixture was extracted twice with ethyl acetate. The extract was washed with water and brine, dried, and the solvent was then evaporated. The residue was recrystallized from ethyl acetate. Yield: 4.1 g. of large crystals, m.p. 118°-121°; second crop 1.8 g.; [α]D + 41.2° (MeCN), ir (CHCl3) 1800, 1785, 1745 and 1735 cm-1, nmr (CDCl3) δ 2.15 (s, 3, CH3); 3.0 and 3.7 (ABq, 2, J = 15 Hz), 3.8 (s, 3, CH3), 5.11 (d, 1, J = 4.5 Hz), 5.28 (s, 2, CH2), 5.75 (d, 1, J = 4.5 Hz), 6.8- 7.8 (m, 8).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH:15](OCC2CCCC2)[C:16]2[N:21]=[C:20]([O:22]C)[C:19]([Cl:24])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].O.[CH:33]1([SH:38])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[C:5]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]([S:38][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:16]2[NH:21][C:20](=[O:22])[C:19]([Cl:24])=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)([CH3:6])([CH3:7])[CH3:8]
Reactant: SC1CCCC1
Reactant: COc1nc(C(OCC2CCCC2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1ccc(C(SC2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
Aluminum chloride (66 mg) was added to a solution of 6-[(4-tert-butylphenyl)(cyclopentylmethoxy)methyl]-3-chloro-2-methoxypyridine (64 mg) in cyclopentanethiol (1 mL) under ice-cooling, and then the mixture was stirred at 40° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:10) to give the title compound as a pale yellow solid (15 mg, 25%).
Reaction SMILES: O1CCOCC1.Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[C:10]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]2[CH3:27])[N:9]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:17]([N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:8]([C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]1[CH3:27])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Cn1cnc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1cnc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Yield: 76.4 %

Procedure:
A dioxane (5 ml)-water (1 ml) suspension of 2-chloro-9-isobutyl-6-[(3S)-3-methylmorpholin-4-yl]-9H-purine (317 mg, 1.02 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (226 mg, 1.02 mmol), sodium carbonate (325 mg, 3.07 mmol), and tetrakis triphenylphosphine palladium (118 mg, 0.10 mmol) was heated to reflux for 2.5 hours. The reaction mixture was returned to room temperature. Water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=96:4). The residue was purified by flash silica gel column chromatography (ethyl acetate) to give the title compound (287 mg, 76%) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]([CH3:20])[CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:16]([CH3:20])[CH2:17][C:18]#[N:19])[CH:10]=2)[O:3]1
Reactant: CC(Br)CC#N
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(CC#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 3-bromobutanenitrile (46 mg, 0.31 mmol, TCI America, Cat. No. B 1452), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. for 3 hours. After cooling it was quenched with water, extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 60 mg product. It was directly used in the next step reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1.[F-].[Cs+].[N+](C1C=C(S(O[CH2:33][CH:34]2[CH2:36][O:35]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][CH:34]2[CH2:36][O:35]2)=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Reactant: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CO2)c(-c2cc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a solution of compound 4-bromo-2-(1H-indol-2-yl)phenol (1 g, 3.48 mmol) in DMF (35 mL) was added CsF (1.59 g, 10.45 mmol) and oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.81 g, 6.97 mmol). The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate and washed with water and brine. The crude product was purified using chromatography (petroleum ether:EA=14:1) to provide compound 2-(5-bromo-2-(oxiran-2-ylmethoxy)phenyl)-1H-indole (1 g, yield: 84.0%). 1H-NMR (DMSO-d6, 400 MHz) δ 11.33 (s, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.38˜7.44 (m, 2H), 7.07˜7.12 (m, 3H), 6.97 (t, J=7.2 Hz, 1H), 4.49˜4.53 (m, 1H), 3.97˜4.01 (m, 1H), 3.46˜3.49 (m, 1H), 2.88 (t, J=4.4 Hz, 1H), 2.74˜2.76 (m, 1H). MS (M+H)+: 344/346.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)[NH:22][CH2:23][C@H:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([CH3:46])([CH3:45])[C:36]([N:38]3[CH:42]4[CH2:43][CH2:44][CH:39]3[CH2:40][CH2:41]4)=[O:37])[CH:33]=2)[NH:28][C:27]=1[C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[C:49]([CH3:54])[CH:48]=1)[CH3:25])(C)(C)C>>[NH2:22][CH2:23][C@H:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([CH3:46])([CH3:45])[C:36]([N:38]3[CH:42]4[CH2:43][CH2:44][CH:39]3[CH2:40][CH2:41]4)=[O:37])[CH:33]=2)[NH:28][C:27]=1[C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[C:49]([CH3:54])[CH:48]=1)[CH3:25]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (S)-{2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-propyl}-carbamic acid tert-butyl ester (2.6 g in 90 mL methylene chloride) at 0° C. was added 5.2 mL anisole followed by 37 mL trifluoroacetic acid and the mixture stirred at 0° C. After 2 hours, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene. Purification by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:7:1) gave the title compound (2.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:27][CH2:26][CH2:25][C@H:8]3[S:9](=[O:24])(=[O:23])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13]C(=O)OC(C)(C)C)=[N:12][C@:7]3([CH3:28])[C:6]=2[CH:29]=1.Cl[C:31]1[C:32]2[N:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:33]=2[N:34]=[CH:35][N:36]=1.CC(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C([O-])(O)=O.[Na+]>[NH2:13][C:11]1[C:10]([CH3:21])([CH3:22])[S:9](=[O:24])(=[O:23])[C@@H:8]2[CH2:25][CH2:26][O:27][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]4[C:32]5[N:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:33]=5[N:34]=[CH:35][N:36]=4)=[CH:29][C:6]=3[C@@:7]2([CH3:28])[N:12]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Reactant: COc1cnc2c(Cl)ncnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1cnc2c(Nc3ccc4c(c3)[C@@]3(C)N=C(N)C(C)(C)S(=O)(=O)[C@@H]3CCO4)ncnc2c1
Reaction time: 0.42 h
Yield: 61.3 %

Procedure:
A disposable tube was charged with tert-butyl ((4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (60 mg, 0.142 mmol), 4-chloro-7-methoxypyrido[3,2-d]pyrimidine (30.5 mg, 0.156 mmol) and 2-propanol (708 μl, 0.142 mmol), followed by p-toluenesulfonic acid monohydrate (53.9 mg, 0.283 mmol). The resulting mixture was stirred from rt to 90° C. for 25 min. The reaction mixture was diluted with sat. NaHCO3 and extracted with EtOAc to yield the crude product as a yellow solid. The crude material was absorbed onto a plug of silica gel and purified by column chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 20% to 35% to 50% EtOAc/MeOH/NEt3 (80/20/2) in (40% EtOAc in Heptane), to provide (4aR,11bR)-2-amino-10-((7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)-3,3,11b-trimethyl-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazine 4,4-dioxide (42 mg, 0.087 mmol, 61.4% yield) as white solid. MS m/z=483.2 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]([CH2:18][CH3:19])[C:3]1=[O:20].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>O1CCCC1>[CH:9]1([C:7]2[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[N:4]([CH2:18][CH3:19])[C:3](=[O:20])[CH:2]([NH:1][C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN1C(=O)C(N)N=C(C2CCCC2)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A solution of crude 3(R,S)-amino-5-cyclopentyl-l,3-dihydro-1-ethyl-2H-1, 4-benzodiazepin-2-one [Example 5, Step 5] (0.23 g, 0.92 mmol) in dry tetrahydrofuran (15 ml) under an atmosphere of nitrogen, at 0° C., was treated with triethylamine (0.11 ml, 0.92 mmol) followed by a solution of 4-nitrophenyl chloroformate (184 mg, 0.92 mmol) in tetrahydrofuran (10 ml). After stirring at ambient temperature for 30 min the solid which precipitated was removed by filtration and the tiltrate concentrated in vacuo to afford the title compound (0.32 g, 79%) as a colourless solid. mp 136°-138° C. 1H NMR (360 MHz, CDCl3) δ 0.9 (3H, t, J=7 Hz), 1.0-2.2 (8H,m), 3.50 (1H, p, J=7 Hz), 3.70 (1H, m), 4.18-4.28 (1H, m), 5.14 (1H, d, J=8 Hz), 7.30-8.20 (8H, m), 9.12 (1H, d, J=8 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19][NH:30][C:25]3[N:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[N:24]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CNc2nc(C)cc(C)n2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 4,6-dimethylpyrimidin-2-amine. m/e+ 412 for C21H20Cl2N5 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.85 (d, J=1.4 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.48 (d, J=7.7 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.14 (d, J=7.7 Hz, 1H), 6.41 (s, 1H), 5.02 (s, 2H), 2.40 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H) ppm.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[C:10](=[N:12]/[C:13]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:16]=[CH:15][C:14]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH3:11].C([O-])([O-])=O.[K+].[K+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>CN(C=O)C>[CH2:37]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[C:10](=[N:12]/[C:13]1[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)/[CH3:11])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: C/C(=N\c1c(-c2ccccc2)cccc1-c1ccccc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C(=N\c1c(-c2ccccc2)cccc1-c1ccccc1)c1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 0.70 g (1.87 mmol) N-[(1E)-1-(1H-benzimidazol-2-yl)ethylidene]-N-1,1′:3′,1″-terphenyl-2′-ylamine, 1.42 g (10.3 mmol) anhydrous K2CO3 and 0.35 g (2.06 mmol) benzylbromide in 4 ml anhydrous DMF was stirred at room temperature for 10 hours. The reaction mixture was then poured into 80 ml water, stirred for 10 min and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (3×25 ml) and dried over anhydrous Na2SO4. The solvent was evaporated to give an yellow oil which was triturated with 5 ml methanol at −78° C., filtered while cold washed with cold (−78° C.) methanol (2×2 ml) and dried under reduced pressure. Yield 0.56 g (66.2%). 1H NMR (250 MHz, CDCl3), δ, ppm: 2.07 (s, 3H), 5.51 (m, 2H), 6.90 (m, 2H), 7.22 (m, 19H), 7.78 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Cl[C:10]1[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CS(C)=O>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2
Reactant: COC[C@@H]1CCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COC[C@@H]1CCCN1c1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL pressure tank reactor, was placed (S)-2-(methoxymethyl)pyrrolidine (96.45 mg, 0.85 mmol, 5.00 equiv), methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (50 mg, 0.17 mmol, 1.00 equiv), potassium carbonate (46.7 mg, 0.34 mmol, 2.00 equiv), toluene/DMSO (2/0.4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 17 mg (27%) of (S)-methyl 3-(2-(methoxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>CCO>[NH2:2]/[C:1](=[N:17]\[OH:18])/[CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C#N
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOCC1/C(N)=N/O

Procedure:
A solution of of the product of Step 3 (1 eq.), hydroxylamine hydrochloride (1.4 eq.) and triethylamine (1.7 eq.) in EtOH (0.5 M) was refluxed under nitrogen for 5 hours. Mixture was concentrated and residues taken up in EtOAc and washed with water and brine. Combined organics were dried over Na2SO4 and evaporated giving the title compound as a yellow solid.