Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:18]3[CH:19]=[N:20][C:21]([O:24]C)=[CH:22][CH:23]=3)[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[C:11]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1>Cl>[NH2:16][C:12]1[C:11]2[N:17]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:9]([C:18]3[CH:23]=[CH:22][C:21](=[O:24])[NH:20][CH:19]=3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(-n2c(-c3cccc(F)c3)nc3c(N)nccc32)cn1
Agent: Cl
Product: Nc1nccc2c1nc(-c1cccc(F)c1)n2-c1ccc(=O)[nH]c1
Temperature: 110 °C
Reaction time: 7.5 h
Yield: 43 %

Procedure:
A mixture of 2-(3-fluorophenyl)-1-(6-methoxy-3-pyridyl)-1H-imidazo[4,5-clpyridine-4-amine (290 mL) obtained in Example 42 and conc. hydrochloric acid (10 mL) was stirred at 110° C. for 7.5 hours. The reaction solution was evaporated, and the residue was purified by NH-form silica gel column chromatography, to give the title compound (120 mg, 43%)
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>C1COCC1>[Br:30][CH2:2][C:3]1[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(CO)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
5-Hydoxymethylfuran-2-carbononitrile (1.12 g, 9.1 mmol) is dissolved in THF (75 mL), treated with triphenylphosphine (2.9 g, 11.06 mmol), carbon tetrabromide (3.78 g, 11.4 mmol) and stirred at room temperature for 18 hours. Standard workup yields the title compound (1.45 g, 7.8 mmol).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([CH:15]([CH3:18])[CH:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC.C1COCC1>[CH:1]1([CH:16]([OH:17])[CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C=O)c1ccccc1
Reactant: Cl[Mg]C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(c1ccccc1)C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 70.4 %

Procedure:
To a solution of cyclohexylmagnesium chloride (50 mmol) in 25 mL of Et2O and 40 mL of THF at −5° C. was added a solution of 2-phenylpropanaldehyde (5.36 g, 40 mmol) in 10 mL of THF. The reaction mixture exothermed to 5° C. After stirring at room temperature for 75 min, the solution was poured onto ice cold 1 N HCl, extracted with toluene, dried over MgSO4, and concentrated to give the title compound as a colorless oil (6.15 g, 70%):1H NMR (d6-DMSO): δ 7.23-7.30 (m, 2H, phenyl CH), 7.15-7.22 (m, 3H, phenyl CH), 4.17-4.51 (brs, 1H, —OH), 3.23-3.33 (m, 1H, R2CHOH), 2.78 (dq, J=7.0 Hz, J=7.1 Hz, 1H, —CH(CH3)Ph), 1.23-1.83 (m, 6H, cyclohexyl CH), 1.20 (d, J=6.9 Hz, 3H, —CH(CH3)Ph), 0.88-1.18 (m, 5H, cyclohexyl CH).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][NH:13][C:14](=[O:18])[C@@H:15]([CH3:17])[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([NH:34][C@H:35]([C:46](O)=[O:47])[CH2:36][C:37]1[C:42]([CH3:43])=[CH:41][C:40]([OH:44])=[CH:39][C:38]=1[CH3:45])=[O:33])([CH3:30])([CH3:29])[CH3:28].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[C:27]([O:31][C:32]([NH:34][C@H:35]([C:46]([NH:16][C@@H:15]([C:14]([NH:13][CH2:12][C@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])[CH3:17])=[O:47])[CH2:36][C:37]1[C:38]([CH3:45])=[CH:39][C:40]([OH:44])=[CH:41][C:42]=1[CH3:43])=[O:33])([CH3:29])([CH3:30])[CH3:28]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](N)C(=O)NC[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
Benzyl-[(1R)-2-(D-alanylamino)-1-benzylethyl]carbamate (145 mg, 0.41 mmol) was combined with N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosine (described in BioOrg. Med. Chem. Letts, 2003, p 599; 129 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride salt (94 mg, 0.49 mmol), 1-hydroxybenzotriazole monohydrate (69 mg, 0.45 mmol) and N-methylmorpholine (42 mg, 0.41 mmol) in DMF (5 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h and then diluted with 10 mL of EtOAc and washed with 10 mL of a 10% aqueous solution of citric acid, 10 mL of water, 10 mL of a 3% aqueous solution of sodium bicarbonate, and finally 10 mL of a saturated aqueous brine solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 243 mg (92%) of a white foam of the title compound, which was used with no further purification.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].Br[C:6]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C1COCC1.[Zn+2].[Br-].[Br-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([C:6]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: CC[Mg+]
Reactant: COC(=O)c1ccc(C)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCc1cc(C)ccc1C(=O)OC
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a stirred mixture of ZnBr2 (13 g, 57.72 mmol, 2.00 equiv) in THF (230 mL) under nitrogen at 0° C. was added dropwise EtMgBr (19.5 mL, 3 M in THF). After 30 minutes at 0° C., the temperature was lowered to −78° C. and Pd(dppf)Cl2 (2 g, 2.73 mmol, 0.09 equiv) was added followed by dropwise addition of a solution of methyl 2-bromo-4-methylbenzoate (6.6 g, 28.81 mmol, 1.00 equiv) in tetrahydrofuran (200 mL). The resulting mixture was allowed to slowly reach ambient temperature and stirred under nitrogen overnight. The reaction mixture was quenched by the careful addition of 20 mL NH4Cl (aq., sat.) and extracted with 3×100 mL of ethyl acetate. The combined organic layers were washed with 1×200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:30) as eluent to yield 3.7 g (72%) of the title compound as a colorless oil.
Reaction SMILES: CC([C:5]1[C:18]2[N:19]=[C:20]([CH3:22])[S:21][C:17]=2[C:8]2[CH2:9][CH2:10][N:11](C([O-])=O)[CH2:12][CH2:13][C:7]=2[CH:6]=1)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][C:20]1[S:21][C:17]2[C:18]([N:19]=1)=[CH:5][C:6]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[CH:8]=2
Reactant: Cc1nc2c(C(C)(C)C)cc3c(c2s1)CCN(C(=O)[O-])CC3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cc3c(cc2s1)CCNCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-dimethylethyl-2-methyl-6,7,9,10-tetrahydro-8H-[1,3]thiazolo[5,4-g][3]benzazepine-8-carboxylate (167 mg), was dissolved in DCM (5 ml) and added to TFA (2 ml). The mixture was stirred at rt. for 1 h and then concentrated affording a 2:1 mixture of title compound and its regioisomer (139 mg) that was further used as such.
Reaction SMILES: F[C:2](F)(F)CC[Mg]Br.[CH2:9]([O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1)[CH3:10]>O1CCCC1>[CH2:9]([O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])([CH3:2])[CH3:21])=[CH:16][CH:15]=1)[CH3:10]
Reactant: CCOCOc1ccc(C(C)=O)cc1
Reactant: FC(F)(F)CC[Mg]Br
Solvent: C1CCOC1
Product: CCOCOc1ccc(C(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
In a 500 milliliter, three-necked oven-dried round bottom flask equipped with a magnetic stirrer and charged with 200 milliliters of 0.50 M (3,3,3-trifluoropropyl)magnesium bromide in tetrahydrofuran was added 19.4 grams (0.1 mole) of 1-(4-(ethoxymethoxy)phenyl)ethanone and the mixture was stirred at room temperature for 4 hours. The reaction was quenched by slowly pouring the mixture into 400 milliliters saturated ammonium chloride solution and extracting the product into 400 milliliters of ethyl acetate, and washing with brine then water to a neutral pH. The ethyl acetate extracts were then dried over sodium sulfate, filtered, and concentrated in the rotary evaporator affording 20.17 grams (˜96% yield) of 2-(4-(ethoxymethoxy)phenyl)propan-2-ol as an amber oil which was used without further purification. 20 grams (0.096 mole) 2-(4-(ethoxymethoxy)phenyl)propan-2-ol and 11.6 grams (0.11 mole) of triethylamine were dissolved in 40 milliliters of methylene chloride and slowly added to a flask equipped with magnetic stirrer and 11 milliliters (0.105 mole) of methacroyl chloride in 100 milliliters of dichloromethane, which had been cooled to 0° C. The resultant mixture was slowly warmed to room temperature and allowed to stir for 12 hours. Upon completion of the reaction, confirmed by thin layer chromatography, the mixture was quenched by pouring into 400 milliliters of deionized water and the product was extracted into methylene chloride. The methylene chloride extracts were then dried over sodium sulfate, filtered, and concentrated in the rotary evaporator affording 29.3 grams (˜85% yield) of 2-(4-(ethoxymethoxy)phenyl)-5,5,5-trifluoropentan-2-yl methacrylate as an amber oil. The oil was purified further by passing through a silica gel plug eluting with 70/30 hexanes/methylene chloride affording 19 grams of the pure product. 1H NMR (500 MHz, Acetone): δ 7.29-7.26 (d, 2H, 8.5 Hz), 6.98-6.95 (d, 2H, 8 Hz), 6.06 (s, 1H), 5.57 (s, 1H) 5.20 (s, 2H) 3.69-3.66 (q, 2H), 2.48-2.1 (m/m, 4H), 1.884 (s, 3H), 1.80 (s, 3H), 1.17-1.12 (t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=2[CH:18]=1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[NH:22]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=3[CH:18]=2)=[CH:25][CH:24]=1)[C:19]([CH3:20])=[O:21]
Reactant: CC1OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)C(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4-methyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [C:1](/[CH:4]=[CH:5]\[C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([OH:3])=[O:2].NC(N)=S.CS(O)(=O)=O>C(OCC)(=O)C>[C:1](/[CH:4]=[CH:5]/[C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([OH:3])=[O:2]
Reactant: O=C(O)/C=C\C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CS(=O)(=O)O
Agent: NC(N)=S
Solvent: CCOC(C)=O
Product: O=C(O)/C=C/C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
This compound was isomerized to the fumaryl monoamide using the following procedure. (Z)-N-(3-Carboxy-1-oxo-2-propenyl) -L-phenylalanine (260.0 g.) was mixed with 2.6 1. dry ethyl acetate, 3.80 g. thiourea and 7.19 ml. methanesulfonic acid. The mixture was stirred at reflux temperature for one hour and cooled to 25° C. The crystalline precipitate was collected on a filter, rinsed with 500 ml. ethyl acetate, and dried in air at room temperature to constant weight. The yield of (E)-N-(3-carboxy-1-oxo-2-propenyl)-L-phenylalanine was 226.5 g. (87.1% of theory). The NMR indicated that no Z-isomer was present.
Reaction SMILES: [CH3:1][C@H:2]1[C@:8]2([CH3:16])[CH2:9][C@H:10]([C:13](C)=[CH2:14])[CH2:11][CH2:12][C:7]2=[CH:6][C:4](=[O:5])[CH2:3]1.[OH:17]OS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+].CCOC(C)=O>CN(C=O)C.O=[Os](=O)(=O)=O>[C:13]([C@@H:10]1[CH2:11][CH2:12][C:7]2[C@@:8]([CH3:16])([C@@H:2]([CH3:1])[CH2:3][C:4](=[O:5])[CH:6]=2)[CH2:9]1)(=[O:17])[CH3:14]
Reactant: C=C(C)[C@@H]1CCC2=CC(=O)C[C@@H](C)[C@]2(C)C1
Reactant: O=S([O-])OO
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)[C@@H]1CCC2=CC(=O)C[C@H](C)[C@@]2(C)C1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
Nootkatone (250 mg) was dissolved in DMF (15 mL), and OsO4 (0.14 mL, 2.5% in tBuOH) was added and stirred for 5 min. OXONE (1.40 g) was added in one portion and the reaction had a final volume (18 mL). The reaction was stirred at room temperature for 3 hours or until the solution becomes colorless. This usually marks the completion of the reaction which was verified by TLC or GC. Na2SO3 (3.0 g) was added, to reduce the remaining Os(VIII), and stirred for an additional hour or until solution became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (100 mL×3) and brine (100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude product. (4S, 4aR, 6R)-6-Acetyl-4,4a-dimethyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen-2-one was obtained in 60% yield after purification by silica gel column chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Cl:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:21]([O:23][CH3:24])=[O:22]>ClCCl.CN(C1C=CN=CC=1)C>[C:21](=[O:22])([O:23][CH3:24])[O:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=1[Cl:12]
Reactant: CC(C)(C)c1ccc(O)c(Cl)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(C(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of 4-tert-butyl-2-chlorophenol (47.0 g, 0.25 mol) in dichloromethane (200 mL) was added Et3N (50.5 g, 0.50 mol), DMAP (1 g) and methyl chloroformate (35.4 g, 0.38 mol) at 0° C. The reaction was allowed to warm to room temperature and stirred for additional 30 min. The reaction mixture was washed with H2O and the organic layer was dried over Na2SO4 and concentrated to give 4-tert-butyl-2-chlorophenyl methyl carbonate (56.6 g, 92%), which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Oc1ccc(Cl)nc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(Cl)nc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 2,6-dichloropyridin-3-ol (16.3 g, 0.1 mol) and K2CO3 (41.4 g, 0.3 mol) in DMF (200 mL) were added MeI (21.3 g, 0.15 mol). The mixture was allowed to stir at 80° C. for 2 hours. The mixture was then diluted with water (200 mL) and extracted with EtOAc (200 mL×3). The organic layer was washed with brine (200 mL×3), dried over Na2SO4, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloro-3-methoxypyridine (17.0 g, yield: 96.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.12˜7.18 (m, 2H), 3.86 (s, 3H). MS (M+H)+: 178/180/182.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([O:29][C:30]([N:32]([C:40]1[CH:45]=[C:44]([CH3:46])[C:43](CO)=[CH:42][N:41]=1)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[Br:24][CH2:20][C:43]1[C:44]([CH3:46])=[CH:45][C:40]([N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[N:41][CH:42]=1
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc1CBr
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Triphenylphosphine (4.69 g, 17.9 mmol) and CBr4 (4.89 g, 14.8 mmol) was added to a solution of 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-hydroxymethyl-4-methylpyridin (5.00 g, 22.0 mmol) in dichloromethane (130 mL) at 0° C. The reaction mixture was stirred for 3 h and was then diluted with dichloromethane. The organic phase was washed with water, dried and concentrated under reduced pressure. Flash chromatography (hexane/EtOAc, 80:20) gave 5-bromomethyl-2-[N,N-bis(tert-butoxycarbonyl)amino]-4-methylpyridin (5.35 g, 90%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:15]([C:18]1[CH:28]=[CH:27][CH:26]=[C:20]2[C:21]([O:23][C:24](=O)[C:19]=12)=[O:22])([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:28]=[CH:27][CH:26]=[C:20]2[C:19]=1[C:24](=[O:23])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:21]2=[O:22])([O-:17])=[O:16]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(4-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.64 g, 51%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.68 g, 3.34 mmol) and 3-nitrophthalic anhydride (0.84 g, 4.33 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][CH:17]([C:26]#[N:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C>C(O)=O>[C:26]([CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH2:8])#[N:27]
Reactant: COc1ccccc1C(C#N)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Solvent: O=CO
Product: COc1ccccc1C(C#N)NC(=O)[C@@H](N)CC(C)C
Yield: 99.5 %

Procedure:
The product from step (i) (3.70 g) in formic acid (40 ml) was stirred for 90 min at room temperature then the solvent was removed under vacuum to give a yellow oil (2.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:21])=[O:20])=[C:4]([NH:9][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:20])=[O:21])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: Nc1ccc(F)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 37 %

Procedure:
To a solution of 4-fluorobenzene-1,2-diamine (1 mmol) in DCM (2 mL) and pyridine (2 mL) at 0° C., benzothiophene-2-sulfonyl chloride (2.2 mmol) was added in small portions. The reaction mixture was then stirred at rt until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (15 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL), and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 192 mg of N,N′-(4-fluoro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) as a solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@H:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:7][OH:8])=[O:4].[H-].[Na+].Br[CH2:18][CH:19]=[CH2:20]>C1COCC1>[CH2:20]([O:8][CH2:7][C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:13])([F:14])[F:1])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:19]=[CH2:18]
Reactant: CC(C)C[C@H](CO)NC(=O)C(F)(F)F
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC[C@@H](CC(C)C)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
Step AK (2): (R)-2,2,2-trifluoro-N-(1-hydroxy-4-methylpentan-2-yl)-acetamide (200 mg, 0.94 mmol) was dissolved in THF (5 mL) under nitrogen atmosphere. Sodium hydride (80 mg, 1.9 mmol) was added to the reaction mixture in portions. 3-Bromoprop-1-ene (0.16 mL, 1.9 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at rt for 3 h and was extracted with EtOAc. The combined organic phases were washed with water and brine and dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give (R)-N-(1-(allyloxy)-4-methylpentan-2-yl)-2,2,2-trifluoroacetamide (210 mg, 88%) as a colorless oil. LC-MS (M+H)+=254.06. 1H NMR (CD3OD, 500 MHz) δ 5.91 (m, 1H) 5.31-5.17 (m, 2H) 4.21 (m, 1H) 4.05-3.97 (m, 2H) 3.49-3.42 (m, 2H) 1.63 (m, 1H) 1.52 (m, 1H) 1.39 (m, 1H) 0.97-0.93 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[C:18](OC)(OC)(OC)[CH:19]([CH3:21])[CH3:20]>C(O)(=O)C>[CH3:11][N:10]1[CH:9]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:18]1[CH:19]([CH3:21])[CH3:20]
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Reactant: COC(OC)(OC)C(C)C
Solvent: CC(=O)O
Product: Cc1ccsc1C1Cc2ccccc2N=C(C(C)C)N1C
Yield: 26.5 %

Procedure:
A solution of 5.86 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 19.56 g of trimethyl orthoisobutyrate was treated rapidly with 7.94 ml of glacial acetic acid. The solution was refluxed for 8 hours under nitrogen and concentrated on a rotary evaporator at 40° C. The residual oil was acidified with 10% hydrochloric acid solution and extracted with ether (3×100 ml). The aqueous phase was basified with 10% sodium hydroxide solution and extracted with dichloromethane (3×100 ml). The organic phases was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Purification was accomplished by HPLC (Water's Associates Prep LC/System 500A, silcia gel, utilizing methanol followed by 2% triethylamine in methanol as successive eluents). Concentration of the appropriate fractions yielded 1.88 g of 4,5-dihydro-3-methyl-2-(1-methylethyl)-4-(3-methyl-2-thienyl)-3H-1,3-benzodiaze pine as an oil. The oil was treated with ethereal hydrogen chloride and the resulting precipitate was triturated with ether to yield 1.80 g of 4,5-dihydro-3-methyl-2-(1-methylethyl)-4-(3-methyl-2-thienyl)-3H-1,3-benzodiazepine hydrochloride, mp 240.5°-241.0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:10][C@H:11]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[N:18]([CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:20][N:21]=3)[CH2:12]2)=[O:9])=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[N:4][C:5]([C:8]([NH:10][C@H:11]3[CH2:15][CH2:14][N:13]([C:16]4[C:17]5[N:18]([CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:20][N:21]=4)[CH2:12]3)=[O:9])=[N:6][CH:7]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(-c2ccc(F)cc2)cn1
Temperature: 120 °C
Yield: 37.6 %

Procedure:
To a solution of (S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.036 g, 0.093 mmol, 1 eq) in 1.8 mL of DMF was added (4-fluorophenyl)boronic acid (0.10 g, 0.71 mmol, 7.7 eq), followed by K2CO3 (0.18 g, 1.3 mmol, 14 eq) in 0.2 mL of H2O and Pd(dppf)Cl2 (0.02 g, 0.03 mmol, 0.3 eq). After heating for 1 h at 120° C. the mixture was filtered and purified by HPLC to afford (S)-5-(4-fluorophenyl)-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.014 g, 0.035 mmol, 37%). 1H NMR (400 MHz, CD3OD) δ 9.17 (s, 2 H), 7.83 (m, 3 H), 7.71 (d, J=5.4 Hz, 1 H), 7.56 (s, 1 H), 7.31 (t, J=8.5 Hz, 2 H), 6.92 (s, 1 H), 6.85 (d, J=5.9 Hz, 1 H), 5.00-3.60 (br, 5 H), 2.65-2.30 (br, 2 H); MS: (ES) m/z calculated for C22H19FN6O [M+H]+ 403.2, found 403.