Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[N:16]=3)[NH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][NH:3]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[CH3:1][C:2]1([C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[N:16]=3)[NH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][N:3]1[C:30](=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCN4)c3n2)cc(OC)c1OC
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCN4C(C)=O)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
A solution of (2-methyl-pyrrolidin-2-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (8 mg, 0.02 mmol) in anhydrous dichloromethane (0.3 ml) was cooled to 0° C. and treated with acetic anhydride (2 mg, 0.02 mmol). The reaction mixture was stirred for 1 hour and then allowed to warm to room temperature and stir for 3 hours. The reaction mixture was partitioned between EtOAc/saturated aqueous NaHCO3. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a brownish oil. The residue was purified by preparative thin layer chromatography using 50% EtOAc in hexanes as eluant to provide 2 mg (17%) of 1-{2-methyl-2-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidin-1-yl}-ethanone as a light yellow solid. M+H=439.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=O)[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][CH:30]([NH2:32])[CH3:31].C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH2:26][NH:32][CH:30]([CH3:31])[CH3:29])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(C=O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1noc(C)c1-c1cc(CNC(C)C)c2[nH]c(=O)n3c2c1OCC3c1ccccn1
Temperature: 60 °C

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde (15 mg, 0.04 mmol) from Example 137, Step 3 was stirred in methanol (1.0 mL) with 2-propanamine (10 μL, 0.12 mmol), followed by addition of sodium cyanoborohydride (7.5 mg, 0.12 mmol). The mixture was heated at 60° C. overnight, then diluted with methanol. Purification by preparative LCMS (pH 10) afforded the title compound. LCMS calc. for C23H26N5O3 (M+H)+: m/z=420.2. found: 420.1.
Reaction SMILES: [C:1]([N:9]1[CH2:17][C@@H:16]([OH:18])[CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([N:9]1[CH2:17][C@@H:16]([O:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of (cis)-1-benzoyl-4-hydroxy-L-proline, methyl ester (1.9 g, 7.63 mmole) in pyridine (6 ml) was stirred under argon and treated with p-toluenesulfonyl chloride (1.75 g, 9.16 mmole). The reaction was stirred overnight, treated with additional p-toluenesulfonyl chloride (0.145 g, 0.76 mmole) and stirred for 24 hours. Ice water was added followed by ethyl acetate. The organic layer was washed with 1N HCl, brine, and dried. Filtration and concentration in vacuo afforded the title compound as a foam which was used without purification in the subsequent step.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].[N+](C1C=C(S(O[CH2:27][C@H:28]2[O:30][CH2:29]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C=O)C>[O:30]1[CH2:29][C@H:28]1[CH2:27][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1cccc2ccccc12
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(OC[C@@H]3CO3)cccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
1-Naphthol (1.0 g) was dissolved in DMF (8 ml) under nitrogen atmosphere and the solution was cooled to 0° C. 25 Cesium fluoride (2.1 g) was added thereto and the mixture was stirred for 1 hour. Then, (S)-glycidyl m-nitrobenzenesulfonate (1.80 g, 99.3% e.e.) was added thereto and the mixture was stirred for 24 hours at the same temperature. After the reaction water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/ethyl acetate; 6:1) to give 1.34 g of (S)-1-(2,3-epoxypropoxy)naphthalene (yield 96.5%, optical purity 99.2% e.e.) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:46][Si:47]([CH2:52][CH3:53])([CH2:50][CH3:51])[CH2:48][CH3:49])([CH3:45])[CH3:44].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:46][Si:47]([CH2:52][CH3:53])([CH2:48][CH3:49])[CH2:50][CH3:51])([CH3:45])[CH3:44])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCCCBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)CCCCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 95.1 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (200 mg, 0.367 mmol), 1-bromo-5-triethylsilyloxy-5-methylhexane (227 mg, 0.734 mmol), sodium hydride (60% in oil, 44 mg, 1.10 mmol), 15-crown-5 (81 mg, 0.368 mmol) and tetrahydrofuran (0.5 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (reflux under heating for 1 hour), worked up and purified by column chromatography (hexane:toluene=3:2) to give the titled compound (270 mg, 95%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:26]([C@@H:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:28])=[O:27]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1N[C@@H](Cc1ccccc1)C(=O)O
Yield: 39 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with L-phenylalanine to provide the title compound in 39% yield as yellow needles (recrystallization from EtOH).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH:9]([C:22]([OH:24])=[O:23])[CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:28](OC1C=CC=CC=1)=[O:29].Cl>O1CCCC1.O>[O:29]=[C:28]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:10]([C:11]([OH:13])=[O:12])[C@@H:9]([C:22]([OH:24])=[O:23])[N:8]1[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(O)C(NCc1ccccc1)C(NCc1ccccc1)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
220 g (0.67 mol) of meso-2,3-bis(benzylamino)succinic acid were placed under a nitrogen atmosphere in a 2 l flask fitted with two dropping funnels, a pH electrode, and a stirrer. The meso-2,3-bis(benzylamino)succinic acid was then suspended, while stirring, in 800 ml of tetrahydrofuran and 400 ml of deionized water and brought into solution by the addition of 108 ml of a 50% potassium hydroxide solution. 200 ml of 2.4 mole q. phenyl chloroformate were added dropwise to the solution within 3.5 hours. The pH was maintained between 9 and 11 during the addition of phenyl chloroformate by the successive addition of a 50% potassium hydroxide solution, and the internal temperature was maintained between 30° C. and 35° C. After the addition was completed, the mixture was stirred at about 30° C. for 2 hours and the pH was adjusted to about 7-8 with concentrated hydrochloric acid. The aqueous solution was then extracted twice with toluene and 500 ml of tetrahydrofuran were added to the combined aqueous phases. The mixture was adjusted to a pH of 1.0 with 37% hydrochloric acid and the aqueous phase was separated off. 400 ml of toluene were added to the tetrahydrofuran phase and the tetrahydrofuran was distilled off under reduced pressure. The remaining water was removed azeotropically with toluene. The residual brownish, oily solution was seeded and the crystalline solid was filtered off and washed twice with toluene. After drying to constant weight under reduced pressure, there were obtained 181.5 g (76% yield) of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, with a melting point of 172.8° C.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:13]([O:21][CH3:22])(=[O:20])[C:14]#[C:15][C:16]([O:18][CH3:19])=[O:17]>[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)Cl.CO>[C@@H:2]12[N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C@@H:5]([CH:4]=[CH:3]1)[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:13]([O:21][CH3:22])=[O:20]
Reactant: CC(C)(C)OC(=O)n1cccc1
Reactant: COC(=O)C#CC(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1=C(C(=O)OC)[C@@H]2C=C[C@H]1N2C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 72 h
Yield: 52.7 %

Procedure:
A mixture of tert-butyl 1H-pyrrole-1-carboxylate (XLV) (3.50 g 20.93 mmol), dimethyl but-2-ynedioate (XLVI) (2.57 mL, 20.93 mmol) and AlCl3 (28 mg, 0.21 mmol) were stirred for 3 days at 70° C. The crude product was purified by silica gel chromatography using 100% DCM then DCM/MeOH 1000/1→500/1 to give (1R,4S)-7-tert-butyl 2,3-dimethyl 7-azabicyclo[2.2.1]hepta-2,5-diene-2,3,7-tricarboxylate (XLVII) as a yellow oil (3.41 g, 11.04 mmol, 53% yield). 1H NMR (CDCl3) δ ppm 1.40 (s, 9H), 3.80 (s, 6H), 5.44 (s, 2H), 7.13 (d, J=13 Hz, 2H); ESIMS found for C15H19NO6 m/z 332 (M+Na).
Reaction SMILES: C=O.N.[N:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[CH3:12].N1C(C)=CC=C(C)[C:14]=1C>C(C(C)=O)C>[CH3:12][C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[C:9]([CH3:14])[N:4]=1
Reactant: Cc1ccc(C)c(C)n1
Reactant: Cc1cnc(C)c(C)c1
Agent: C=O
Agent: N
Solvent: CCC(C)=O
Product: Cc1cc(C)c(C)nc1C

Procedure:
When the process of the present invention is performed in the form of a fixed bed, the catalyst of the present invention is packed in a reactor and heated to a reaction temperature. Then, the mixture of methyl ethyl ketone, formaldehyde and ammonia was allowed to proceed through the gas phase catalytic reaction while maintaining the suitable reaction temperature. Thus, a reaction product containing 2,3,5-collidine, 2,3,6-collidine and 2,3,5,6-tetramethylpyridine is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.BrCC1C=CC=C(Cl)C=1OC.[C-]#N.[Na+]>CCO.CCOCC>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Cl)cccc1CC#N
Agent: COc1c(Cl)cccc1CBr
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COc1c(Cl)cccc1CCN
Temperature: 100 °C

Procedure:
2-(3-chloro-2-methoxyphenyl)acetonitrile. A solution of 1-(bromomethyl)-3-chloro-2-methoxybenzene (30.8 g, 131 mmol) in EtOH (150 mL) at RT and under N2 was treated with an aq. solution of NaCN (12.8 g, 262 mmol in 50 mL H2O) and the mixture was heated to 100° C. for 3 h. The reaction was then cooled to RT and taken up in Et2O. The mixture was washed with H2O and brine, and the aq. phase was extracted again with Et2O. The combined org. layers dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, Hexane to Hexane/AcOEt 4:1) to afford the title compound (15.8 g) as brown oil. UPLC (2 min) rt 1.383.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5]1([C:26]3[C:17](=[CH:18][C:19]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:25]=3)[O:16][CH2:15]1)[C:6](=[O:14])[NH:7]2.[NH:27]1[C:35]2[C:30](=CC=C[CH:34]=2)[C@@:29]2([C:47]3[C:38](=CC4OCCOC=4C=3)OC2)C1=O.Br.BrCC1C=CC=CN=1.BrCCOCCOC>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5]1([C:26]3[C:17](=[CH:18][C:19]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:25]=3)[O:16][CH2:15]1)[C:6](=[O:14])[N:7]2[CH2:34][C:35]1[CH:30]=[CH:29][CH:47]=[CH:38][N:27]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: COc1cc2c(c(OC)c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2
Agent: Br
Agent: BrCc1ccccn1
Agent: COCCOCCBr
Product: COc1cc(OC)c2c(c1)N(Cc1ccccn1)C(=O)C21COc2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 1-bromo-2-(2-methoxyethoxy)ethane, 4′,6′-dimethoxy-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (78%) as a colorless solid: mp 187-188° C.; 1H NMR (300 MHz, DMSO-d6) δ8.59-8.34 (m, 1H), 7.86-7.66 (m, 1H), 7.44-7.19 (m, 2H), 6.51-6.32 (m, 1H), 6.32-6.14 (m, 3H), 5.17-4.80 (m, 2H), 4.79-4.50 (m, 2H), 4.25-3.95 (m, 4H), 3.66 (s, 3H), 3.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.7, 162.0, 156.7, 155.8, 155.6, 149.4, 144.3, 144.2, 137.7, 137.1, 122.7, 121.5, 120.3, 111.1, 108.9, 98.9, 93.1, 89.5, 64.5, 63.9, 57.1, 55.6, 46.2; MS (ES+) m/z 447.1 (M+1).
Reaction SMILES: [F:1][CH:2]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:16])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[C:3]1=[O:17].[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>C(O)(=O)C>[F:1][CH:2]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:16])=[CH:9][C:10]=3[N+:18]([O-:20])=[O:19])[CH2:5][C:4]=2[C:3]1=[O:17]
Reactant: O=[N+]([O-])O
Reactant: CC1=CC(F)C(=O)C2=C1c1ccc(F)cc1C2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1=CC(F)C(=O)C2=C1c1c(cc(F)cc1[N+](=O)[O-])C2

Procedure:
Treatment of 2,7-difluor-4-methyl-9H-fluorenone in acetic acid with a mixture of nitric acid and sulfuric acid gave 2,7-difluoro-4-methyl-5-nitro-9H-fluorenone as the major product. 5-Amino-2,7-difluoro-4-methyl-9H-fluorenone was obtained by reduction using tin(II)chloride in a mixture of ethanol and aqueous hydrochloric acid. Thermal decomposition in hot xylene of the diazonium tetrafluoroborate, formed with sodium nitrite in aqueous fluorboric acid, provided 2,4,7-tri-fluoro-5-methyl-9H-fluorenone. Treatment of the ketone with potassium cyanide and ammonium carbonate in ethanol at 120° C. for 18 hours provided the title compound.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[O:23]=[C:24](Cl)OC(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:1]([O:8][N:9]1[C:24](=[O:23])[N:14]2[CH2:15][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 2 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To (2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate (1.154 g, 4.37 mmol) was added dehydrated acetonitrile (198 mL), followed by ice-cooling. Triethylamine (1.60 mL) and diphosgene (0.389 mL) were sequentially added dropwise at 5° C. or less, followed by stirring at 2° C. for 20 minutes. Then, to the reaction solution was added 4-dimethylaminopyridine (70.0 mg), followed by stirring at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, followed by substituting and concentrating with ethyl acetate three times, and the solution was concentrated to 30 mL. Ethyl acetate (20 mL) and water (40 mL) were added thereto, followed by liquid separation, and the separated aqueous layer was extracted with ethyl acetate (30 mL) twice. The combined organic layers were washed with 5% citric acid aqueous solution (40 mL), 6.5% sodium bicarbonate aqueous solution (30 mL), and 5% brine (30 mL), and dried over anhydrous sodium sulfate, followed by filtration and concentration under reduced pressure. 1.16 g of the resulting residue was diluted with ethyl acetate (5.5 mL), and n-hexane (11 mL) was added, and a seed crystal was inoculated for crystallization. Further, n-hexane (49 mL) was added, followed by stirring at 0° C. for 1 hour. Subsequently, crystals were filtered, washed with n-hexane (60 mL), and then dried under vacuum to afford 882.3 mg of the title compound as colorless crystalline powder (yield 71%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21]O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:37]=[N+:38]=[N-:39])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:37]([CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)=[N+:38]=[N-:39]
Reactant: OCc1ccccc1-c1cccc(OCc2ccccc2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1ccccc1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of (3′-benzyloxybiphenyl-2yl)methanol from Step E (0.994 g, 3.42 mmol) and diphenylphosphoryl azide (1.13 g, 4.10 mmol) in dry toluene (6 mL) at 0° C., under argon, was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.62 g, 4.10 mmol) dropwise. The resulting mixture was stirred and allowed to warm to ambient temperature overnight. Toluene (6 mL) was added and the mixture was washed with water (2×5 mL), then 1.0 N aq. HCl (5 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 5% EtOAc in hexane, to give the titled product as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:27]Br.O>C(#N)C>[Br:27][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:21]
Reactant: Cc1cc(C)c2c(c1C)OCC2c1ccc(C(C)C)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1c(C)c2c(c(C)c1Br)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixture of 3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran synthesized in Reference Example 13 (6.10 g, 21.8 mmol) and sodium acetate (1.97 g, 24.0 mmol) in acetonitrile (30 mL) was added bromine (1.17 mL, 22.9 mmol), and the mixture was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The extract was washed with a saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was crystallized from methanol to obtain 7.90 g (yield 99%) of the title compound. Melting point: 86-87° C. (methanol).
Reaction SMILES: [BrH:1].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]>C(Cl)Cl>[Br:1][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=1
Reactant: CCCCc1ccc(CO)cc1
Reactant: Br
Solvent: ClCCl
Product: CCCCc1ccc(CBr)cc1
Reaction time: 0.75 h

Procedure:
HBr was bubbled into a solution of (4-butyl-phenyl)-methanol (10.0 g, 60.9 mmol) in CH2Cl2 (100 mL) for 15 minutes. The reaction was stirred for an additional 45 minutes and was poured onto ice water. The aqueous solution was extracted with CH2Cl2 (2×) and was dried (MgSO4), filtered, and concentrated to provide the title compound which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.29 (d, 2H), 7.14 (d, 2H), 4.49 (s, 2H), 2.60 (t, 2H), 1.58 (m, 2H), 1.36 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1.CN(C)[C:15]1[O:16][C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=1>C(O)(=O)C>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([N:6]2[C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[NH:20][C:15]2=[O:16])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: CC(=O)O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc([N+](=O)[O-])c(Cl)cc1F
Yield: 80.6 %

Procedure:
A solution of 4-chloro-2-fluoro-5-nitroaniline (5.0 g, 26.3 mmol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (5.73 g, 27.6 mmnol) in acetic acid is refluxed for 4 hours and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a beige solid (7.5 g, 81% yield, mp 230-232° C.) which is identified by 1H, 13C and 19F NMR spectral analyses.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO.C1COCC1>[Br:12][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(CO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7.00 g (46.6 mmol) 1-(4-hydroxymethyl-phenyl)-ethanone in 100 mL THF is added 22.5 g (46.6 mmol) tetrabutylammonium-tribromide dissolved in MeOH/THF. The reaction mixture is stirred 1 h at RT and the solvent is evaporated. The residue is dissolved with water and tertbutylmethylether. The organic phase is washed eight times with water. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is elutriated with diisopropylether and the precipitate is collected and dried.