Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23](Br)=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:8]3[CH:7]=[C:6]4[C:5](=[CH:10][CH:9]=3)[C:3](=[O:4])[O:2][CH2:1]4)=[CH:22][C:20]=2[N:21]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc4c(c3)COC4=O)cc2N=C(N)C1
Temperature: 100 °C

Procedure:
(1E,4E)-2-Amino-8-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide was prepared as follows, substituting 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one for 4-(methoxycarbonyl)phenylboronic acid. (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. 1H NMR (400 MHz, CDCl3) δ 7.96-8.00 (m, 1H), 7.78-7.82 (m, 1H), 7.72-7.74 (m, 1H), 7.52-7.55 (m, 1H), 7.38-7.42 (m, 1H), 7.30-7.35 (m, 1H), 6.85 (s, 1H), 5.37 (s, 2H), 3.60-3.71 (m, 2H), 3.39-3.53 (m, 4H), 2.85 (m, 2H), 1.59-1.75 (m, 4H), 0.90-0.99 (m, 6H); m/z (APCI-pos) M+1=418.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][Zn+])=[CH:18][CH:17]=1.Cl>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]([F:24])([F:25])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: FC(F)(F)Oc1ccc(C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccc(OC(F)(F)F)cc2)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 92.3 %

Procedure:
To a solution of methyl 2-chloroisonicotinate (4.80 g, 28 mmol) and Pd(PPh3)4 (0.647 g, 0.56 mmol) in tetrahydrofuran (50 mL) under nitrogen in a dried flask was added a freshly prepared solution of (4-(trifluoromethoxy)benzyl)zinc(II) bromide (12.56 g, 39.20 mmol) in tetrahydrofuran (90 mL). The resulting bright yellow mixture was heated to 60° C. for 2 h 30 min, then cooled to room temperature. The reaction was quenched by the addition of 10% aqueous NH4Cl. It was diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was suspended in 50 mL MTBE and sonicated, then the yellow insolubles were filtered off and washed with MTBE. The volume of the filtrate was increased to ca. 150 mL, then 5 mL MeOH was added, followed by hydrogen chloride (4 M in dioxane) (7.00 mL, 28.00 mmol). A colorless precipitate formed, which then dissolved again. The solvents were evaporated. The residue was dissolved in ca. 15 mL DCM and then MTBE and heptanes were added. An oil had formed that was triturated and after a few minutes a solid started to form. It was sonicated and then stirred at room temperature for 20 min. The formed solid was collected and washed with MTBE and dried. The solid was dissolved in DCM and washed with 10% K2CO3. After phase separation, the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(4-(trifluoromethoxy)benzyl)isonicotinate (8.04 g, 92%) was isolated as a pale yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.22 (s, 2H), 7.11-7.17 (m, 2H), 7.24-7.31 (m, 2H), 7.67-7.72 (m, 2H), 8.68-8.72 (m, 1H). MS m/z 312 (M+H)+
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:24](=[O:25])[NH:23][C:22](=[O:26])[NH:21]2)[C:13]1=[O:27].C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC>[CH2:5]([O:4][C:2]([N:21]1[C:14]2([C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]([CH2:11][C:10]3[CH:28]=[CH:29][C:30]([Cl:31])=[C:8]([Cl:7])[CH:9]=3)[C:13]2=[O:27])[C:24](=[O:25])[NH:23][C:22]1=[O:26])=[O:3])[CH3:6]
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)N1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A solution of ethyl chloroformate (0.55 g.) in 1,2-dimethoxyethane (20 ml.) was added dropwise to a stirred mixture of 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.) and sodium carbonate (2.0 g.) in 1,2-dimethoxyethane (60 ml.). When the addition was completed, the mixture was stirred for 16 hours and then evaporated. The residual solid was dissolved in warm water (150 ml.) and the solution obtained was slowly acidified (concentrated hydrochloric acid). The solid which was precipitated was separated by filtration, washed with water, air-dried and recrystallised twice from propan-2-ol/petrol 60-80 to give 3-ethoxycarbonyl-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.35 g.), m.p. 192°-194° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](F)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Tl].[C:25]1(=[O:32])[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH2:26]1>CCOCC>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([CH:26]3[C:27](=[O:31])[CH2:28][CH2:29][CH2:30][C:25]3=[O:32])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)F
Reactant: O=C1CCCC(=O)C1
Agent: [Tl]
Solvent: CCOCC
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)C1C(=O)CCCC1=O

Procedure:
2-[4-(4-Trifluoromethylphenoxy)phenoxy]propionic acid fluoride (0.10 mol) is added to a solution of the thallium salt of cyclohexane-1,3-dione in ether (200 ml) over a period of 30 minutes. The mixture is filtered and the filtrate is concentrated to give 2-[[2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl]]cyclohexane-1,3-dione (V; Y is H, Z is CF3, R1 is CH3 and n is two).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[O:23])[CH:20]=2)[N:15]=[C:14]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:13]=1>O1CCCC1>[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[OH:23])[CH:20]=2)[N:15]=[C:14]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:13]=1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2n1
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of thiazole (255 mg, 3.00 mmol, 2.00 equip) in tetrahydrofuran (15 mL). To the resulting mixture was then added n-BuLi (1 mL, 1.70 equip, 2.5 M) dropwise with stirring at −78° C. The resulting solution was stirred for 50 min at −78° C. To the resulting mixture was added a solution of (4-bromo-2-tert-butoxyquinolin-6-yl) (4-chlorophenyl) methanone (630 mg, 1.50 mmol, 1.00 equip) in tetrahydrofuran (5 mL) dropwise with stirring at −78° C. The resulting solution was allowed to react, with stirring, for an additional 40 min at −78° C. The resulting solution was stirred for 30 min at 0° C. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and brine (1×50 mL). The resulting mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:4) to yield (4-bromo-2-tert-butoxyquinolin-6-yl)(4-chlorophenyl)(thiazol-2-yl)methanol as a white solid. (ES, m/z): [M+H]+ 505
Reaction SMILES: [CH3:1][C:2]1[CH:7]=C(C)C=C(C)[C:3]=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].C(Cl)(=O)C(C)C>N1C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:1]([CH:2]([CH3:7])[CH3:3])[N:22]=[C:16]2[CH:17]=1
Reactant: Nc1cc(Br)cc[n+]1N
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)c1nc2cc(Br)ccn2n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
A mixture of 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (2 g, 5.15 mmol) and isobutyryl chloride (809 μl, 7.73 mmol) in pyridine (12 ml) is stirred for 18 hours at 100° C. The solvent is evaporated and the orange residue triturated for 2 hrs with sat. aqueous sodium hydrogen carbonate solution. The solid is collected by filtration, washed several times with water and dried affording 7-bromo-2-isopropyl-[1,2,4]triazolo[1,5-a]pyridine (378 mg, 30.6%) as a light brown solid. MS: m/z=240; 242 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C@@:5]2([N:28]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:21]2[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:46][C:47]([F:50])([F:49])[CH3:48])(=O)=O)=CC=1.N#N.[I-].[K+]>CN(C=O)C.O.CCOC(C)=O>[F:49][C:47]([F:50])([CH3:48])[CH2:46][O:19][C:16]1[CH:15]=[C:14]([F:20])[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:21]4[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:4][S:3][C:2]([NH2:1])=[N:28]3)[C:18]=2[CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(F)F)cc1
Reactant: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(O)cc12
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(F)(F)COc1cc(F)c2c(c1)[C@]1(CSC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 160 °C
Yield: 2.9 %

Procedure:
A glass microwave reaction vessel was charged with (S)-2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (230 mg, 0.58 mmol, prepared as described in Method BB26 and Example 2 but using 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one), cesium carbonate (302 mg, 0.93 mmol) and 2,2-difluoropropyl 4-methylbenzenesulfonate (159 mg, 0.64 mmol) in DMF (2.5 mL). The reaction mixture was purged with N2 and finally potassium iodide (192 mg, 1.16 mmol) was added. The reaction mixture was stirred and heated in a Initiator microwave reactor at 160° C. for 1.5 h. Then it was diluted with water and extractd by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc again. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide crude product that was purified by chromatography through a Redi-Sep pre-packed silica gel column (24 g), eluting with a gradient of 15% to 30% to 60% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane to provide (S)-2′-(2,2-difluoropropoxy)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (18 mg, 0.017 mmol, 4.78% yield) as off-white solid. MS m/z=486.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 1.75 (t, J=19.32 Hz, 3 H) 3.34-3.49 (m, 2 H) 4.19-4.43 (m, 2 H) 6.81 (dd, J=2.89, 1.61 Hz, 1 H) 7.05 (s, 2 H) 7.16 (dd, J=12.28, 2.98 Hz, 1 H) 7.36-7.44 (m, 1 H) 7.50 (ddd, J=7.26, 5.01, 1.91 Hz, 1 H) 7.58-7.66 (m, 2 H) 8.09 (ddd, J=10.34, 7.51, 1.91 Hz, 1 H) 8.25 (dt, J=4.82, 1.55 Hz, 1 H)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][CH2:14][CH2:15][C:10]=3[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:25])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][CH2:14][CH2:15][C:10]=3[CH:9]=2)=[CH:6][C:5]([Br:25])=[CH:4][N:3]=1
Reactant: Nc1ncccc1-c1cc2c(s1)C(=O)NCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ncc(Br)cc1-c1cc2c(s1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 2-(2-aminopyridin-3-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (250 mg, 1.02 mmol) in DMF (3 ml) was added NBS (199 mg, 1.12 mmol). The reaction was stirred at room temperature for 1 h, then concentrated and taken up in DCM (10 mL). The organic solution was washed with a sat. aq. Na2S2O3, then dried over Na2SO4, and concentrated to give 2-(2-amino-5-bromopyridin-3-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (320 mg, 97% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (d, J=2.0 Hz, 1H), 7.73 (br. s., 1H), 7.66 (d, J=1.8 Hz, 1H), 7.29 (s, 1H), 6.23 (br. s., 2H), 3.40-3.50 (m, 2H), 2.83 (t, J=6.9 Hz, 2H); MS (EI) m/z=325.2 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH3:20]>C(#N)C>[CH2:17]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1])[CH2:18][CH2:19][CH3:20]
Reactant: OCc1ccccc1O
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1ccccc1CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
2-Hydroxymethyl phenol (1.2 g, 9.6 mmol) was dissolved in 10 mL of dry acetonitrile. Potassium carbonate (1.3 g, 9.6 mmol) and 1-iodobutane (1 mL, 8.8 mmol) were added and the reaction was stirred at room temperature for 3 days and at 50° C. for 1 day. The solvent was removed and the residue partitioned between ethyl acetate and 1N hydrochloric acid. The acidic aqueous layer was extracted with ethyl acetate(3×25 mL). The combined organic extracts were washed with 0.5 N sodium hydroxide (3×20 mL), dried over MgSO4, filtered and concentrated to provide the title compound (800 mg, 50% yield) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:18][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[2-(Bromomethyl)phenoxy](tert-butyl)dimethylsilane was prepared according to the literature procedure (J. Chem. Soc. Perkin Trans.1; 1988; 1417). To a solution of (2-([tert-butyl(dimethyl)silyl]oxy}phenyl)methanol (9.9 g/41.5 mmol) in acetonitrile (200 ml) was added carbon tetrabromide (14.5 g/43.6 mmol), triphenylphosphine (11.4 g/43.6 mmol) successively at 0° C., and then the resulting solution was stirred at room temperature for 16 hours. The solvent was evaporated. The residue was purified by column chromatography (SiO2, 200-350 mesh/hexane:ethyl acetate=100:1-20:1-10:1) to afford a colorless oil (12.0 g/96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[N:38]2)[CH:32]=1)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:28](=[O:27])[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Yield: 39.7 %

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) (163 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) (181 mg, 0.7 mmol) according to the general procedure K. Obtained as a yellow oil (107 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].C[O-].[Na+].[I-].[K+].Br[CH:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>CO.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[O:12][CH:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[CH:26][CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)c1ccc(O)c(Cl)c1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1Cl)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 4.62 g of 2-chloro-4-tert-butylphenol, 1.188 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is heated at reflux overnight. The mixture is worked up as described in Example 68 to yield a yellow oil. Chromatography on 100 g of silica gel (benzene, 400 ml) affords an oil which solidifies. Recrystallization from hexane yields white plates, mp 85.5°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:26][CH:22]4[CH2:23][NH:24][CH2:25][CH:21]4[CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[C:34](#N)C.O.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O>[F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:26][CH:22]4[CH2:23][N:24]([CH3:34])[CH2:25][CH:21]4[CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CC#N
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CNCC2C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CN(C)CC2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (2.1 g, 3.9 mmol, 1.0 eq.) and acetonitrile/water 1:1 (5 ml, 5 ml). The reaction mixture was then cooled to 0° C. and 37% solution of formaldehyde in water was added (0.2 g, 7.8 mmol, 2.0 eq). While keeping the temperature at 0° C. Na(OAc)3BH was added (4.4 g, 20.7 mmol, 3.0 eq). After 1 hour the pH was adjusted to 10 and the aqueous was extracted 2×DCM (100 ml). Removal of the DCM resulted in a white solid. The compound was further purified with a biotage system using an eluent EtOAc and 5% MeOH, affording 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydrocyclopenta-[c]pyrrol-5-ylmethoxy)-quinoline (0.9 g, 50% yield). 1H NMR (400 MHz, CDCl3): 8.57 (d, 1H), 8.14 (dd, 1H), 8.12 (dd, 1H), 7.41 (s, 2H), 7.34 (t, 1H), 6.54 (d, 1H), 4.19 (d, 2H), 4.01 (s, 3H), 2.61 (m, 4H), 2.43 (m, 1H), 2.33 (s, 3H), 2.11 (m, 4H), 1.32 (m, 2H); MS (EI) for C25H26FN3O5: 468 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([C:21]([O:23]C)=[O:22])=[CH:19][C:18]([N+:25]([O-:27])=[O:26])=[C:17]([CH3:28])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]([N+:25]([O-:27])=[O:26])=[C:17]([CH3:28])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
A solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-methoxycarbonyl-2-methylnitrobenzene (4.9 g) in concentrated hydrochloric acid (100 ml) was stirred at 80° C. for 5 hours. The reaction mixture was concentrated in vacuo. To a solution of the residual white solid in a mixture of water (30 ml) and acetone (30 ml) were added sodium hydrogencarbonate (2.3 g) and di-t-butyl dicarbonate (3.3 g) at room temperature. The resulting mixture was stirred at 40° C. for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the desired compound (4.8 g, yield quantitative) as a yellow amorphous solid.
Reaction SMILES: [F-].[Cd+2:2].[F-].[Cd].OO.[C:7]([OH:10])(=[O:9])[CH3:8]>>[C:7]([O-:10])(=[O:9])[CH3:8].[Cd+2:2].[C:7]([O-:10])(=[O:9])[CH3:8]
Reactant: CC(=O)O
Agent: OO
Agent: [Cd+2]
Agent: [Cd]
Product: CC(=O)[O-]

Procedure:
The preparation procedure for cadmium fluoride is somewhat different. High purity cadmium metal (typically 99.999 percent pure) is reacted with acetic acid and hydrogen peroxide to yield cadmium acetate. This compound is then reacted with hydrogen fluoride to yield cadmium fluoride. The cadmium fluoride is slowly heated to the melting point in an atmosphere of carbon tetrafluoride to ensure removal of water, oxide and oxyfluoride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH:12]=O.N1CCCCC1.[BH4-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ccncn2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
A solution of 4-aminopyrimidine (20.0 g, 210 mmol), 2,4-dimethoxybenzaldehyde (69.9 g, 421 mmol) and piperidine (2.08 mL, 21.0 mmol) in toluene (1 L) was stirred for 7 hours under reflux, and the solvent was subjected to azeotropic distillation with water. After allowing to cool, the reaction solution was diluted with ethanol (500 mL). Sodium borohydride (7.96 g, 210 mmol) was added thereto with cooling on ice, and the mixture was stirred at room temperature for 16 hours. To the reaction solution, water (500 mL) was added, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (ethyl acetate/methanol=95:5) to yield the title compound (27.0 g, 52%) as a colorless solid.