Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24].[NH4+].[Cl-]>CCOCC.O>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2([OH:24])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccccc1Br
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
40 g (1.65 mol) magnesium shavings were overlaid with 100 ml ether, and after the addition of a small amount of iodine, they were carefully heated until the reaction kicked off. 203 ml (1.65 mol) bromanisole, dissolved in 450 ml ether, were dropped in to the boiling solution so slowly that the reaction continually proceeded at a low boil. Subsequently, with slight cooling to 20° C., 75 g (0.41 mol) 5-chlorisatin in 750 ml water-free tetrahydrofurane were added in by drops. After this, everything was stirred for 30 minutes more at room temperature. The reaction solution was poured into an aqueous NH4Cl solution while being stirred. This aqueous phase was extracted a number of times with ethyl acetate and the combined aqueous phases were washed with water four times, dried and concentrated in a vacuum. The residue obtained was crystallised from isopropanol, wherein 106 g of the intermediate product resulted.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[Cl:23]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[Cl:23]
Reactant: Clc1cccc(Br)c1Cl
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Product: CC1(C)C(=O)N(C2CC3CCC2C3)N1c1cccc(Cl)c1Cl

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 1-bromo-2,3-dichlorobenzene were used for a similar reaction and treatment as Example 181, and the title compound was obtained as a pale yellow crystalline powder.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[S:40][C:16]2[N:17](C(OCC)=O)[N:18]=[C:19]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:15]=2[CH:14]=1)=[O:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]>CO.C(N(CC)CC)C>[CH3:3][C:2]([NH:10][C:11]([C:13]1[S:40][C:16]2[NH:17][N:18]=[C:19]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:15]=2[CH:14]=1)=[O:12])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(NC(=O)c1cc2c(NC(=O)c3ccc(N4CCOCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 86.7 %

Procedure:
A suspension of ethyl 5-{[(1-methyl-1-phenylethyl)amino]carbonyl}-3-[(4-morpholin-4-ylbenzoyl)amino]-1H-thieno[2,3-c]pyrazole-1-carboxylate (3.71 g, 6.6 mmol) in methanol (MeOH, 70 mL) and triethylamine (TEA, 7 mL) was stirred at 70° C. for 5 hours. After evaporation of the solvent under reduced pressure, the residue was taken up with DCM and washed with water. The organic layer was separated, dried over sodium sulfate and evaporated. Purification by chromatography (DCM/MeOH 47:3) gave 2.8 g of the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:20])[CH2:18]Br)=[CH:15][CH:14]=1>C(O)C.O.CCOC(C)=O>[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:20])[CH2:18][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: COc1cccc(S)c1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(SCC(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 104.5 %

Procedure:
14.27 ml (115.0 mmol) 3-mercaptoanisole were added to a solution of 7.3 g (115.0 mmol) KOH in 120 ml ethanol and 50 ml water. 25.0 g (115.2 mmol) 4-fluorophenacyl bromide in 120 ml EtOAc were added slowly at 0° C. and the solution was stirred at RT over night. The suspension was concentrated and dissolved in EtOAc and water. The inorganic phase was extracted with EtOAc, the combined organic phases were washed with water and brine and dried over Na2SO4. Evaporation yielded 33.2 g crude 1-(4-Fluoro-phenyl)-2-(3-methoxy-phenylsulfanyl)-ethanone as light yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:32][C:26]1[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=[C:24]([NH:23][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[CH:25]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1nn(C(C)C)cc1C(O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C(C)C)cc1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-isopropyl-1H-pyrazole-3-carboxylate (Step 41.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.65 min (HPLC 1); tR: 1.07 min (LC-MS 2); ESI-MS: 463 [M+H]+ (LC-MS 2); Rf=0.30 (EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]#[N:26])=[CH:7]2.[NH2:27][NH2:28].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:7]2
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccc(Cl)c23)C1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3cccc(Cl)c23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((8-chloro-3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (450 mg, 1.21 mmol) in MeOH (5 mL) was added NH2NH2—H2O (5 mL). The resulting mixture was heated to reflux for 2 hours and the solvent was subsequently removed to give the title compound as a yellow solid, which was used without further purification (450 mg, 91%). ESI-MS m/z [M+H]+ 405.2.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:17]1([P:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>C1COCC1>[C:34]1([P:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[NH:32][CH:31]([C:2]2[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=2)[CH:30]=[CH:29]3)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: c1ccc(P(c2ccccc2)c2cccc3cccnc23)cc1
Reactant: Brc1cccc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C1=CC(c2cccc3ccccc23)Nc2c1cccc2P(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of 1-bromonaphthalene (8.57 mL, 60 mmol) in dry THF (100 mL) under nitrogen was added n-BuLi (37.5 mL, 1.6 M in hexanes, 60 mmol) at −78° C. and the solution was stirred for 30 minutes at −78° C. before adding 8-diphenylphoshinoquinoline (1) (9.4 g, 30 mmol). After stirring at 0° C. for 10 minutes the solution was again cooled down to −78° C., saturated aqueous NH4Cl solution (10 mL) was added and the mixture was warmed to room temperature. Products were then extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give the 11 as a tan solid (13.0 g, 98%). 1H NMR (400.13 MHz, CDCl3) δ 8.0-7.9 (m, 1H, C5′—H), 7.8-7.7 (m, 1H, C8′—H), 7.66 (d, 1H, J=8.0 Hz, C2′—H), 7.5-7.3 (m, 2H, C6′/7′—H), 7.36 (d, 1H, J=6.4 Hz, C4′—H), 7.3-7.1 (m, 11H, C3′—H/Ph-H), 6.86 (dd, 1H, J=7.2, 1.2 Hz, C5—H), 6.64 (ddd, 1H, J=8.0, 6.4, 1.6 Hz, C7—H), 6.48 (t, 1H, J=7.6 Hz, C6—H), 6.35 (dd, 1H, J=9.6, 1.6 Hz, C4—H), 6.16 (t, 1H, J=1.6 Hz, C2—H), 5.70 (ddd, 1H, J=10.0, 3.6, 1.6 Hz, C3—H), 5.02 (bd, 1H, J=7.6 Hz, N—H) ppm; 13C NMR (100.61 MHz, CDCl3) δ 146.6, 146.5, 139.8, 129.5, 128.7, 128.6, 128.5, 128.4, 128.3 (m), 127.7, 135.1 (d, J=8.1 Hz), 134.9 (d, J=7.1 Hz), 134.5 (d, J=5.1 Hz), 133.9, 133.5 (d, J=13.1 Hz), 133.3 (d, J=12.1 Hz), 126.2, 125.6, 125.3, 125.2, 124.8, 124.4, 122.5, 118.8, 117.1, 116.3, 54.0 ppm; 31P NMR (161.97 MHz, CDCl3) δ −23.1 ppm.
Reaction SMILES: C([NH:5][S:6]([CH2:9][CH2:10][CH2:11][CH:12]([O:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:13])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:15]([O:14][CH:12]([CH3:13])[CH2:11][CH2:10][CH2:9][S:6]([NH2:5])(=[O:8])=[O:7])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(CCCS(=O)(=O)NC(C)(C)C)OC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CCCS(N)(=O)=O)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
A mixture of N-t-butyl-4-benzoyloxy-1-pentanesulfonamide (15.0 g) and trifluoroacetic acid (70 ml) was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. Water and chloroform were added to the residue. Then, a saturated aqueous solution of sodium hydrogencarbonate was added thereto while stirring to adjust the pH of the aqueous to neutral. The chloroform layer was dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluate: ethyl acetate) to obtain 4-benzoyloxy-1-pentanesulfonamide (11.1 g).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][C@H:16]([OH:21])[C@:15]3([CH3:22])[C@H:5]1[CH2:4][CH2:3]2.[CH3:23][C:24](C)([O-])C.[K+]>[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[CH3:23]/[CH:24]=[C:10]1/[CH2:9][CH2:8][C@@H:7]2[C@:2]/1([CH3:1])[CH2:3][CH2:4][C@H:5]1[C@H:6]2[CH2:12][CH:13]=[C:14]2[C@:15]1([CH3:22])[C@@H:16]([OH:21])[CH2:17][C@H:18]([OH:20])[CH2:19]2
Reactant: C[C@]12C(=CC[C@@H]3[C@@H]1CC[C@]1(C)C(=O)CC[C@@H]31)C[C@@H](O)C[C@@H]2O
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C/C=C1/CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 9.12 g (30 mmol) of 1α-hydroxydehydroepiandrosterone and 25.1 g (60 mmol) of ethyltriphenylphosphonium iodide in 250 ml of tetrahydrofuran under a nitrogen atmosphere was added portionwise over ca. 5 min., 6.7 g (60 mmol) of potassium tert.-butoxide. The reaction temperature rose to 30°. After stirring at room temperature over night (16 hr.), the reaction was heated at reflux (oil bath) for 4.5 hr. to produce (Z)-1α,3β-pregna-5,17(20)-diene-1,3-diol (Tlc: EtOAc, showed starting material was consumed). On cooling to 50°, 60 ml of pyridine and 30 ml of acetic anhydride were added, and the reaction solution left stirring over night (18 hr.) and then heated at reflux for 2 hr. Acetylation was still incomplete (Tlc: 4:1, hexane--ethyl acetate showed mono and diacetates). Consequently, 100 mg of 4-dimethylaminopyridine was added, and heating at reflux was continued for 5 hr. Then, the reaction solution was diluted with 250 ml of 80% aqueous methanol (v/v) and, after cooling to room temperature, was extracted with 3×200 ml of hexane. The organic phases were washed in a countercurrent manner with 250 ml of 80% aq. methanol (v/v) and evaporated under reduced pressure to give 12.0 g of crude product. Chromatography on 500 g of silica gel prepared in hexane, and elution with 200 ml fractions of 8:1, hexane--ethyl acetate afforded, in fractions 7-11, 6.8 g of impure product and, in fractions 12-17, 4.2 g of pure product. The combined fractions 7-11, on rechromatography, gave 6.2 g of pure product. Thus, a total of 10.4 g (87%) of pure 1α,3β-diacetyloxypregna-5,17(20)-diene as an amorphous solid, was obtained as a 95:5 mixture of Z and E isomers, respectively. An analytical sample of (Z)-1α,3β-diacetyloxypregna-5,17(20)-diene, obtained by two recrystallizations from methanol, had mp 90°-91°.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1)[CH2:14][CH2:15][CH3:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:13]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[C:19]([F:24])[CH:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Yield: 40 %

Procedure:
2,3,4-Trifluorobenzoic acid and 4-butyl-2-fluoroaniline were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B, affording crude 2-(4-butyl-2-fluoroanilino)-3,4-difluorobenzoic acid after workup. The crude material was further purified by flash chromatography on silica (10% EtOAc/Hexane as eluant) to give the desired compound (40%). 1H NMR [400 MHz, CH30D] δ 7.86 (ddd, J=8.4, 5.8, 2.1 Hz, 1 H), 6.96–6.86 (m, 3 H), 6.78 (ddd, J=9.4, 9.4, 7.1 Hz, 1 H), 2.58 (t, J=7.7 Hz, 2 H), 1.63–1.55 (m, 2 H), 1.36 (sextet, J=7.4, 2H), 0.94 (t, J=7.5, 3 H). LCMS (ACPI+) 329 (100%).
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[C:16]2[O:15][CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>[Pd].CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:16]2[O:15][CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COC/C=C/c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: COCCCc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Reaction time: 12 h
Yield: 85 %

Procedure:
A mixture of tert-butyl 9-[(1E)-3-methoxypropa-1-ene-1-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.622 mmol) and 10% palladium on carbon (50.0 mg) in methanol (4 ml) was stirred under a hydrogen atmosphere for 12 hr. The reaction mixture was filtered, and the filtrate was concentrated. The residue was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (170 mg, 85.0%) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([F:13])[CH:7]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:2][C:3](=[O:4])[NH:5]2)=[CH:10][C:9]=1[CH3:12]
Reactant: Cc1ccc(NC(=O)CCl)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc2c(cc1F)NC(=O)C2
Temperature: 0 °C
Reaction time: 4 h
Yield: 2.9 %

Procedure:
An intimate mixture of 11.62 g (57.6 mmol) of N-(2-chloroacetyl)-3-fluoro-4-methylaniline and 30.6 g (229.5 mmol) of anhydrous aluminum chloride was heated to 210°-220° C. After 4 hours, the reaction mixture was cooled and then added to 100 ml of 1N hydrochloric acid and 50 ml of ice. A tan solid formed, which was collected by filtration and recrystallized from aqueous ethanol. Three crops were obtained, weighing 4.49 g, 2.28 g and 1.0 g, respectively. The crop weighing 1.0 g was further recrystallized from water to give 280 mg of the title compound, m.p. 168.5°-171° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][C:19](=[CH:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)=[CH:12][C:11]=2[F:25])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[FH:26].C(=O)([O-])O.[Na+]>ClCCl.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:17][CH2:18][C:19]([F:26])([CH2:22][CH2:23][CH3:24])[CH2:20][CH2:21]3)=[CH:12][C:11]=2[F:25])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: F
Reactant: CCC=C1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1(F)CCC(c2ccc(-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
8.0 g of 3,4,5,2'-tetrafluoro-4'-(4-propylidenecyclohexyl)biphenyl in 16 ml of dichloromethane were introduced into a Teflon apparatus and cooled to -25° C. 80 ml of a 70% solution of hydrogen fluoride in pyridine were then added dropwise with stirring, and the mixture was stirred for 30 minutes at -25° C. and then for a further 1 hour at room temperature. The reaction solution was poured into a suspension of 10 g of sodium hydrogencarbonate and 200 g of ice-water. The mixture was then extracted with 3×80 ml of hexane. The combined organic extracts were washed once with 50 ml of sodium chloride solution, dried using sodium sulfate, filtered and evaporated to a residue. The crude product was purified by means of a silica-gel frit and the eluate was evaporated to a residue, giving 3,4,5,2'-tetrafluoro-4'-(4-fluoro-4-propylcyclohexyl)-biphenyl (C 73 N (48.8) I, Δε=15.3, Δn=+0.111).
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12](=[O:18])[C:13](=[O:17])[NH:14]2)=[CH:10][CH:9]=1>C(OCC)C.C1COCC1>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([OH:18])([CH3:5])[C:13](=[O:17])[NH:14]2)=[CH:10][CH:9]=1
Reactant: CI
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Agent: C[Mg]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)C(=O)Nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
To a ice-cold solution of methyl magnesium iodide prepared from magnesium (1.7 g, 70.78 mmoles) and methyl iodide (4.40 ml, 70.78 mmoles) in diethyl ether (60 ml), 6-bromoisatin (4 g, 17.69 mmoles) in THF (120 ml) was added and warmed to room temperature. After 12 h, the reaction mixture was cooled to 0° C., quenched with dilute HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as brown solid (4.2 g, 93% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 10.34 (s, 1H), 7.23 (t, J=7.9 Hz, 1H), 7.14 (dd, J=7.9, 1.7 Hz, 1H), 6.93 (d, J=1.6 Hz, 1H), 5.92 (s, 1H), 1.33 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.I([Cl:31])(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl>[Cl:31][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(Cl)ccc3O)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the title compound from Example 1 Step B (1.00 g, 2.65 mmol) in DCM (13 mL) was added benzyltrimethylammonium tetrachloroiodate (1.13 g, 2.70 mmol) and the resulting mixture was allowed to stir at ambient temperature. After 24 h, the mixture was concentrated in vacuo. Purification by chromatography on silica gel (0 to 18% EtOAc in hexanes, then 18 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 412.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 11.98 (s, 1H), 8.18 (s, 1H), 8.10 (t, J=8.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.78 (br s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.30 (dd, J=9.0, 2.0 Hz, 1H), 6.98 (d, J=9.0 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.[Cl-].[NH4+]>CC(C)=O.O.[Zn]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: Fc1ccc(C2CCCc3c(Cl)nc(Cl)nc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: Fc1ccc(C2CCCc3cnc(Cl)nc32)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
A mixture of 2,4-dichloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (115 mg, 0.387 mmol), Ammonium chloride (26.9 mg, 0.503 mmol) and zinc (266 mg, 4.06 mmol) in acetone (1 mL) and water (1.000 mL) was heated at 90° C. with stirring for 2 h. The reaction mixture was filtered through a short plug of celite. The solvent was removed in vacuum, and the residue was partitioned between dichloromethane and water. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-chloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (20 mg, 0.076 mmol, 19.67% yield) as a white solid. LC-MS (M+H)+=263.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH2:11].[CH:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14].O.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:13]=[CH2:14])=[N:6][C:5]=1[NH2:11]
Reactant: COC(=O)c1ccc(Cl)nc1N
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: C=Cc1ccc(C(=O)OC)c(N)n1
Temperature: 130 °C
Yield: 66.5 %

Procedure:
2-Amino-6-chloro-nicotinic acid methyl ester (2.95 g, 15.8 mmol), vinyl tri-n-butyltin (5.01 g, 15.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.83 g, 1.58 mmol) were suspended in xylene (15 mL), and heated for 1 hour at 130° C. The reaction mixture was allowed to room temperature, water and ethyl acetate were added thereto, this mixture was filtered through Celite pad, then, the filtrate thereof was partitioned. The organic layer was separated, the solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography to obtain the title compound (1.87 g, 10.5 mmol, 66%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20]>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[OH:11]
Reactant: COc1ccc(C(C)O)cc1
Reactant: COc1ccccc1O
Product: COc1ccc(C(O)COc2ccccc2OC)cc1

Procedure:
2-(2-methoxyphenoxy)-1-(4-methoxyphenyl)ethan-1-ol (30 mg, 1.4×10−4 mol) and wet Raney Ni 4200 (25 mg, 4.2×10−4 mol, 100 mol %) is weighed into a reaction flask under argon. Degassed i-PrOH (5 mL) is added and the flask is capped with a rubber septa and the mixture is heated (80° C.). The reaction is run for 18 hours and the reaction mixture is cooled. Nickel was removed with a magnet. Concentration gave 25 mg of a reaction mixture which is, according to analysis by HNMR, is 1-(4-methoxyphenyl)ethan-1-ol and 2-methoxyphenol. The β-O-4 bond was 100% broken.