Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[C:19]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:20]3[CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[O-]S(C(F)(F)[F:49])(=O)=O.F[N+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[S:3][C:4]([C:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([F:49])=[C:19]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:20]3[CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(=O)c2ccc3c(F)c(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Temperature: 25 °C
Yield: 26.7 %

Procedure:
To a solution of 5 (170 mg, 0.25 mmol) in 3 mL CH2Cl2 was added 1-fluoropyridinium triflate (75 mg, 0.30 mmol), and then the mixture was stirred at room temperature until no 5 was detected by NMR. The resulting mixture was diluted with 40 mL Et2O, washed with brine (2×10 mL), dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/9:1) gave 6 (45 mg, 26%) as a yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.78-7.63 (m, 6H), 7.56 (s, 1H), 7.50-7.41 (m, 5H), 4.25 (t, J=7.2 Hz, 2H), 3.71 (s, 3H), 3.69 (s, 2H), 3.49 (t, J=6.8 Hz, 2H), 1.66-1.60 (m, 2H), and 1.50-1.45 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 186.88, 170.13, 168.24, 143.76, 142.84, 140.39, 135.53, 134.70, 133.95, 133.90, 132.08, 132.02, 131.85, 131.39, 129.70, 128.91, 128.87, 128.72, 128.21, 128.18, 127.32, 127.12, 123.20, 121.58, 120.91, 119.94, 119.78, 116.78, 116.76, 112.32, 52.30, 43.37, 36.95, 34.81, 27.06, and 25.51.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@@H](C2C=CC=CC=2)CO)C1.[CH3:37][NH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1>>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([N:38]([C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=2)[CH3:37])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: COCO[C@H]1CCN(C[C@H](O)c2ccccc2)C1
Agent: COCO[C@H]1CCN([C@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(C[C@@H](c2ccccc2)N(C)c2ccc(C(=O)OC)cc2)C1
Yield: 49 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(S)-phenylethanol and methyl 4-methylaminobenzoate in 49% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: C(Cl)CCl.[C:5]([OH:13])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[Cl-].[CH3:15][O:16][NH2+:17][CH3:18]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:15][O:16][N:17]([CH3:18])[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C[NH2+]OC
Reactant: C=CCCCCC(=O)O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CCCCCC(=O)N(C)OC
Reaction time: 14 h
Yield: 97 %

Procedure:
EDC (1.1 eq.) was added in small portions over 1.5 h to a stirred mixture of hept-6-enoic acid, methoxy(methyl)ammonium chloride (1.1 eq.) and DMAP (1.1 eq.) in CH2Cl2 (0.2 M). After 14 h, the mixture was diluted with CH2Cl2, then washed sequentially with hydrochloric acid (1 M), NaOH (1M), brine and dried (Na2SO4). Evaporation of the solvent afforded the title compound (97%) as a colorless oil. 1H NMR (400 MHz, CDCl3, 300 K) δ 5.87-5.75 (m, 1H), 5.01 (d, J 17.1, 1H), 4.95 (d, J 10.1, 1H), 3.68 (s, 3H), 3.18 (s, 3H), 2.48-2.36 (m, 2H), 2.13-2.04 (m, 2H), 1.71-1.60 (m, 2H), 1.50-1.40 (m, 2H).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH2:19][Zn+])[CH:12]=[N:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[CH:6]=[CH:7][CH:8]=1.BrCCBr.C[Si](Cl)(C)C.BrC[C:32]1[CH:33]=[C:34](C2C=CC=C(Cl)C=2)[C:35](OC(F)F)=[N:36][CH:37]=1>C1COCC1.[Zn]>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([O:15][CH:16]([F:18])[F:17])=[N:13][CH:12]=[C:11]([CH2:19][C:35]3[CH:34]=[CH:33][CH:32]=[CH:37][N:36]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)Oc1ncc(C[Zn+])cc1-c1cccc(Cl)c1
Reactant: FC(F)Oc1ncc(CBr)cc1-c1cccc(Cl)c1
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: FC(F)Oc1ncc(Cc2ccccn2)cc1-c1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
((5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)zinc(II) bromide. To a suspension of zinc (42.77 mg, 0.65 mmol) in THF (1 mL) was added 1,2-dibromoethane (2.48 μL, 0.03 mmol). The resulting mixture was heated at 70° C. for 10 minutes before being cooled to room temperature. Once cooled, trimethylsilylchloride (2.92 μL, 0.02 mmol) was added and the solution was stirred at room temperature for an additional 30 min. To the activated zinc solution was added 5-(bromomethyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine (Intermediate 12, 200 mg, 0.57 mmol) and the resulting mixture was heated at 70° C. for 8 h. The reaction mixture was cooled to room temperature and decanted from the solids to afford a ˜0.5 M solution of the title compound.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1.[CH2:12]([CH:15]([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([C:15]([CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1)([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14]
Reactant: COC(=O)c1cnn(CCl)c1
Reactant: C=CCC(C#N)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(C#N)Cn1cc(C(=O)OC)cn1
Yield: 45.2 %

Procedure:
0.79 g of 1-(chloromethyl)-4-methoxycarbonyl-1H-pyrazole and 0.49 g of allyl malononitrile were dissolved in 15 ml of N,N-dimethylformamide. 1.26 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then recrystallized from hexane-chloroform to obtain 0.50 g of allyl [{4-(methoxycarbonyl)-1H-pyrazole-1-yl}methyl]malononitrile (referred to as the compound of the present invention (24), hereinafter) shown by below formula.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[C:4]([CH3:21])[N:3]=1.N[CH2:23][C:24]1[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:25]=1>>[CH3:21][C:4]1[N:3]=[C:2]([NH:1][CH2:23][C:24]2[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:25]=2)[C:7]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)=[C:6]([CH3:20])[N:5]=1
Reactant: CCOC(=O)c1ccc(CN)o1
Reactant: Cc1nc(C)c(C#Cc2ccc(C(F)(F)F)cc2)c(N)n1
Product: CCOC(=O)c1ccc(CNc2nc(C)nc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1

Procedure:
The method described in any one of Example 1 to Example 10 and Example 23 was repeated except that 4-amino-2,6-dimethyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine was used in place of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine or ethyl 5-aminomethyl-2-furancarboxylate was used in place of ethyl (4-aminomethyl)benzoate to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [Na].Br[C:3]1[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=[C:5]([Cl:20])[C:4]=1[CH3:21].[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>O.C1(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>[Cl:20][C:5]1[C:4]([CH3:21])=[C:3]([C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cc(F)cc(F)c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc(Cl)c(C)c(-c2ccncc2)c1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 6.5 %

Procedure:
To a solution of sodium hydrogenecarbonate (0.093 g, 1.1 mmol) in water (2 mL) was added a solution of 1-(6-bromo-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone (0.20 g, 0.56 mmol) in toluene (2 mL) followed by 4-pyridinylboronic Acid (0.082 g, 0.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.033 g, 0.029 mmol). The mixture was bubbled with N2 for 5 min and then heated at 80° C. overnight. The organic layer was concentrated and flashed on silica gel (eluting with 0-35% of ethyl acetate in hexanes) to afford the desired product (13 mg, 6.5%). LCMS calculated for C20H15ClF2NO (M+H)+: m/z=358.1. found: 358.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[F:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2([OH:60])[CH2:59][CH2:58][NH:57][CH2:56]2)=[CH:51][CH:50]=1>CN(C=O)C>[F:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2([OH:60])[CH2:59][CH2:58][N:57]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:56]2)=[CH:53][CH:54]=1
Reactant: OC1(c2ccc(F)cc2)CCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)(c3ccc(F)cc3)C2)cc1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (20 mg, 0.1 mmol), TBTU (39 mg, 0.12 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (35 μL, 0.2 mmol, 2 equ) in DMF (1 mL) was added to 3-(4-fluorophenyl)pyrrolidin-3-ol hydrochloride (22 mg, 0.1 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (30 mg). MS (ESI, pos. ion) m/z calcd for C21H19FN2O3: 366.1380, found 366.1380.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:15][CH2:16]Cl)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[C:21]([CH3:28])[CH:20]=1.[NH2-].[Li+]>CC1C=CC=CC=1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:26]#[N:27])[CH2:16][CH2:15][N:4]([S:5]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)(=[O:7])=[O:6])[CH2:3][CH2:2]2)=[C:21]([CH3:28])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: Cc1cc(F)ccc1CC#N
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC(C#N)(c3ccc(F)cc3C)CC2)cc1
Reaction time: 8 h
Yield: 72.6 %

Procedure:
A solution of 29.6 parts of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide and 14.9 parts of 4-fluoro-2-methylbenzeneacetonitrile in 90 parts of methylbenzene is added dropwise to a solution of 5.6 parts of lithium amide in 270 parts of methylbenzene at about 90° C. Upon completion, the whole is heated to reflux and stirred overnight at reflux temperature. The reaction mixture is cooled, poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 27 parts (72.6%) of 4-(4-fluoro-2-methylphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.CC1(C)C2C(=CC=CC=2Br)SCC1.C([Li])(C)(C)C.[C:32](=[O:34])=[O:33]>CCOCC.CCCCC>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([C:32]([OH:34])=[O:33])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2cc(Br)ccc21
Reactant: O=C=O
Agent: CC1(C)CCSc2cccc(Br)c21
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC1(C)CCSc2cc(C(=O)O)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.0 g (3.9 mmol) of the 4,4-dimethyl-7-bromothiochroman and 4,4-dimethyl-5-bromothiochroman mixture in 12 ml of anhydrous ether at -78° C. was added, dropwise under nitrogen, 6.0 ml of 1.7 M 10.2 mmol) tert-butyllithium in pentane. The reaction mixture was stirred at -78° C. for 1 hour and then a rapid stream of dry carbon dioxide gas was passed through it with vigorous stirring. The reaction mixture was warmed to -20° C. and then quenched with water. The mixture was warmed to room temperature and its pH adjusted to 10 with ammonium hydroxide. The basic solution was washed with 2×10 ml ether and then acidified with dilute HCl. The mixture was extracted with 3×20 ml of ether. The ether extracts were combined and washed with water and saturated NaCl solution and then dried (MgSO4). The ether solution was filtered and the solvent removed in-vacuo. The residue was recrystallized from a mixture of ethyl acetate and hexane to give the captioned compound as a white solid. PMR (CDCl3): δ1.33 (6H, s), 1.96 (2H, s), 3.04 (2H, m), 7.42 (1H, d, J~8.1 Hz), 7.66 (1H, dd, J~8.1 Hz, 1.8 Hz), 7.77 (1H, d, J~1.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][O:10][CH:11]([CH:33]=[CH2:34])[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].Cl.[NH2:42][OH:43]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:9][O:10][CH:11]([CH2:12][O:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:33]1[CH2:34][O:43][NH:42]2
Reactant: NO
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)c1ccccc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Fc1ccccc1C12COC(COC(c3ccccc3)(c3ccccc3)c3ccccc3)C1CON2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A reactor was charged with 1-(2-fluorophenyl)-2-((1-(trityloxy)but-3-en-2-yl)oxy)ethanone (61.2 g, 1.0 equiv), toluene (428 mL) and sodium acetate (16.1 g, 1.5 equiv). Upon complete addition, the reaction mixture was stirred at ambient temperature for 5 minutes. Hydroxylamine hydrochloride (10.0 g, 1.1 Eq) was added and the suspension was heated to 111° C. After stirring for >20 hours at 111° C., the reaction mixture was allowed to cool down to ambient temperature, and the suspension was filtered and the solids rinsed with toluene (245 mL) and then THF (10 volumes) The filtrate was concentrated under reduced pressure (bath temp. ≦40° C.) and chased with 2-propanol (275 mL) 2-Propanol (428 mL) was added to the solids and the suspension was heated to 83° C. After stirring for 1 hour at 83° C., the mixture was allowed to cool down to ambient temperature. The slurry was cooled to 0° C. over a 1 hour period and stirred at 0° C. for 1 hour. The suspension was filtered and the solids rinsed in two portions with cold 2-propanol (490 mL) to give 6a-(2-fluorophenyl)-4-((trityloxy)methyl)hexahydrofuro[3,4-c]isoxazole (42.3 g) as a solid.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15]>C1COCC1>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
4-Methylamino-3-nitro-benzoic acid (25 g) was prepared by following general procedure A starting from 4-fluoro-3-nitro-benzoic acid (25 g) and 2 M methylamine in THF (100 mL).
Reaction SMILES: O.[C:2]([C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[C:20](=C\OC)/[C:21]([O:23][CH3:24])=[O:22])[CH:8]=1)#[N:3].[Mn]([O-])(=O)(=O)=[O:33].[K+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC>[C:2]([C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](=[O:33])[C:21]([O:23][CH3:24])=[O:22])[CH:8]=1)#[N:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Reaction time: 16 h
Yield: 70.6 %

Procedure:
To a vigorously stirred mixture of water (20 ml) and a solution of (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (3.2 g, 7.94 mmol) in dichloromethane (20 ml) was added potassium permanganate (2.5 g, 15.9 mmol) in one portion and tetra-n-hexylammonium hydrogen sulphate (200 mg). The reaction mixture was stirred overnight (16 hours) and then filtered. The filter was washed through with ether and water and then the combined filtrates were extracted with ether (×3). The ether extracts were washed with water (×3) and brine (×1), dried, filtered and evaporated. The residue was chromatographed (eluent dichloromethaneacetone, 98:2). Recrystallisation (ether-pentane) of the major component afforded methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-ketoacetate (2.105 g, 71%) as a white crystalline solid; mp 96°-97° C.; 1H NMR (CDCl3) δ 3.83(3H,s), 6.61(1H,s), 7.27-7.47(4H,m), 7.67-7.76(3H,m), 8.02(1H,dd), 8.39(1H,s) ppm; IR maxima 2234(CN), 1743(CO, ester); 1688(CO, ketone)cm-1.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[CH:34]=[CH:33][C:31]=1[NH2:32].CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)=[N:4][C:5]([NH:32][C:31]2[CH:33]=[CH:34][C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:39][CH2:38]3)=[CH:36][C:30]=2[O:29][CH3:28])=[N:6][CH:7]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(Cl)ncc3Br)c3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Br)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc23)n1
Yield: 52.8 %

Procedure:
3-(5-Bromo-2-chloropyrimidin-4-yl)-1-tosyl-1H-indole (INTERMEDIATE 6, 372 mg, 0.83 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27, 343 mg, 0.83 mmol), and DIEA (0.145 mL, 0.83 mmol) in n-butanol (4.0 mL) were heated at 170° C. for 3 h. The reaction mixture was concentrated in vacuo and the crude residue was purified by chromatography on silica gel (10% MeOH/1% NH4OH in DCM) to give the title product (320 mg, 53.9%). m/z 718.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([O:13][CH3:14])[C:5]2[O:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[C:3]=1[F:15].C([Li])CCC.[CH:21](N1CCOCC1)=[O:22].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:15][C:3]1[C:4]2[O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]=2[C:11]([O:13][CH3:14])=[CH:12][C:2]=1[CH:21]=[O:22]
Reactant: COc1cc(Br)c(F)c2c1OCCCO2
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c2c1OCCCO2
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
To a solution of 548 mg of 7-bromo-6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepine in 15 ml of THF there was added dropwise 0.81 ml of n-butyllithium (2.55 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −72° C. for 30 minutes, 0.3 ml of N-formylmorpholine was added and the temperature was raised from −78° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (239 mg) as a solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].FC(C(O)=O)(F)F.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[C:38]1([NH:44][C:45]([NH:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)CC(C)C
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)Nc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of Leu-DTrp-βAla-OEt.TFA (40.6 mg) obtained in Example 51-(1) in chloroform (2 ml) were added TEA (20 μl) and phenyl isocyanate (15 μl) at room temperature under nitrogen. The reaction mixture was stirred for 1 h, and concentrated under reduced pressure. The residue was purified by dry column flash chromatography (Merck, Kieselgel 60) with chloroform/methanol=10/1 for elution to give the product (39.6 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[C-:12]#[N:13].[Na+].C(Cl)Cl.C([O-])(O)=O.[Na+]>O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:12]#[N:13])[CH:5]=[N:4][C:3]=1[O:10][CH3:11]
Reactant: COc1ncc(CBr)cc1Br
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ncc(CC#N)cc1Br
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 3-bromo-5-bromomethyl-2-methoxy-pyridine (Step AM2) (3.9 g, 14.0 mmol) in H2O was added NaCN (750 mg, 15.3 mmol) and the mixture was stirred at 50° C. for 1.5 h. CH2Cl2 and a saturated aqueous solution of NaHCO3 were added and the phases were separated. The organic layer was washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (heptane/EtOAc, 80:20→0:100). tR: 0.88 min (LC-MS 1).