Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH2:38]([O:40][C:41](=[O:53])[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:47]3[CH:48]=[CH:49][C:44]([CH2:43][CH2:42][C:41]([O:40][CH3:38])=[O:53])=[CH:45][CH:46]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 160 °C
Yield: 49.2 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), [4-(3-ethoxy-3-oxopropyl)phenyl]boronic acid (40 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylamino phenyl)phosphine)dichloropalladium(II) (6.3 mg, 0.01 mmol) and K3PO4 (72 mg, 0.27 mmol) in DMF/water (0.9 mL, 6:1, v/v) was heated at 160° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by HPLC. To the fraction, conc. HCl (3 ml) and methanol (3 ml) were added and the residue was evaporated after 24 h. The residue was purified by HPLC to give the titled compound as a white solid (24 mg, 42%). 1HNMR (DMSO-d6) 400 MHz δ: 8.54 (s, 1H), 8.22 (s, 1H), 8.07 (dd, J=4.6, 1.7 Hz, 1H), 7.94 (dd, J=7.7, 1.4 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H), 7.34 (td, J=7.7, 1.5 Hz, 1H), 7.28 (dd, J=8.0, 1.1 Hz, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.14 (d, J=8.6 Hz, 2H), 7.11 (t, J=8.0 Hz, 1H), 6.86 (dd, J=8.0, 1.1 Hz, 1H), 6.72 (dd, J=7.7, 4.9 Hz, 1H), 3.58 (s, 3H), 2.83 (t, J=7.4 Hz, 2H), 2.63 (t, J=8.0 Hz, 2H), 2.43-2.36 (m, 2H), 2.20-2.13 (m, 2H), 2.09-2.00 (m, 1H), 1.75-1.66 (m, 1H); LCMS: 542 [M+H].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[N:3][CH:2]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccncn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccncn1)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl pyrimidin-4-ylcarbamate (200 mg, 0.739 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (182 mg, 0.739 mmol), diisopropylethylamine (0.258 ml, 1.48 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (110 mg, 40.7%) as a solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>OC(C)=O.O.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:20][C:16]1[CH:15]=[C:14]([C:12]2[N:13]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[NH:10][C:11]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CSc1ccc(-c2nc(-c3cccc([N+](=O)[O-])c3)c(-c3ccncc3)[nH]2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(-c2nc(-c3cccc(N)c3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 0.161 g (0.41 mmol) of 2-(4-methylthiophenyl)-4-(3-nitrophenyl)-5-(4-pyridyl)-1H-imidazole [See Ex. 62 below] in 3.4 mL of HOAc-H2O (1:1) was treated with 1.81 mL (2.87 mmol) of 20% aqueous titanium (III) chloride in one single portion. The mixture was stirred at rt for 20 min, then made basic with 10% NaOH. The aqueous mixture was extracted with 95:5 CH2Cl2/MeOH. The organic extracts were washed with H2O and saturated NaCl. Evaporation of solvent in vacuo afforded a yellow solid which was filtered through a plug of silica gel, eluting with 90:10 CHCl3/MeOH. The title compound was isolated as a pale yellow solid (0.129 g, 78%): CIMS (NH3, m/z): 359.1 (M++H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1.CO>CN(C)C1C=CN=CC=1.ClCCl>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][N:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:3])[CH3:2])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Acetyl chloride (0.71 mL, 0.79 g, 10.0 mmol) was added dropwise to a stirred, cooled (0° C.) solution of N-phenyl-1-t-butoxycarbonylpiperidine-4-methylamine (2.42 g, 8.3 mmol), pyridine (1.01 mL, 0.99 g, 12.5 mmol) and 4-dimethylaminopyridine (204 mg, 1.7 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 1 h. Methanol (5 mL) was added and the solvent was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate (saturated, 50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×50 mL), aqueous sodium hydrogen carbonate (saturated, 50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.73 g, 99%), δH (250 MHz, CDCl3) 7.47-7.15 (5H, m), 4.06 (2H, br m), 3.62 (2H, br m), 2.64 (2H, br m), 1.85 (3H, s), 1.66 (3H, m), 1.44 (9H, s), and 1.20 (2H, m).
Reaction SMILES: [CH3:1][CH:2]([C:16](N)=[O:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([F:15])[CH:4]=1.C(Cl)(=O)C(Cl)=[O:21]>C(Cl)Cl.ClCCCl>[CH3:1][CH:2]([C:16]([OH:17])=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([F:15])[CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(N)=O)c1ccc(-c2ccccc2)c(F)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of flurbiprofen amide (3.0 g, 12.33 mmol) in DCM (70 mL) was added oxalyl chloride (1.87 g, 14.79 mmol) at 0° C. and refluxed for 16 h. Reaction mixture was cooled to RT and treated with LI-2b (2.45 g, 12.33 mmol) in DCE (10 mL) and stirred overnight. After usual aqueous work-up and chromatographic purification, 0.5 g of I-C1-NOPD14a were obtained. 1H NMR (CDCl3, 300 MHz): δ 1.55 (d, 3H, J=6.9 Hz), 2.94-2.97 (bs, 4H), 4.38-4.47 (bs, 3H), 4.68 (t, 2H, J=6.6 Hz), 7.13-7.55 (bs, 8H) MS: ES+ m/z 469.03 [M+H]+, 467.16 [M−H]+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(N(CC)CC)C>>[Br:13][CH2:14][CH2:15][CH2:16][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCCCBr
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCCCBr
Yield: 53.4 %

Procedure:
This compound was produced by modifications of the methods used J. Med. Chem., 1991, 34, 1071 starting with N-hydroxyphthalimide (10.0 g, 61.3 mmol), 1,3-dibromo-propane (24.8 g, 123 mmol) and triethylamine (12.4 g, 123 mmol). The crude material was purified by flash chromatography through silica gel using chloroform to give 2-(3-bromo-propoxy)-isoindole-1,3-dione (9.30 g, 53%) as a white powder. 1H NMR (400 MHz, CDCl3); δ 7.81 (m, 2H), 7.73 (m, 2H), 4.34 (t, 2H), 3.68 (t, 2H), 2.28 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1>>[F:24][C:22]1[CH:23]=[C:18]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:19]=[C:20]([F:25])[CH:21]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(F)c3)cc21

Procedure:
6-(3,5-difluoro-phenyl)-4,4-dimethyl-1,4-dihydrobenzo-[d][1,3]oxazin-2-one was prepared, according to the procedure of Example 5 from (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1-bromo-3,5-difluorobenzene, as a white solid: mp 218-219° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 7.67-7.65 (m, 2H), 7.49 (d, 2H, J=7.73 Hz), 7.19 (t, 1H, J=9.29 Hz), 6.96 (d 1H, J=8.88 Hz), 1.7 (s, 6H); MS (APCI) m/z 290 ([M+H]+, 100%); Anal. Calc. For C16H13F2NO2: C, 66.43; H, 4.53; N, 4.84. Found: C, 66.01; H, 4.46; N, 4.67.
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:8][CH2:9][C@@H:10]([OH:22])[CH2:11][C:12](=[O:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.COB(CC)CC.[BH4-].[Na+]>O.C(O)(=O)C.CO>[C:29]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:8][CH2:9][C@@H:10]([OH:22])[CH2:11][C@@H:12]([OH:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To the crude tert-butyl 6-triphenylmethyloxy-5(S)-hydroxy-3-oxohexanoate was added 150 mL of THF followed by 15 mL of MeOH and was chilled to −60° C. 26 mL of methoxydiethylborane (50% solution in THF) was added over a period of 20 minutes and stirring was continued for a further 30 minutes. The reaction mixture was cooled to −80° C. and 5 g of sodium borohydride was added in portions and the after completion of addition the reaction mixture was stirred for 5 hours at −78° C. Acetic acid was added to adjust the pH to 7 and water was added. The aqueous layer was extracted using EtOAC, washed with brine, dried and concentrated to give the title compound which was used as such for the next step.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[O:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:27][C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=4)=[CH:26][CH:25]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1
Reactant: Fc1ncccc1C1CCCOC1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc(Nc2ccc(Oc3ncccc3C3CCCOC3)cc2)nc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
2-Fluoro-3-(tetrahydro-2H-pyran-3-yl)pyridine (0.10 g, 0.55 mmol), 4-(pyridin-2-ylamino)phenol (0.26 g, 1.38 mmol), and cesium carbonate (0.54 g, 1.66 mmol) were mixed in NMP (2 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide (1×), sat. sodium chloride (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give N-(4-(3-(tetrahydro-2H-pyran-3-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 348.1 (M+1). IC50 (uM) 0.012.
Reaction SMILES: S(=O)(=O)(O)O.COC(C1C=CC2C(=CC=CC=2)C=1C1C2C(C(C3C4C(=CC=CC=4)C=CC=3C(OC)=O)=C3C=1C=CC=C3)=CC=CC=2)=O.C(Cl)(Cl)Cl.[CH:52]1[C:57]2=[C:58]3[C:75](=[CH:76][CH:77]=[C:56]2[CH:55]=[CH:54][CH:53]=1)[C:74](=[O:78])[C:73]1[C:60]2[C:61]4[C:70](=[CH:71][CH:72]=1)[C:69](=[O:79])[C:68]1[C:63](=[C:64]5[CH:83]=[CH:82][CH:81]=[CH:80][C:65]5=[CH:66][CH:67]=1)[C:62]=4[C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][C:89]=1[C:59]3=2>O>[CH:76]1[C:75]2[C:74](=[O:78])[C:73]3[C:60]4[C:59]([C:58]=2[C:57]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:77]=1)=[C:89]1[C:84]2[C:85](=[CH:86][CH:87]=[CH:88]1)[C:69](=[O:79])[C:68]1[CH:67]=[CH:66][C:65]5[C:64]([C:63]=1[C:62]=2[C:61]=4[CH:70]=[CH:71][CH:72]=3)=[CH:83][CH:82]=[CH:81][CH:80]=5
Reactant: O=C1c2ccc3ccccc3c2-c2c3ccccc3c3c4c(ccc1c24)C(=O)c1ccc2ccccc2c1-3
Agent: COC(=O)c1ccc2ccccc2c1-c1c2ccccc2c(-c2c(C(=O)OC)ccc3ccccc23)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1c2ccc3ccccc3c2c2c3cccc4c(=O)c5ccc6ccccc6c5c(c5cccc1c52)c43
Yield: 28 %

Procedure:
Anthracene-9,10-diboronic acid (15.0 g, 56.4 mmol), palladium acetate (633 mg, 2.82 mmol), tri(t-butyl)phosphine (1.71 g, 8.46 mmol), methyl-1-bromonaphthalene-2-carboxylate (31.4 g, 118 mmol) and cesium carbonate (73.5 g, 226 mmol) were dissolved in 200 mL of xylene and the solution was reacted under reflux at the boiling point for 5 hours in a nitrogen atmosphere to obtain dimethyl-1,1′-(anthracene-9,10-diyl)bis(2-naphthoate) at a yield of 78%. Concentrated sulfuric acid (400 mL) was added to the dimethyl-1,1′-(anthracene-9,10-diyl)bis(2-naphthoate) (24.0 g, 44.0 mmol) to react at 180° C. for 4 hours. Thereafter, chloroform and water were added to the reaction mixture to separate the organic phase. The organic phase was washed with water and a saturated sodium chloride solution, and concentrated under reduced pressure. The resulting reaction mixture was purified by silica gel column chromatography (chloroform) to obtain dinaphtho[1,2-a:1′,2′-j]perylene-10,20-dione (yield: 28%) and dibenzo[a,o]naphtho[1,2,3,4-rst]pentaphene-7,10-dione (22%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH2:8][C:9]3([CH2:27][C:4]=2[CH:3]=1)[C:17]1[C:12](=[N:13][CH:14]=[CH:15][CH:16]=1)[N:11](COCC[Si](C)(C)C)[C:10]3=[O:26].[CH2:28]([N:31]1[C@@:36]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=2)([CH3:37])[CH2:35][N:34](C(OC(C)(C)C)=O)[C:33]([CH3:54])([CH3:53])[C:32]1=[O:55])[CH:29]=[CH2:30].C1(CNCC2CCCCC2)CCCCC1.[C:71]([OH:77])([C:73]([F:76])([F:75])[F:74])=[O:72].[OH-].[Na+].C(N)CN>CC(N(C)C)=O.C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:73]([C:71]([OH:77])=[O:72])([F:76])([F:75])[F:74].[F:45][C:40]1[CH:39]=[C:38]([C@:36]2([CH3:37])[CH2:35][NH:34][C:33]([CH3:54])([CH3:53])[C:32](=[O:55])[N:31]2[CH2:28]/[CH:29]=[CH:30]/[C:2]2[N:7]=[CH:6][C:5]3[CH2:8][C:9]4([CH2:27][C:4]=3[CH:3]=2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]4=[O:26])[CH:43]=[C:42]([F:44])[CH:41]=1
Reactant: C=CCN1C(=O)C(C)(C)N(C(=O)OC(C)(C)C)C[C@@]1(C)c1cc(F)cc(F)c1
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cnc(Cl)cc3C2)c2cccnc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: [Na+]
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)NC[C@@](C)(c2cc(F)cc(F)c2)N(C/C=C/c2cc3c(cn2)CC2(C3)C(=O)Nc3ncccc32)C1=O
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (±)-3-chloro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (0.404 g, 1.004 mmol, described in Intermediate 32) and tert-butyl (5R)-4-allyl-5-(3,5-difluorophenyl)-2,2,5-trimethyl-3-oxopiperazine-1-carboxylate (0.36 g, 0.913 mmol) in degassed DMA (5.4 mL) in a large microwave vessel was added N,N-dicyclohexylmethylamine (0.215 mL, 1.00 mmol) and the mixture was degassed for 5 min. To the resulting mixture was added bis(tri-t-butylphosphine)palladium(0) (0.154 g, 0.301 mmol) and the mixture was degassed again. The reaction mixture was heated in a microwave reactor for 20 minutes at 150° C., cooled to ambient temperature, and filtered. The filtrate was partitioned between EtOAc (100 mL) and H2O (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. To the crude alkene in CH2Cl2 (10 mL) was added TFA (1.05 mL, 13.6 mmol) and the resulting mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, dissolved in MeOH and 1 N sodium hydroxide (2.73 mL, 2.73 mmol) and ethylenediamine (0.323 mL, 4.79 mmol) were added. The reaction mixture was stirred for 12 h at ambient temperature, concentrated in vacuo, and purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1, to give the title compound. MS: m/z=530 (M+1), HRMS: m/z=530.2360 (M+1); calculated m/z=530.2362 (M+1) for C30H30F2N5O2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31]([NH:33][CH3:34])=[O:32]>CN(C)C=O.Cl.C(OCC)(=O)C>[ClH:29].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:30][C:31]([NH:33][CH3:34])=[O:32])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CCl
Reactant: c1ccc(COc2cccc(CCNCC3CC3)c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)CN(CCc1cccc(OCc2ccccc2)c1)CC1CC1
Temperature: 120 °C
Yield: 72.6 %

Procedure:
A mixture of 0.24 g (0.85 mmol) of [2-(3-benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amine, 0.14 ml (1.00 mmol) of triethylamine, 0.11 g (1.02 mmol) of 2-chloro-N-methyl-acetamide in 3 ml of dimethylformamide was heated with microwaves to 120° C. for 2 hours. The solvent was removed and the crude residue was purified by flash chromatography (dichloromethane/methanol/NH3 100:0:0→95:5:0.5 gradient). The product obtained was dissolved in anhydrous hydrochloric acid in ethyl acetate, the solvent was removed under vacuum and the residue was triturated with diethyl ether. 0.24 g (80% yield) of the title compound was isolated as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:9]([CH:11]1[CH2:13][CH2:12]1)=O)[C:6](=O)[CH3:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].COS(C(F)(F)F)(=O)=O.Cl.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([NH2:38])=[NH:37].CC(C)([O-])C.[Na+]>C(#N)C.CCOC(C)=O.C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:9]([CH:11]2[CH2:13][CH2:12]2)=[N:37][C:36]([C:35]2[CH:39]=[CH:40][CH:41]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=2)=[N:38][C:6]=1[CH3:7])=[O:14])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)C(=O)C1CC1
Reactant: N=C(N)c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: COS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(-c2cccc(C(F)(F)F)c2)nc1C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
2-Cyclopropanecarbonyl-3-oxo-butyric acid ethyl ester [Jung, J.-C.; Watkins, E. B.; Avery, M. A. Tetrahedron (2002), 58(18), 3639-3646] (4.7 g, 24 mmol) was dissolved in acetonitrile (40 ml) and cooled to 0° C. Cesium carbonate (7.8 g, 24 mmol) was added and the reaction stirred for 0.5 h before the addition of trifluoro-methanesulfonic acid methyl ester (2.6 ml, 24 mmol) and the reaction stirred for a further 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried (Na2SO4) and concentrated to afford a crude mixture of (E,Z)-2-cyclopropanecarbonyl-3-methoxy-but-2-enoic acid ethyl ester and/or 2-[1-cyclopropyl-1-methoxy-meth-(E,Z)-ylidene]-3-oxo-butyric acid ethyl ester (6.3 g, quant). A third of this material (2.1 g, 8 mmol) was dissolved in ethanol (10 ml) and added dropwise to a solution of 3-trifluoromethyl-benzamidine hydrochloride (1.8 g, 8 mmol) and sodium tert-butoxide (0.8 g, 8 mmol) and the mixture stirred overnight. The reaction was concentrated, re-dissolved in EtOAc, washed with 1N hydrochloric acid solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/Heptane 1:9) afforded the title product (1.2 g, 42%) as clear oil. MS: 351.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Cl:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1Cl>[Cl:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: Nc1cccc(Cl)c1O
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Product: ClCc1ccc(-c2nc3cccc(Cl)c3o2)cc1

Procedure:
158.5 g of 2-(4'-chloromethylphenyl)-7-chlorobenzoxazole (produced by condensation of 2-amino-6-chlorophenol with 4-chloromethyl-benzoyl chloride and subsequent cyclisation in o-dichlorobenzene in the presence of p-toluenesulfonic acid, melting point 141° to 142° C.) is heated with 400 ml of triethyl phosphite in the course of 2 hours at 155° C., and the mixture is subsequently stirred at 155° to 158° C. for a further 7 hours. After cooling to 90° C., the unreacted triethyl phosphite is distilled off in vacuo. The reaction product, which is still oily, is stirred into 1000 ml of petroleum ether, and after a short time crystallisation occurs. The product is filtered off, washed with petroleum ether and dried. The yield is 210 g (97% of theory) of 2-(4'-diethylphosphonomethylphenyl)-7-chlorobenzoxazole having a melting point of 92° to 93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].N1C=CC=CC=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23]>O1CCCC1>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:22](=[O:23])[CH2:21][O:20][CH3:19])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: COCC(=O)Cl
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -50 °C
Yield: 0 %

Procedure:
6-Amino-5-fluoro-1,3-dihydro-indol-2-one 3d (2.028 g, 12.2 mmol) was dissolved in 30 ml of tetrahydrofuran under stirring, and added with 1.3 ml of pyridine to the solution at room temperature. The reaction system was cooled down to about −50° C. in a dry ice-ethanol bath. A solution of methoxy-acetyl chloride (1.35 g, 12.5 mmol) in tetrahydrofuran (20 ml) was added dropwise to the above reaction system. Upon completion of the addition, the ice-ethanol bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The resulting solid was washed with water (10 mL×3) and recrystallized with methanol to obtain N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a (1.18 mg, yield 40.6%) as a gray solid.