Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C(C[NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:15]=2)=[O:13])C=C(OC)C=1.[CH:44]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)=[O:45].[C:55]([O-:58])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][N:22]([CH2:12][C:14]3[CH:15]=[C:16]([C:48]4[CH:49]=[CH:50][CH:51]=[C:46]([CH:44]=[O:45])[CH:47]=4)[CH:17]=[C:18]([O:58][CH3:55])[CH:19]=3)[C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([NH2:11])=[O:13])[CH:15]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Br)cc(OC)c2)c1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1cc(OC)cc(-c2cccc(C=O)c2)c1)C(=O)c1cccc(C(N)=O)c1
Temperature: 150 °C
Yield: 169.7 %

Procedure:
A mixture of N-{[3-bromo-5-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (782 mg, 1.20 mmol), 3-formylphenyl boronic acid (234 mg, 1.57 mmol), Na2CO3 (383 mg, 3.61 mmol), Pd(PPh3)4 (69.6 mg, 0.06 mmol), and water (3 mL) in dioxane (9 mL) was degassed for 5 min. This mixture was then heated under microwave for 30 min at 150° C. It was quenched with water and then extracted with ethyl acetate twice. The combined organic layers were washed with water and brine. The organic layer was filtered though a 0.45 μM filter and then concentrated to give a crude residue. It was then purified with Combi Flash chromatography eluting with 0 to 10% MeOH in DCM. The product fractions were combined and concentrated under vacuum to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N-{[3′-formyl-5-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide as a solid (687 mg, 85%). LC-MS m/z 676 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]([C:18]2([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[C:20]([NH2:28])=[N:19]2)[CH:15]=[CH:16][CH:17]=1>>[F:27][C:24]1[CH:25]=[C:26]2[C:21]([C:20]([NH2:28])=[N:19][C:18]2([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:13]=2)[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:22][CH:23]=1
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cc(F)ccc21
Reactant: OB(O)c1cccnc1F
Product: NC1=NC(c2ccncc2)(c2cccc(-c3cccnc3F)c2)c2cc(F)ccc21

Procedure:
The title compound was prepared as described in Example 78 (Scheme #14, N) using (2-fluoropyridin-3-yl)boronic acid and 1-(3-bromophenyl)-6-fluoro-1-pyridin-4-yl-1H-isoindol-3-amine (Example 82) (22.5% yield): 1H NMR (CDCl3) δ 8.54 (m, 2 H), 8.18 (m, 1 H), 7.79 (m, 1 H), 7.50 (m, 1 H), 7.48-7.39 (m, 3 H), 7.32 (m, 1 H), 7.29-7.23 (m, 4 H), 7.18 (m, 1 H); MS (ESI) m/z 399 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:10](=[O:11])[C:6]2=[N:7][S:8][N:9]=[C:5]2[C:4](=[O:12])[CH:3]=1.[N:13]1([CH:19]=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10](=[O:11])[C:6]2=[N:7][S:8][N:9]=[C:5]2[C:4](=[O:12])[C:3]=1[N:16]1[CH2:17][CH2:18][N:13]([CH:19]=[O:20])[CH2:14][CH2:15]1
Reactant: O=CN1CCNCC1
Reactant: O=C1C=C(Cl)C(=O)c2nsnc21
Product: O=CN1CCN(C2=C(Cl)C(=O)c3nsnc3C2=O)CC1

Procedure:
A 600 mg portion of 6-chlor-2,1,3-benzothiadiazole-4,7-dione and 342 mg of 1-piperazinecarboxaldehyde were reacted as described in Example 8, giving 164 mg of the desired product, mp 191°-194°.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:13][CH:14]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)[C:15](O)=[O:16].C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:15](=[O:16])[CH:14]([OH:13])[C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=C(O)C(O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Solvent: CO
Product: CC(C)(C)c1ccc(CNC(=O)C(O)c2cccc3cnccc23)cc1

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(tert-butyl)benzylamine and hydroxy(5-isoquinolinyl)acetic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. [α]22D −47.2 (c 0.7, MeOH); MS (ESI+) m/z 349 (M+H)+; MS (ESI−) m/z 347 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.26 (s, 9H), 3.69 (s, 1H), 4.27 (d, J 6.1, 2H), 5.62 (s, 1H), 6.52 (br s, 1H), 7.17 (d, J 8.1, 2H), 7.29 (m, 3H), 7.67 (t, J 8.1, 1H), 7.82 (d, J 7.1, 1H), 8.10 (m, 2H), 8.44 (d, J 5.8, 1H), 8.71 (t, J 6.1, 1H), 9.30 (s, 1H); Anal. Calcd for C22H24N2O2+0.25H2O: C, 74.87; H, 7.00; N, 7.94. Found: C, 75.22; H, 7.40; N, 7.80.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.I[CH2:19][CH3:20].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH:17]=1
Reactant: CCI
Reactant: CS(=O)(=O)c1cccc(-c2ccncc2)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CC=C(c2cccc(S(C)(=O)=O)c2Cl)CC1

Procedure:
Preparation according to preparation 6: 4-[2-chloro-3-(methylsulfonyl)phenyl]-pyridine (1.77 g, 6.6 mmol), 1-iodoethane (5 ml), ethanol (40 ml), sodium borohydride (2.2 g, 58 mmol). Yield: 0.6 g. MS m/z (rel. intensity, 70 eV) 300 (M+, 24), 299 (M+, 71), 298 (33), 284 (bp), 110 (74).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24](F)=[CH:23][C:22]=1[NH:31][C:32](=[O:34])[CH3:33]>O>[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([O:2][C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])=[CH:23][C:22]=1[NH:31][C:32](=[O:34])[CH3:33]
Reactant: Oc1ccccc1O
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cc(Oc2ccccc2O)c([N+](=O)[O-])cc1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
1.1 g of catechol and 2.76 g of potassium carbonate were added to 20 ml of N,N-dimethylformamide, and the mixture was heated to 60° C. Into this mixture was added dropwise a solution comprising 2.16 g of N-(2,5-difluoro-4-nitrophenyl)acetamide and 10 ml of N,N-dimethylformamide at temperatures from 65 to 70° C. The temperature of the mixture was kept for 1 hour, then, the mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic layer was washed with dilute hydrochloric acid, washed with water, dried over magnesium sulfate, concentrated, and the resulted crystal was washed with t-butyl methyl ether to obtain 2.56 g of N-[2-fluoro-5-(2-hydroxyphenoxy)-4-nitrophenyl]acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].ClCCl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(N(CC)CC)C>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (689 mg) (starting compound A) and 4-t-butylphenylboronic acid (450 mg) (starting compound B) were dissolved in a mixed solution composed of dichloromethane (50 ml) and triethylamine (0.7 ml) to prepare a solution. Copper(II) acetate (450 mg) was added to the solution, and the mixture was stirred at room temperature for 16 hr. The mixture was filtered, and the filtrate was then concentrated to give a crude which was then purified by chromatography on silica gel to give the title compound (500 mg, yield 50%).
Reaction SMILES: [F-].[K+].[F:3][C:4]([O:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[F:23])([C:8]([F:11])([F:10])[F:9])[C:5]([F:7])=[O:6].[F:24]C1C(O)=C(F)C(F)=C(F)C=1F.S(F)(O[C:40]([F:47])([F:46])[C:41]([F:45])=[C:42]([F:44])[F:43])(=O)=O>COCCOCCOC>[F:43][C:42]([F:44])=[C:41]([F:45])[C:40]([F:47])([F:46])[O:6][C:5]([F:24])([F:7])[C:4]([F:3])([O:12][C:13]1[C:14]([F:23])=[C:15]([F:22])[C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19])[C:8]([F:11])([F:10])[F:9]
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Reactant: O=C(F)C(F)(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: [F-]
Agent: [K+]
Solvent: COCCOCCOC
Product: FC(F)=C(F)C(F)(F)OC(F)(F)C(F)(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reaction time: 0.5 h
Yield: 17 %

Procedure:
A suspension of 17.4 g (0.30 mol) of flame-dried KF in 500 ml of diglyme was stirred at 5° while 86.1 g (0.26 mol) of perfluoro-2-phenoxypropionyl fluoride prepared by reaction of a metal salt of pentafluorophenol with HFPO) was added dropwise. The mixture was stirred for 30 min at 5°, after which the KF had partially dissolved. Then 69.0 g (0.30 mol) of perfluoroallyl fluorosulfate was added dropwise, and the mixture was stirred at 5°-10° for 3 hr. The cooling bath was removed, and the mixture was stirred overnight. The reaction mixture was then drowned in 2 l. of water, and the lower layer was washed with 1 l., then with 500 ml of water, dried over CaSO4, filtered and distilled to afford 20.8 g (17%) of perfluoro-6-phenoxy-4-oxa-1-heptene, bp 68°-75° (10 mm). A late fraction was analyzed. IR (neat): 5.58 (CF=CF2), 6.57 and 6.80 (arom. C=C), 7.5-9 IR (neat): 5.58 (CF=CF2), 6.57 and 6.80 (arom. C=C), 7.5-9μ (CF, C=O) with a weak peak at 5.64 (-OCF=CFCF3). NMR (CCl4) : 19F -77.8 (d of d of t of d, JFF 25.5, 13.7, ~13, 7.2 Hz, 2F, OCF2C=), -79.8 (m, 3F, CF3), -83.0 (m, 2F, CF2O), -91.7 (d of d of t, JFF 52.0, 39.2, 7.2 Hz, 1F, cis-CF2CF=CFF), -105.1 (d of d of t, JFF 118.0, 52.0, 25.5 Hz, 1F, trans-CF2CF=CFF), -139.9 (t of m, JFF 18.7 Hz, 1F, CF), -150.8 (m, 2F, arom. CF), -156.1 (t, JFF 21.0 Hz, 1F, arom. CF), -162.3 (m, 2F, arom. CF), and -190.6 ppm (d of d of t of t, JFF 118.0, 39.2, 13.7, 1.6 Hz, 1F, CF2CF=). Impurity bands ascribable to the isomer C6F5OCF(CF3)CF2OCF=CFCF3 were also present.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][N:7]([C:9](OC(C)(C)C)=[O:10])[CH:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32]([B:37]2[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]2)=[CH:31][CH:30]=3)[CH2:5]1.Cl.[CH3:47][O:48][C@H:49]([CH3:59])[C@H:50]([NH:54][C:55]([O:57][CH3:58])=[O:56])C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:58][O:57][C:55](=[O:56])[NH:54][CH:50]([CH:49]([O:48][CH3:47])[CH3:59])[C:9]([N:7]1[CH2:8][CH:4]([CH2:3][O:2][CH3:1])[CH2:5][CH:6]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]1[C:29]2[C:34]([CH2:35][O:36][C:23]=1[CH:22]=3)=[CH:33][C:32]([B:37]1[O:38][C:39]([CH3:44])([CH3:45])[C:40]([CH3:43])([CH3:42])[O:41]1)=[CH:31][CH:30]=2)=[O:10]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COCC1CC(c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CC(c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)C(NC(=O)OC)C(C)OC)C1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 85.5 %

Procedure:
To a solution of tert-butyl 4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (0.25 g, 0.41 mmol) in a mixture of CH2Cl2 (4.0 mL) and MeOH (1.0 mL) was added HCl (in dioxanes, 4M, 3.0 mL, 12.0 mmol). The resulting solution was stirred at 40° C. for 45 min. The solution was cooled to room temperature and concentrated to dryness under reduced pressure. To the crude intermediate in CH2Cl2 (4.0 mL) was added (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (0.08 g, 0.42 mmol), HATU (0.17 g, 0.45 mmol), and DIPEA (0.4 mL, 2.3 mmol). The resulting solution was stirred at room temperature for 48 h and diluted with CH2Cl2. The solution was washed with brine. The aqueous layer was backextracted with CH2Cl2 (2×). The resulting organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (30% to 100% EtOAc (w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford methyl(1-{4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methoxy-1-oxobutan-2-yl)carbamate (0.24 g, 92%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3C=C[CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39]C1.[CH:44](N(CC)C(C)C)(C)C.CI>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:43]=[CH:25][CH:24]=[C:3]([CH:2]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:10][CH2:9][N+:40]([CH3:39])([CH3:44])[CH2:41][CH2:42]1.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:43]=[CH:25][CH:24]=[C:3]([CH:2]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:10][CH2:9][N+:40]([CH3:39])([CH3:44])[CH2:41][CH2:42]1
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: C[N+]1(C)CCN(c2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Product: O=C([O-])C(F)(F)F
Reaction time: 16 h
Yield: 128.1 %

Procedure:
A solution of 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) (20 mg, 32 μmol) and N,N-diisopropylethylamine (27 μL, 0.16 mmol) in dichloromethane (0.3 mL) was treated with methyl iodide (10 μL, 0.16 mmol) and stirred for 16 h. The reaction mixture was purified by preparative LCMS to give the desired product (15 mg, 72%) as a solid. LCMS for C24H28ClN6 (M)+: m/z=435.1. 1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 9.17 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 7.81 (d, J=2.3 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 7.11-7.07 (m, 2H), 6.87 (d, J=9.2 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 3.55-3.53 (m, 4H), 3.22 (s, 6H), 3.15 (br s, 4H), 2.95-2.90 (m, 4H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:40][CH:39]=2)[CH2:36][CH2:37]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 120 mg, 0.298 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (68 mg, 0.3555 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 64% yield (0.109 g, 0.1893 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[N:12]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[NH:1]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[NH2:12]
Reactant: Nc1ccc2c(c1)C(=O)CC2
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-aminoindan-1-one (7.2 g, 11.8 mmol) in conc. HCl (20 mL) at 0° C. was added dropwise an aqueous solution of NaNO2 (0.9 g, 13 mmol). After 30 min, a solution of SnCl2.2H2O (5.9 g, 26.2 mmol) in conc. HCl was added dropwise at such a rate that the reaction temperature never rose above 5° C. After the addition was completed, the mixture was stirred at RT for 2 h. The mixture was extracted with Et2O to afford 6-hydrazinoindan-1-one. MS (ESI) m/z: 199 (M+H+).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[CH:32][CH:31]=1>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][CH:14]=[C:13]([C:37]#[C:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[CH:12]=3)[N:19]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#Cc1ccc(OC)cc1
Product: COc1ccc(C#Cc2ccc3c(=NO)cc(-c4cc5ccccc5cn4)oc3c2)cc1

Procedure:
2-isoquinolin-3-yl-7-(4-methoxyphenyl)ethynyl-chromen-4-one oxime was prepared in 9% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 4-methoxyphenylacetylene. The title compound was purified by preparative HPLC (gradient 35-20% Water/acetonitrile+0.05% trifluoroacetic acid) and isolated as a yellow solid and as a 95/05 mixture of Z/E oxime isomers.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=3)[C:18]([NH:20][CH:21]3[CH2:24][C:23]([F:26])([F:25])[CH2:22]3)=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:32].C(N(C(C)C)C(C)C)C.[C:42](=[O:53])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH:54]1([CH2:57][NH2:58])[CH2:56][CH2:55]1>ClCCl>[CH:54]1([CH2:57][NH:58][C:42](=[O:53])[NH:1][C:2]2[CH:31]=[CH:30][C:5]([C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][C:15]4[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=4)[C:18]([NH:20][CH:21]4[CH2:22][C:23]([F:26])([F:25])[CH2:24]4)=[O:19])[CH2:10][CH2:9]3)=[O:7])=[CH:4][C:3]=2[F:32])[CH2:56][CH2:55]1
Reactant: Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC4CC(F)(F)C4)c3)CC2)cc1F
Reactant: NCC1CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC4CC(F)(F)C4)c3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
A mixture of 3-((4-(4-amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-(3,3-difluorocyclobutyl)benzamide (0.224 mmol, 0.1 g) and N-ethyl-N-isopropylpropan-2-amine (0.672 mmol, 0.111 mL, 0.087 g) in dichloromethane were added dropwise to a stirred solution of bis(trichloromethyl) carbonate (0.083 mmol, 0.025 g) in dichloromethane (10 mL). The reaction mixture was allowed to stir for 30 minutes at room temperature. Cyclopropylmethylamine (0.448 mmol, 0.039 mL, 0.032 g) was added and the reaction mixture allowed to stir for a further 2 hours. The reaction mixture was washed with water and the organic phase was concentrated under vacuum. The resulting residue was purified by acidic reverse phase HPLC and converted to the free base to afford the title compound (28 mg). MS (ESI) m/z 544.5 [M+H]+
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].ClC(O[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.Cl.[C:17]([OH:20])(=[O:19])C>>[C:17]([NH:3][CH2:2][CH2:1][NH:4][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:20])=[O:19]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCN
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)NCCNCc1ccccc1

Procedure:
According to scheme VIII, ethylenediamine is first treated with an excess of benzyl chloroformate followed by mono-hydrolysis using hydrochloric acid in glacial acetic acid giving N-carboxybenzylethylenediamine 25 which is treated with N-acetyl-β-alanine methyl ester 5, giving the protected carbamate [2-[[-(acetylamino)-1-oxopropyl]amino]ethyl]carbamic acid, phenylmethyl ester 26 which is deprotected using palladium on carbon in refluxing ethanol/cyclohexane, giving amine 3-(acetylamino)-N-(2-aminoethyl)propanamide 27. Amine 27 is reacted with oleoyl chloride 1 to give the amide isostere product N-[2-[[3-(acetylamino)-1-oxopropyl]amino]ethyl]-9(Z)-octadecenamide 28. ##STR16##
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][NH:4][C:5]([NH2:7])=[S:6].[CH3:10][I:11]>CCO>[IH:11].[F:1][C:2]([F:9])([F:8])[CH2:3][NH:4][C:5](=[NH:7])[S:6][CH3:10]
Reactant: NC(=S)NCC(F)(F)F
Reactant: CI
Solvent: CCO
Product: CSC(=N)NCC(F)(F)F
Product: I

Procedure:
A solution of 2,2,2-trifluoroethylthiourea (8.0 g.) and methyl iodide (3.5 g.) in EtOH (40 ml.) was heated under reflux for 70 minutes, then evaporated to dryness in vacuo. The residue was triturated with ether to give 2,2,2-trifluoroethyl-S-methylisothiourea hydroiodide, m.p. 154°-156° (90%).