Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH3:24]
Reactant: CCc1ccc(O)c(Oc2ccccc2)c1
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Product: CCc1ccc(Oc2cc(F)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(Oc2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-ethyl-2-phenoxy-phenol as in Example 18 to afford 0.139 g (52%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C30H27O5F 487.1921, found 487.1906.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:46])[CH:21]([N:25]([C:27](=[O:45])[CH:28]([NH:37]C(OCCCC)=O)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:19][C:20](=[O:46])[CH:21]([N:25]([C:27](=[O:45])[CH:28]([NH2:37])[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCOC(=O)NC(Cc1ccc(F)cc1)C(=O)N(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nccs1)N(C)C(=O)C(N)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
To a solution of 2-((2-butoxycarbonylamino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(thiazol-2-yl)ethylamide (A) (1.49 g, 2.28 mmol) in methylene chloride (20 ml), TFA (10 ml) was added and stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to remove the solvent under reduced pressure; the thus obtained residue was mixed with methylene chloride, washed with a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: methanol:aqueous ammonia:methylene chloride=3:0.1:100), giving the titled compound (430 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[OH-].[K+].[F:14][C:15]([F:19])=[C:16]([F:18])[F:17]>CN(C)C=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:16]([F:18])([F:17])[CH:15]([F:19])[F:14]
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: FC(F)=C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
7.0 Grams of 2-fluoro-4-nitrophenol was dissolved in 70 ml of N,N-dimethylformamide, and 1.0 g of potassium hydroxide was added thereto. Tetrafluoroethylene was blown into the resulting solution at an inner temperature of 100° C., after which stirring was continued for 6 hours at an inner temperature of 100° C. The reaction solution was poured into ice water and extracted with ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue obtained was subjected to column chromatography on silica gel with toluene as an eluent to obtain 6.97 g of 3-fluoro-4-(1',1',2',2'-tetrafluoroethoxy)nitrobenzene. 1H-NMR (CDCl3): δ(ppm) 7.10-8.2(3H), 5.59(1H, tt, J=53, 3 Hz)
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[Cl:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[Cl:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH2:18][CH2:17]1.[CH2:14]([OH:15])[CH2:13][CH2:25][CH3:24]
Reactant: Cn1cc(Br)c(=O)n(C)c1=O
Reactant: Clc1ccccc1OC1CCNCC1
Product: CCCCO
Product: Cn1cc(N2CCC(Oc3ccccc3Cl)CC2)c(=O)n(C)c1=O
Yield: 17 %

Procedure:
The compound 35 (oil) is prepared from the uracil 1c and from the intermediate 8a according to the synthesis method 1 in n-butanol (yield: 17%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:1]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)[CH:31]([CH2:30][CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:32]2=[O:33])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)CCCCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C2C(CCCc3ccccc3)C(=O)N2c2ccc(OC)cc2)cc1
Reaction time: 0.25 h
Yield: 92 %

Procedure:
Reflux a solution of methyl 4-formylbenzoate (5.23 g, 31.9 mmol) and p-anisidine in toluene (50 mL) overnight with azeotropic removal of water via a Dean-Stark trap. Add n-tributylamine (22.8 mL, 95.6 mmol), followed by 5-phenylvaleryl chloride (47.8 mL, 47.8 mmol, 1M in toluene) and reflux overnight. Cool the reaction to room temperature, quench with 1M HCl and stir 15 min. Dilute the reaction mixture with ethyl acetate (EtOAc), wash with 1M HCl, water and brine, dry over Na2SO4 and concentrate. Dissolve the resulting residue in tetrahydrofuran (THF), dilute with an equal volume of CH3OH, add NaBH4 (1.22 g, 32 mmol) and stir for 30 min. Add 1M HCl, dilute with EtOAc and wash with 1M HCl, water and brine. Dry over Na2SO4, filter and concentrate on enough silica gel to obtain a free-flowing powder. Load the powder onto a chromatography column packed with silica and 30% EtOAc/hexanes and elute with the same solvent to obtain 12.2 g (92%) of methyl 4-[1-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-oxo-4-azetidinyl]benzoate as a 12/1 trans/cis mixture. 1H NMR (400 MHz, CDCl3, trans isomer) 8.05(2H, d; J=8.2 Hz), 7.39(2H, d, J=8.2 Hz), 7.28(3H, m), 7.17(6H, m), 6.77(2H, d, J=6.9 Hz), 4.65(1H, d, J=2.1 Hz), 3.91(3H, s), 3.73(3H, s), 3.09(1H, m), 2.65(2H, m), 1.97(1H, m), 1.82(3H, m). Diagnostic C-4 proton for cis diastereomer 5.18(J=5.7 Hz). MS(EI): 429(M+,6), 269(13), 149(100).
Reaction SMILES: CC1[N:6]2[CH2:7][C:8]3[N:9]([CH2:19][CH:5]2[CH2:4][O:3]1)[S:10](=[O:18])(=[O:17])[C:11]1[S:16][CH:15]=[CH:14][C:12]=1[CH:13]=3.C([Li])CCC.[S:25](=[O:27])=[O:26].[NH2:28]OS(O)(=O)=O>C1COCC1.CO.ClCCl>[OH:3][CH2:4][CH:5]1[CH2:19][N:9]2[S:10](=[O:18])(=[O:17])[C:11]3[S:16][C:15]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:14][C:12]=3[CH:13]=[C:8]2[CH2:7][NH:6]1
Reactant: CC1OCC2CN3C(=Cc4ccsc4S3(=O)=O)CN21
Reactant: NOS(=O)(=O)O
Reactant: O=S=O
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)N1CC(CO)NCC1=C2
Yield: 6 %

Procedure:
A solution of the product of Step G (1 g, 3.1 mmol) in THF (20 mL) at -78° C. was treated with 2.5M n-butyllithium (1.86 g, 4.65 mmol), sulfur dioxide, and hydroxylamine-O-sulfonic acid (1.05 g, 9.3 mmol) as described in Example 1, Step F to provide, after column chromatography (silica, methanol/dichloromethane, 1:9), the desired compound (70 mg, 6%) as an off-white solid: mp 170° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[CH2:31]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([NH:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[CH2:31]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: NC1CCCC(O)C1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(NC3CCCC(O)C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Yield: 48.2 %

Procedure:
A suspension of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (100 mg, 0.204 mmol, obtained from Example 7, Step B), 3-aminocyclohexanol (70.5 mg, 0.612 mmol), Cu(I)I (7.77 mg, 0.0408 mmol), K2CO3 (141 mg, 1.02 mmol) and L-proline (9.39 mg, 0.082 mmol) was stirred in DMSO (5 mL) and heated to 100° C. for 12 hours. Water (5 mL) was added and the reaction mixture was extracted with CH2Cl2. The organic layer washed with water and brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (47 mg, 48.3% yield) as a brown oil. LRMS (APCI pos) m/e 694.2 (M+H).
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[C@@:7]2([CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])[CH2:13][CH:11]3[O:12][C@@:8]2([O:32][CH3:33])[C@H:9]([C:29](=[O:31])[CH:30]=1)[C@:10]3([CH3:28])[CH2:14][CH2:15][CH2:16][C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18].C(N(CC)CC)C.BrB(C)C.CC[O:52]C(C)=O>CCCCCC>[OH:12][C@@H:11]1[C@@:10]([CH3:28])([CH2:14][CH2:15][CH2:16][C:17]([CH3:18])([O:19][Si:20]([CH2:21][CH3:22])([CH2:23][CH3:24])[CH2:25][CH3:26])[CH3:27])[C@@H:9]2[C@:8]([OH:52])([O:32][CH3:33])[C@@:7]([CH2:34][CH:35]=[C:36]([CH3:37])[CH3:38])([C:6]([O:5][CH3:4])=[CH:30][C:29]2=[O:31])[CH2:13]1
Reactant: CCOC(C)=O
Reactant: CC[Si](CC)(CC)OC(C)(C)CCC[C@]1(C)C2C[C@]3(CC=C(C)C)C(OC)=CC(=O)[C@H]1[C@]3(OC)O2
Agent: CB(C)Br
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C)(C)CCC[C@@]1(C)[C@H]2C(=O)C=C(OC)[C@@](CC=C(C)C)(C[C@@H]1O)[C@@]2(O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
A DCM (20 mL) solution of 38 (794 mg, 1.57 mmol, 1 equiv.) and triethylamine (131 μL, 0.940 mmol, 0.6 equiv.) was cooled to −95° C. in a 100-mL recovery flask, and a DCM solution of bromodimethylborane (1.59 M, 5.9 mL, 9.4 mmol, 6 equiv.) was added slowly over 5 min. The resulting bright yellow solution was stirred at −95° C.±3° C. for 10 min, whereupon it was quenched through the sequential addition of NEt3 (6 mL) and saturated aqueous NaHCO3 at −95° C. The mixture was warmed to room temperature and extracted thrice with EtOAc. The organic extracts were combined, washed successively with 2 N HCl, H2O, saturated aqueous NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yellow foam. Flash column chromatography (150 mL SiO2, 8:2 to 7:3 hexane:EtOAc) afforded 471 mg (0.897 mmol, 57% yield) of 39 as a white flocculent solid. TLC Rf 0.30 (7:3 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.46 (s, 1H), 5.26 (d, J=10.3 Hz, 1H), 3.74 (s, 3H), 3.61 (dd, J=11.8, 5.3 Hz, 1H), 3.55 (s, 1H), 3.25 (s, 3H), 2.87-2.82 (m, 2H), 2.25 (d, J=14.2 Hz, 1H), 1.95 (t, J=12.4 Hz, 1H), 1.73 (s, 3H), 1.70-1.65 (m, 4H), 1.43 (td, J=13.0, 4.2 Hz, 1H), 1.39-1.35 (m, 1H), 1.32-1.27 (m, 3H), 1.21 (s, 3H), 1.20 (s, 3H), 1.09 (s, 3H), 0.93 (t, J=7.9 Hz, 9H), 0.55 (q, J=7.6 Hz, 6H). 13C NMR (126 MHz; CDCl3): δ 198.2, 176.0, 137.4, 122.1, 104.1, 100.6, 73.8, 73.3, 57.6, 56.5, 51.1, 48.5, 45.9, 40.9, 39.4, 37.0, 30.8, 30.0, 29.4, 26.2, 18.0, 17.0, 7.3, 7.0. HRMS-ESI (m/z): [M+Na]+ calculated for C29H52O6Si, 547.3425. found, 547.3404.
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[C@@H:7]([NH:31][C:32](=[O:51])[NH:33][C@@H:34]([CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](ON1C(=O)CCC1=O)=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH2:53][C@@H:54]([CH2:58][CH2:59][CH2:60][CH2:61][N:62]([CH2:77][C:78]1[N:79]([CH2:83][C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH:80]=[CH:81][N:82]=1)[CH2:63][C:64]1[N:65]([CH2:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])[CH:66]=[CH:67][N:68]=1)[C:55]([OH:57])=[O:56].CCN(C(C)C)C(C)C>CN(C=O)C>[C:72]([O:71][C:70](=[O:76])[CH2:69][N:65]1[CH:66]=[CH:67][N:68]=[C:64]1[CH2:63][N:62]([CH2:77][C:78]1[N:79]([CH2:83][C:84](=[O:85])[O:86][C:87]([CH3:90])([CH3:89])[CH3:88])[CH:80]=[CH:81][N:82]=1)[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:54]([C:55]([OH:57])=[O:56])[NH:53][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13](=[O:30])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:52])[NH:31][C:32](=[O:51])[NH:33][C@H:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:42][CH2:43][C:44](=[O:45])[O:46][C:47]([CH3:49])([CH3:50])[CH3:48])([CH3:73])([CH3:75])[CH3:74]
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)N[C@@H](CCCCN(Cc1nccn1CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 22.8 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.291 g, 0.45 mmol), (S)-2-amino-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (0.22 g, 0.412 mmol) and DIPEA (1.0 mL) in DMF (4.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to give a residue, which was purified by Biotage eluting with DCM/MeOH to give (7S,11S,26S)-26-(4-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-2,2-dimethyl-4,9,17,24-tetraoxo-3-oxa-8,10,16,25-tetraazaheptacosan-27-oic acid (0.1089 g, 21%). MS (ESI), 581 (M/2+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=[O:23])=[CH:4][C:5]2[C:10](=[O:11])[O:9][CH2:8][N:7]([C:12]3[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=3[CH3:19])[C:6]=2[C:20]=1[F:21].[F:25][C:26]1[C:31](OC(=O)C(F)(F)F)=[C:30]([F:39])[C:29]([F:40])=[C:28]([F:41])[C:27]=1[F:42].N1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[F:25][C:26]1[C:31]([O:23][C:22]([C:3]2[C:2]([F:1])=[C:20]([F:21])[C:6]3[N:7]([C:12]4[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=4[CH3:19])[CH2:8][O:9][C:10](=[O:11])[C:5]=3[CH:4]=2)=[O:24])=[C:30]([F:39])[C:29]([F:40])=[C:28]([F:41])[C:27]=1[F:42]
Reactant: Cc1cc(I)ccc1N1COC(=O)c2cc(C(=O)O)c(F)c(F)c21
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(I)ccc1N1COC(=O)c2cc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c(F)c21
Reaction time: 4 h
Yield: 83 %

Procedure:
To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid (0.3 g, 0.67 mmol) in N,N-dimethylformamide (3 mL) is added trifluoroacetic acid pentafluorophenyl ester (0.127 mL, 0.74 mmol) and pyridine (0.60 mL, 0.74 mmol). After stirring for 4 hours the reaction mixture is diluted with ethyl acetate and washed 3 times with 1.0 M HCl solution, 3 times with 5% aqueous NaHCO3 solution, 2 times with water and once with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid pentafluorophenylester as a dark orange oil (0.34 g, 83.1%). To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid pentafluorophenylester (0.33 g, 0.54 mmol) in freshly distilled THF (10 mL) is added methylamine hydrochloride (0.037 g, 0.54 mmol) and N,N-diisopropylethylamine (0.019 mL, 1.08 mmol). After stirring for 17 hours, the reaction mixture was diluted with ethyl acetate and washed 2 times with water and 2 times with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid methylamide as a yellow solid (0.19 g, 76.9%); mp 219–223° C.; 1NMR (400 MHz; DMSO-d6) 8.40 (s, 1H), 8.06 (d, 1H, J=6.8), 7.74 (s, 1H), 7.50 (d, 1H, J=8.4), 6.87 (d, 1H, J=8.0), 5.61 (s, 2H), 2.76 (d, 3H, J=4.4), 2.25 (s, 3H); MS(APCI)m+1=459; Anal.calcd/found for C17H13F2IN2O3 C 45.00/45.39, H 3.01/3.16, N 6.05/5.88.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:36])[C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[OH:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(CC)CC)C>C(O)CCCC.Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[C:4]([CH3:36])=[CH:3][C:2]([N:43]4[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][OH:37])[CH2:41][CH2:42]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1cc(Cl)nn2c(-c3ccnc4c3ccn4S(=O)(=O)c3ccccc3)c(-c3ccc(F)cc3)nc12
Agent: Cl
Solvent: CCCCCO
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCN(CCO)CC2)nn2c(-c3ccnc4c3ccn4S(=O)(=O)c3ccccc3)c(-c3ccc(F)cc3)nc12
Temperature: 150 °C
Reaction time: 48 h
Yield: 35.3 %

Procedure:
A mixture of 0.530 g (1.02 mmol) of 6-chloro-2-(4-fluorophenyl)-8-methyl-3-[1-(phenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, prepared according to the method described in step 1.4 from Example 1, 0.266 g (2.05 mmol) of 1-(2-hydroxyethyl)piperazine (CAS 103-76-4) and 0.14 ml (1.0 mmol) of triethylamine in 5 ml of pentanol is stirred for 2 days at 150° C. The reaction medium is diluted with 20 ml of an aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is then basified by addition of aqueous ammonia and the product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The brown oil obtained is then purified by chromatography on a silica gel column (40 g) by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in order to give 0.220 g of 2-{4-[2-(4-fluorophenyl)-8-methyl-3-{1-[phenylsulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol in the form of an amorphous powder which is used in the following step.
Reaction SMILES: [Br:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10](OC(C)C)=[CH:9][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].IC1C=CC([C:30]([F:33])([F:32])[F:31])=CC=1>[Cu]I.CS(C)=O>[Br:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([C:30]([F:33])([F:32])[F:31])=[CH:11][CH:12]=2)[N:3]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CC(C)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(-n2cnc(Br)n2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
3-Bromo-1-(4-isopropoxyphenyl)-1H-1,2,4-triazole (7.15 g, 48.3 mmol), copper(I) iodide (1.25 g, 6.56 mmol), cesium carbonate (18.9 g, 58.0 mmol), and 1-iodo-4-(trifluoromethyl)benzene (8.29 g, 30.5 mmol) were added to dimethylsulfoxide (50 mL) and the solution was degassed with nitrogen for 10 minutes. The solution was heated at 100° C. for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through Celite®. The resulting filter cake was rinsed with additional ethyl acetate (100 mL). Saturated aqueous ammonium chloride was added to the filtrate which was then stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated onto Celite®. Purification by silica gel chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a white solid (5.64 g, 64%): mp 87-89° C.; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.85-7.77 (m, 4H); ESIMS m/z 292.0 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]/[CH3:22]>>[C:14]1([C@@H:12]([N:8]2[C:6]3=[N:7][C:2](/[CH:20]=[CH:21]\[CH3:22])=[CH:3][N:4]=[C:5]3[N:10]=[C:9]2[OH:11])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C/C=C\B(O)O
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Product: C/C=C\c1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 90 °C
Yield: 63 %

Procedure:
A scintillation vial equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), (Z)-prop-1-enyl boronic acid (2.0 equiv) and (DPPF)PdCl2 (0.10 equiv). The vial was fitted with a septum-lined cap and purged with nitrogen for 5-10 min. To this mixture was added dioxane (16.6 volume equivalents) and degassed 2N K2CO3 (4.2 volume equivalents) by syringe. The resulting mixture was heated to 90° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc, washed with twice with saturated aq. NaHCO3, and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Biotage MPLC 5%-40% EtOAc/Hexanes) provided the title compound (63%) as an off-white foam. LCMS m/z (APCI)=281.1 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: CCCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Product: CCCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), and butylamine (2 ml) the subtitle compound was obtained (563 mg, 100%). MS 388 m/z (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@@H:35]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]4)=[O:33])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl(R)-3-amino-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.