Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH2:35][CH3:36])=[CH:21][N:20]=2)[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[CH2:35]([C@H:26]1[CH2:27][N:28]([CH:31]2[CH2:32][O:33][CH2:34]2)[CH2:29][CH2:30][N:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=[C:12]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:39]4[CH2:51][CH2:50][N:42]5[C:43]6[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=6[CH:49]=[C:41]5[C:40]4=[O:52])[C:6]=3[CH2:5][OH:4])[CH:17]=2)=[N:20][CH:21]=1)[CH3:36]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
A mixture of 131a (150 mg, 0.21 mmol) and LiOH (50 mg, 2.1 mmol) in iPrOH/THF (1:1, 4 mL) and H2O (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 131 (26 mg, 25%) as a white solid. LCMS: [M+H]+ 665. 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J=2.0, 1H), 8.50 (d, J=5.0, 1H), 7.93 (d, J=2.5, 1H), 7.83 (d, J=1.5, 2H), 7.38 (d, J=5.0, 1H), 7.27 (d, J=5.0, 1H), 6.90 (s, 1H), 6.83 (d, J=8.5, 1H), 4.73-4.64 (m, 5H), 4.50 (s, 1H), 4.33-4.31 (m, 1H), 4.20-4.16 (m, 2H), 3.88-3.86 (m, 1H), 3.73 (s, 3H), 3.53-3.51 (m, 1H), 3.33 (s, 1H), 3.13 (t, J=5.0, 2H), 2.61-2.56 (m, 4H), 2.45 (d, J=4.0, 2H), 2.37 (s, 1H), 1.91-1.79 (m, 7H), 1.39-1.40 (m, 1H), 0.83 (t, J=7.0, 3H).
Reaction SMILES: [OH:1][C@H:2]([CH2:7][C@H:8](O)[CH2:9][CH2:10][C@@H:11]1[C@@H:20]2[C:15](=[CH:16][C@@H:17]([OH:22])[CH2:18][C@@H:19]2[OH:21])[CH:14]=[CH:13][C@@H:12]1[CH3:23])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>O1CCCC1>[OH:22][C@H:17]1[CH2:18][C@H:19]([OH:21])[C@H:20]2[C:15]([CH:14]=[CH:13][C@H:12]([CH3:23])[C@@H:11]2[CH2:10][CH2:9][C@H:8]2[O:5][C:4](=[O:6])[CH2:3][C@H:2]([OH:1])[CH2:7]2)=[CH:16]1
Reactant: C[C@H]1C=CC2=C[C@@H](O)C[C@H](O)[C@@H]2[C@H]1CC[C@@H](O)C[C@@H](O)CC(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1C=CC2=C[C@@H](O)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O)CC(=O)O1

Procedure:
The whole of the crude (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6,8-dihydroxy-2-methyl-1,2,6,7,8,8a-hexahydro-1-naphthyl]heptanoic acid, prepared as described in Step 2, above, was mixed with 1000 ml of tetrahydrofuran. 38 ml (0.27 mol) of triethylamine were then added to the mixture, followed by 38 ml (0.25 mol) of diethyl cyanophosphonate, whilst ice-cooling and stirring. The resulting mixture was then stirred at room temperature for 1.5 hours. At the end of this time, the tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure and the residue was triturated with a mixture of diethyl ether and ethanol to stimulate crystallization. The resulting crystals were collected by filtration to provide 47.7 g of the title compound. This was then recrystallized from a mixture of ethyl acetate and ethanol to produce colorless plates melting at between 161° and 163° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:17])=[C:7]([CH:16]=1)[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:26]=[C:27]([C@H:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1>CN(C=O)C.O.CCOCC>[Si:9]([O:8][C:7]1[CH:16]=[C:3]([CH:4]=[CH:5][C:6]=1[Cl:17])[CH2:2][NH:33][C@@H:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=1)[CH3:32])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(CBr)ccc1Cl
Reactant: C[C@@H](N)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H](NCc1ccc(Cl)c(O[Si](C)(C)C(C)(C)C)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A solution of (5-(bromomethyl)-2-chlorophenoxy)(tert-butyl)dimethylsilane 81 (1.00 g, 2.98 mmol) and potassium carbonate (0.453 g, 3.28 mmol) in DMF was stirred at room temp under N2. (R)-1-(3-Chlorophenyl)ethanamine (0.464 g, 2.98 mmol) was added to the solution and the reaction was stirred at room temperature for 8 h. The reaction was checked by TLC for completion. The reaction mixture was diluted with water and ether. The ether solution was washed with water (2×) and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 5% to 30% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give (R)—N-(3-(tert-butyldimethylsilyloxy)-4-chlorobenzyl)-1-(3-chlorophenyl)ethanamine 82 (0.612 g, 50.1% yield) as a colorless oil. The product was carried forth to the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:10]=2)[NH:5][CH:4]=1)#[CH:2].Cl[C:25](=[N:42][OH:43])[C:26]1[CH:27]=[C:28]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])[CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>C1COCC1>[CH:21]([S:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:10]=[C:11]3[C:3]([C:1]4[O:43][N:42]=[C:25]([C:26]5[CH:27]=[C:28]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])[CH:29]=[CH:30][CH:31]=5)[CH:2]=4)=[CH:4][NH:5][C:6]3=[N:7][CH:8]=2)=[CH:17][CH:16]=1)(=[O:20])=[O:19])([CH3:23])[CH3:22]
Reactant: C#Cc1c[nH]c2ncc(-c3ccc(S(=O)(=O)C(C)C)cc3)nc12
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(C(Cl)=NO)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(NC(=O)OC(C)(C)C)c1cccc(-c2cc(-c3c[nH]c4ncc(-c5ccc(S(=O)(=O)C(C)C)cc5)nc34)on2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.8 %

Procedure:
To a solution of 7-ethynyl-2-(4-isopropylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine (72 mg, 0.2213 mmol) and tert-butyl 1-(3-(chloro(hydroxyimino)methyl)phenyl)ethylcarbamate (66.12 mg, 0.2213 mmol) in THF (2.5 mL) was added triethylamine (26.88 mg, 37.02 μL, 0.2656 mmol) The mixture was stirred at ambient temperature for 45 minutes then heated at 65° C. for 3.5 hours. The reaction was cooled to ambient temperature and the solvent removed in vacuo. The residues was dissolved in warm DCM (50 mL) and washed with saturated aqueous NaHCO3(×1), dried (MgSO4), filtered and concentrated in vacuo. The residue triturated from hot MeCN and the precipitate obtained on cooling was isolated by filtration and washed with MeCN to give the sub-title compound as a pale yellow powder (83 mg, 64% Yield). 1H NMR (400 MHz, DMSO) δ 1.28 (d, 6H), 1.41-1.45 (m, 3H), 1.43 (s, 9H), 3.58 (sept, 1H), 4.79 (br t, 1H), 7.52-7.62 (m, 4H), 7.92 (d, 1H), 8.00 (s, 1H), 8.10 (d, 2H), 8.68 (d, 2H), 8.76 (s, 1H), 9.25 (s, 1H) and 13.08 (br s, 1H) ppm; MS (ES) 588.1.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:12]=[C:11]([O:13]CC2C=CC(C3C=CC=CC=3C3N=NN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=3)=CC=2)[C:10]2C[CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.C([Li])CCC.BrC1C=CC(C)=CC=1.IC1C=CC=CC=1[C:69]([O:71][CH3:72])=[O:70]>CCCCCC.C1COCC1.CCOCC.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:2][C:3]1[NH:4][C:5]([CH2:6][CH2:7][CH3:8])=[CH:10][C:11](=[O:13])[C:12]=1[C:69]([O:71][CH3:72])=[O:70]
Reactant: FC(F)(F)c1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCCC2
Reactant: COC(=O)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(Br)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCc1cc(=O)c(C(=O)OC)c(C)[nH]1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
The starting material (A) was obtained as follows: (i) A 1.6M solution of butyllithium in hexane (24.0 ml) was added dropwise to a stirred solution of 4-bromotoluene (6.0 g) in dry THF (50 ml) at -78° C. under an atmosphere of argon. The temperature was maintained at -78° C. for 20 minutes and then a 1M solution of anhydrous zinc chloride in ether (38.6 ml) was added. The solution was kept at -78° C. for 15 minutes, and then tetrakis(triphenylphosphine)palladium (60 mg) in THF (5 ml) was added, followed by methyl 2-iodobenzoate (6.1 g) in THF (10 ml). The solution was allowed to reach ambient temperature over 1 hour, then heated under reflux for 5 hours. The solvent was removed by evaporation and the residue was dissolved in chloroform (150 ml). The solution was washed with a solution of ethylenediaminetetracetic acid (10 g) in water (100 ml) and the aqueous layer was re-extracted with chloroform (100 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:9 v/v), to give methyl 4'-methylbiphenyl-2-carboxylate (B) as a colourless oil (4.4 g); NMR: 2.4(s,3H), 3.65(s,3H), 7.2(s,4H), 7.35(m,3H), 7.5(m,1H), 7.8(d,1H).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:41])([F:40])[C:6]([NH:8][CH:9]1[CH2:38][C:13]2=[CH:14][N:15]([S:20]([C:23]3[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][C:26]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:24]=3[CH:35]([CH3:37])[CH3:36])(=[O:22])=[O:21])[C:16]3[CH:17]=[CH:18][CH:19]=[C:11]([C:12]=32)[C:10]1=[O:39])=[O:7]>C1COCC1>[OH:39][C:10]1([CH3:1])[C:11]2[C:12]3[C:13](=[CH:14][N:15]([S:20]([C:23]4[C:24]([CH:35]([CH3:37])[CH3:36])=[CH:25][C:26]([CH:32]([CH3:33])[CH3:34])=[CH:27][C:28]=4[CH:29]([CH3:30])[CH3:31])(=[O:21])=[O:22])[C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:38][CH:9]1[NH:8][C:6](=[O:7])[C:5]([F:4])([F:40])[F:41]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)n2cc3c4c(cccc42)C(=O)C(NC(=O)C(F)(F)F)C3)c(C(C)C)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)n2cc3c4c(cccc42)C(C)(O)C(NC(=O)C(F)(F)F)C3)c(C(C)C)c1
Yield: 84 %

Procedure:
Methyl magnesium bromide (1M THF solution 8 equivalents) was allowed to react with a solution of 3,4-dihydro-4-trifluoroacetylamino-1-(2,4,6-triisopropylphenylsulfonyl)-5H-benz[cd]indol-5-one (1.5 g, 1.43 mmol) in THF (14.3 ml). The reaction mixture was processed in a conventional manner. The residue was subjected to silica gel column chromatography, eluting with n-hexane-ethyl acetate (4:1) to afford 1.3 g (84%) of the title compound as an amorphous crystalline product.
Reaction SMILES: [CH:1]1[C:17]2[C:5](=[C:6]3[CH:48]=[CH:47][CH:46]=[CH:45][C:7]3=[C:8]3[C:16]=2[CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=2)[C:14]2[C:9]3=[C:10]3[CH:44]=[CH:43][CH:42]=[CH:41][C:11]3=[C:12]3[CH:40]=[CH:39][CH:38]=[CH:37][C:13]3=2)[CH:4]=[CH:3][CH:2]=1.C([O:51][C:52](=O)[CH2:53][C:54](=[O:64])[C:55]1[CH:60]=[C:59]([F:61])[C:58]([F:62])=[CH:57][C:56]=1[F:63])C.C.CO>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.C(Cl)Cl.CO>[F:63][C:56]1[CH:57]=[C:58]([F:62])[C:59]([F:61])=[CH:60][C:55]=1[C:54](=[O:64])[CH2:53][C:52]([O:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:15]2[C:14]3[C:9](=[C:10]4[CH:44]=[CH:43][CH:42]=[CH:41][C:11]4=[C:12]4[CH:40]=[CH:39][CH:38]=[CH:37][C:13]4=3)[C:8]3[C:16]2=[C:17]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=[C:6]2[CH:48]=[CH:47][CH:46]=[CH:45][C:7]2=3)=[CH:34][CH:33]=1)=[O:51]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Reactant: OCc1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(CC(=O)c1cc(F)c(F)cc1F)OCc1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-[[10-(17H-Tetrabenzo[a,c,g,i]fluoren-17-yl)decyl]oxy]benzenemethanol (8) (44.9 mg, 0.071 mmol) and DMAP (3.2 mg, 0.026 mmol) were added to an oven-dried flask and dissolved in freshly distilled toluene (8 mL). 3-Oxo-3-(2,4,5-trifluoro-phenyl)-propionic acid ethyl ester (7) (46.2 mg, 0.19 mmol) was added and the resultant solution refluxed under an atmosphere of nitrogen for 20 hours. The reaction was cooled to room temperature and solvent removed in vacuo to yield an orange oil. This was dissolved in DCM/methanol (3:2, 25 mL). Charcoal (prewashed with toluene, 510 mg) was added and the suspension stirred at room temperature for 15 minutes. Methanol was added in portions (total 45 mL) and stirring continued until TLC analysis showed that none of the desired product was present in the supernatant liquid. The supernatant was removed by centrifugation and the charcoal residue then suspended in toluene (40 mL). The suspension was then stirred at 40° C. for 15 minutes and the supernatant removed by centrifugation. This was repeated with fresh toluene until no fluorescent products were detected in the supernatant by TLC. The toluene washes were combined and solvent removed in vacuo. The yellow residue was purified by flash column chromatography using DCM as eluent to yield the desired product (35.2 mg, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][CH:11]1[CH2:17][CH2:16][CH:15]2[CH2:18][CH:12]1[C:13](=O)[O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][CH:22](C[AlH]CC(C)C)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1.C1COCC1.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C@H:11]1[CH2:17][CH2:16][C@@H:15]([OH:14])[CH2:18][C@@H:12]1[CH:13]=[CH:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC2CC1C(=O)O2)OCc1ccccc1
Reactant: CC(C)C[AlH]CC(C)C
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC=C[C@H]1C[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of (7-Oxo-6-oxa-bicyclo[3.2.1]oct-2-yl)-carbamic acid benzyl ester (2.26 g, 8.2 mmol) in toluene (80 mL) was cooled to −78° C. and treated dropwise with DIBAL-H (11 mL of a 1.0 M toluene solution). The reaction mixture was stirred for 2 h at −78° C. and quenched with 50 mL of 1 N HCl. The mixture was allowed to warm to RT and then extracted with EtOAc (1×). The organic phase was washed with half-saturated brine. The combined aqueoues phases were back extracted with EtOAc (1×). The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to afford a colorless oil. This material was dissolved in THF (100 mL). The resultant solution was cooled to 0° C. and charged successively with ethyltriphenylphosphonium iodide (5.3 g, 12.3 mmol) and KHMDS (49 mL of a 0.5 M solution in toluene). The ice bath was removed and the reaction was stirred for 4 h at RT before being quenched with the addition of 1 N HCl (50 mL). The biphasic mixture was partitioned between 1 N HCl (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. Purification of the residue via flash chromatography afforded the desired [(1S,2R,4R)-(4-hydroxy-2-propenyl-cyclohexyl)]-carbamic acid benzyl ester as a colorless oil (0.56 g). MS found: (M+H)+=312.26.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[S:14][C:13]2[C:8](=[N:9][CH:10]=C[C:12]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(NC(=O)CC3C=CC=CC=3)=S)=[CH:18][C:17]=2[F:35])[CH:7]=1.CCCCCCCCCCCC[NH2:48]>>[F:35][C:17]1[CH:18]=[C:19]([NH2:22])[CH:20]=[CH:21][C:16]=1[O:15][C:12]1[C:13]2[S:14][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:7][C:8]=2[N:9]=[CH:10][N:48]=1
Reactant: CCCCCCCCCCCCN
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: Nc1ccc(Oc2ncnc3cc(-c4nccs4)sc23)c(F)c1
Yield: 7 %

Procedure:
Starting from the nitro compound 150, following the procedure described above for the synthesis of compound 13a (via the intermediate amine 12, scheme 2, example 12), title compound 152a was obtained [via intermediate 3-fluoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)benzenamine (151)] in 7% yield. Characterization of 152a is provided in the Table 14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:16](=[O:20])[C:17]([OH:19])=[O:18])[N:10]([CH3:15])[C:11]=1[C:12]([OH:14])=[O:13].Cl.[CH2:25](O)[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:16](=[O:20])[C:17]([O:19][CH2:25][CH3:26])=[O:18])[N:10]([CH3:15])[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CCO
Reactant: Cn1c(C(=O)C(=O)O)cc(COc2cccc(Cl)c2)c1C(=O)O
Agent: Cl
Product: CCOC(=O)C(=O)c1cc(COc2cccc(Cl)c2)c(C(=O)O)n1C
Yield: 42 %

Procedure:
4-(m-Chlorophenoxy)methyl-5-hydroxycarbonyl-1-methyl-α-oxopyrrole-2-acetic acid (5.5 g, 16,3 mmol) is suspended in absolute ethanol (40 ml) and concentrated HCl (1.0 ml) is added. The mixture is heated to reflux for 35 minutes, then cooled and the product crystallizes. The solid is filtered and dried to give 2.51 g (42%) of pure ethyl 4-(m-chlorophenoxy)methyl-5-hydroxycarbonyl-1-methyl-α-oxopyrrole-2-acetate.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3](=O)[C:4](=[CH:9][N:10]1CCCCC1)[C:5]([O:7][CH3:8])=[O:6].O.[NH2:19]N>C1(C)C=CC=CC=1>[F:1][CH:2]([F:17])[C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][NH:10][N:19]=1
Reactant: NN
Reactant: COC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c[nH]nc1C(F)F
Temperature: -50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
At −50° C., a solution of methyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate (97.9%, 20.0 g, 79 mmol) in toluene (150 ml) was added dropwise to a solution of hydrazine hydrate (100%, 4.36 g, 87 mmol) in toluene (150 ml). The reaction mixture was stirred at −50° C. for 2 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (100 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. According to GC analysis, the residue obtained (9.2 g) consisted to 65.3% of methyl 3-difluoromethyl-1H-pyrazol-4-yl-carboxylate (Yield: 66%). 1H-NMR (CDCl3): δ=3.9 (s, 3H), 7.25 (t, 1H), 8.2 ppm (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C([Li])CCC.CON(C)[C:21]([CH:23]1[CH2:26][CH:25]([O:27][C:28]2[C:33]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:32][C:31]([F:40])=[CH:30][N:29]=2)[CH2:24]1)=[O:22]>C1COCC1>[F:40][C:31]1[CH:32]=[C:33]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:28]([O:27][CH:25]2[CH2:26][CH:23]([C:21]([C:5]3[N:4]([CH2:3][O:2][CH3:1])[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[N:6]=3)=[O:22])[CH2:24]2)=[N:29][CH:30]=1
Reactant: CON(C)C(=O)C1CC(Oc2ncc(F)cc2C2CCOCC2)C1
Reactant: COCn1cnc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1c(C(=O)C2CC(Oc3ncc(F)cc3C3CCOCC3)C2)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a solution of 1-(methoxymethyl)-1H-benzo[d]imidazole (1.5 g, 9.04 mmol) in THF (20 mL) at −78° C. was added butyllithium (2.5 M in hexane) (3.7 mL, 9.16 mmol). The solution was stirred at −78° C. for 30 min and a solution of 3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutanecarboxylic acid methoxy-methyl-amide (2.2 g, 6.87 mmol) in THF (20 mL) was added dropwise via cannula. The reaction mixture was stirred at −78° C. for 30 min and then warmed to RT and quenched with water. The reaction mixture was extracted with EtOAc (3×25 mL) and the organic phases were combined and washed with water (1×10 mL), brine (1×10 mL), dried over MgSO4, filtered, and concentrated to get a residue, which was purified by flash column chromatography on silica gel (10% to 60% EtOAc in hexanes) to give the product (1.2 g) as yellow oil.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:4]1[CH:5]=[CH:6][C:2]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH3:7])=[CH:3]1
Reactant: Brc1ccsc1
Reactant: COc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccsc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 3-bromothiophene (978 mg, 6 mmol) in 50 ml of dioxane is degassed with argon. Tetrakis-(triphenylphosphine)-palladium(0) (700 mg, 0.6 mmol) is added and the mixture is stirred for 5 minutes. 2-Methoxybenzene boronic acid (1.824 g, 12 mmol) and 12 ml of aqueous 2 N sodium carbonate are successively added and the resulting mixture is stirred for 16 hours at 85° C. The mixture is allowed to cool to room temperature then is extracted with dichloromethane (2×50 ml). The organic extracts are washed with water (2×30 ml) then dried over sodium sulfate, filtrated and evaporated. The residue is purified via flash column on silica (eluent: hexane/ethyl acetate 99:1 gradient to give 2-(thien-3-yl)anisole.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:13][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Br:1])=[O:14]
Reactant: O=C(O)c1ccc2ccccc2c1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2ccccc2c1Br

Procedure:
To 2.00 g 1-bromo-naphthalene-2-carboxylic acid in 20 ml of dry methanol 5 ml of sulfuric acid were added. After 5 h at reflux, the reaction was poured onto ice-water, and the precipitated product was collected by filtration and washed until neutral. After recrystallization from heptane 1.90 g 1-bromo-naphthalene-2-carboxylic acid methyl ester were obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17].CCO.C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:13]([CH3:20])([CH3:19])[CH3:12])=[CH:15][C:16]([NH2:17])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(N)cc2C(C)(C)C)cc1

Procedure:
A mixture of 4-methoxyphenylhydrazine hydrochloride (3.5 g), 4,4-dimethyl-3-oxopentanenitrile (2.5 g), EtOH (30 mL), and AcOH (1 mL) was heated at the reflux temperature for 3 h, cooled to room temp., and poured into a mixture of EtO (100 mL) and a 10% Na2CO3 solution (100 mL). The organic layer was washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The solid residue was washed with pentane to afford the desired pyrazole as a pale brown solid. (4.25 g): 1H-NMR (DMSO-d6) δ 1.18 (s, 9H); 3.78 (s, 3H); 5.02 (br s, 2H); 5.34 (s, 1H); 6.99 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H).