Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH:14][C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH2:20][NH2:21])=[O:16])=[CH:9][CH:10]=2)[CH2:5]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:56][C:57]1[CH:65]=[C:64]([O:66][CH3:67])[C:63]([O:68][CH3:69])=[CH:62][C:58]=1[C:59](O)=[O:60]>CN(C=O)C>[Br:56][C:57]1[CH:65]=[C:64]([O:66][CH3:67])[C:63]([O:68][CH3:69])=[CH:62][C:58]=1[C:59]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:15](=[O:16])[NH:14][C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][N:4]([CH3:3])[CH2:5]3)=[CH:10][CH:9]=2)[CH:18]=1)=[O:60]
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Reactant: COc1cc(Br)c(C(=O)O)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(Br)c(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(C)CC4)c2)cc1OC
Yield: 40.9 %

Procedure:
Dissolved 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)benzylamine dihydrochloride (36.8 mg, 0.10 mmol) in DMF (1.0 mL) and added 4-methylmorpholine (0.044 mL, 0.4 mmol). Dissolved HATU (57.0 mg, 0.15 mmol) in 1.0 mL DMF and added to the 2-bromo-4,5-dimethoxybenzoic acid (25.5 mg, 0.12 mmol) and stirred to dissolve. Added the amine to the 2-bromo-4,5-dimethoxybenzoic acid solution and shook at room temperature 48 hours. The solvent was removed under reduced pressure. The residue was dissolved in 10% water/DMSO (900 uL). Purified by prep HPLC to give 22.0 mg of 2-bromo-4,5-dimethoxy-N-[3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide. MS, electrospray, 538 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][C:3]=1[C:4]#[N:5].[Br:15]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C=O)C>[Br:15][C:12]1[S:11][C:10]([C:7]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=2)[C:4]#[N:5])=[N:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cc(-c2nccs2)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ncc(Br)s2)ccc1F
Temperature: 25 °C
Reaction time: 23 h
Yield: 0.1 %

Procedure:
To 2-fluoro-5-(thiazol-2-yl)benzonitrile (21.8 g, 106.7 mmol) in anhydrous DMF (200 mL) was added recrystallized N-bromosuccinimide (22.7 g, 128 mmol). The reaction mixture was stirred at room temperature for 23 h under N2. The reaction mixture was basified with 1N NaOH and washed with EA and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated to yield orange oil. The crude product was purified by silica gel flash chromatography (20% EA/Hexanes) to produce 21 mg (70%) of 5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile THZ INT-2 as half-white solid. LCMS-ESI (m/z) calculated for C10H4BrFN2S: 283.1; found 284.9 [M+H]+, tR=3.82 min. 1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J=5.9, 2.3 Hz, 1H), 8.08 (ddd, J=8.8, 4.9, 2.3 Hz, 1H), 7.78 (d, J=4.8 Hz, 1H), 7.31 (t, J=8.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:7]([O:8][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[N:3]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc([N+](=O)[O-])nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A solution of 2-methyl-6-nitro-pyridin-3-ol (0.77 g, 5.00 mmol) in acetone (50.00 ml) was treated with acetic anhydride (1.00 g, 9.80 mmol) and potassium carbonate (2.07 g, 15.00 mmol). The mixture was stirred for 1 h at room temperature then filtered, washing with acetone. The solvent was removed, yielding acetic acid 2-methyl-6-nitro-pyridin-3-yl ester (0.75 g, 77%) as a white solid, MS (ISP): m/e=196.1 (M+), which was used crude.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[C:6]([CH3:16])([CH3:15])[S:5]1(=[O:18])=[O:17]>CCO>[CH3:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]([OH:14])[C:6]([CH3:16])([CH3:15])[S:5]1(=[O:17])=[O:18]
Reactant: CN1c2ccccc2C(=O)C(C)(C)S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN1c2ccccc2C(O)C(C)(C)S1(=O)=O
Reaction time: 8 h
Yield: 100 %

Procedure:
NaBH4 (45 mg, 1.2 mmol) is added to a solution of 1,3,3-Trimethyl-2,2-dioxo-2,3-dihydro-1H-benzo[c][1,2]thiazin-4-one (190 mg, 0.8 mmol) in 15 mL of EtOH at 0° C. The resulting mixture is stirred at this temperature for overnight. The reaction is quenched by HCl (1M), and extracted with ethyl acetate (15 mL×3). The combined extracts are dried over anhydrous Na2SO4. After filtration and concentration, the residue is purified by flash column and yields the title compound as oil (193 mg).
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]1[O:25][C@H:24]2[C@:19]([CH3:29])([C@H:20]3[CH2:26][C@@H:22]([CH2:23]2)[C:21]3([CH3:28])[CH3:27])[O:18]1)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])(C)(C)C.[CH:32]([C:35]1[CH:36]=[C:37]([NH:41][C@@H:42]([CH2:46][C:47]2[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=2)C(O)=O)[CH:38]=[CH:39][CH:40]=1)([CH3:34])[CH3:33]>>[CH:32]([C:35]1[CH:36]=[C:37]([NH:41][C@@H:42]([CH2:46][C:47]2[CH:48]=[C:49]([O:57][CH3:58])[C:50]([O:55][CH3:56])=[C:51]([O:53][CH3:54])[CH:52]=2)[C:6]([NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]2[O:25][C@H:24]3[C@:19]([CH3:29])([C@H:20]4[CH2:26][C@@H:22]([CH2:23]3)[C:21]4([CH3:27])[CH3:28])[O:18]2)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])=[O:31])[CH:38]=[CH:39][CH:40]=1)([CH3:34])[CH3:33]
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: COc1cc(C[C@H](Nc2cccc(C(C)C)c2)C(=O)O)cc(OC)c1OC
Product: COc1cc(C[C@H](Nc2cccc(C(C)C)c2)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)cc(OC)c1OC

Procedure:
The title compound is prepared as described in example 1 but using {(S)-1-[(R)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester and (S)-2-(3-Isopropyl-phenylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][N:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[N+:18]([O-:20])=[O:19])[C:3]1=2.S(OCC)(O[CH2:25][CH3:26])(=O)=O>[OH-].[Na+]>[O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]([CH2:25][CH3:26])[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[N+:18]([O-:20])=[O:19])[C:3]1=2
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C1CCCc2[nH]nc(-c3ccc(Cl)cc3[N+](=O)[O-])c21
Agent: [Na+]
Agent: [OH-]
Product: CCn1nc(-c2ccc(Cl)cc2[N+](=O)[O-])c2c1CCCC2=O
Reaction time: 1 h

Procedure:
2.08 g (7.13 mmol) of 4,5,6,7-tetrahydro-4-oxo-3-(4-chloro-2-nitrophenyl)-1H-indazole are dissolved in 80 ml of 10% aqueous sodium hydroxide solution, insolubles are filtered off, and 1.2 g (7.8 mmol) of diethyl sulfate are then added to the solution. Stirring is subsequently continued for 1.5 hours at room temperature and for 1 hour at 0° C., during which process a precipitate starts to separate out after as early as approx. 10 minutes. When the reaction is complete, the precipitate is filtered off with suction and chromatographed on silica gel using ethyl acetate/dichloromethane (1:2). The fraction of Rf =0.72 contains 0.34 g (15.3% of theory) of the desired product of the formula ##STR7## and of melting point 184° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[N:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[N:3]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nc(Cl)c2c(n1)CCC2
Agent: [Na+]
Solvent: CO
Product: COc1nc(S(C)(=O)=O)nc2c1CCC2
Reaction time: 2 h

Procedure:
18.05 g (90 mmol) of 4-chloro-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine [sic] were dissolved in 200 ml of methanol. At 45° C., 16.7 g of sodium methoxide (as 30% strength solutions [sic] in methanol) were added dropwise, and the mixture was stirred for 2 hours. The solution was evaporated, taken up in ethyl acetate and acidified with dilute hydrochloric acid, and the ethyl acetate extract was evaporated. 15.5 g of an oil remained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:12]([C:23]([OH:25])=[O:24])[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:35]([O:42][CH2:43][CH2:44][CH2:45]O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:35]([O:42][CH2:43][CH2:44][CH2:45][O:24][C:23]([C:12]1[CH:13]=[C:14]2[C:22](=[C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:11]=1[CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:18]1[O:19][CH2:20][O:21][C:17]=1[CH:16]=[CH:15]2)=[O:25])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Reactant: OCCCOCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCCCOCc1ccccc1)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
Compound 5 (54.8 mg, 0.12 mmol) in CH2Cl2 (2 mL) at 0° C. was added dropwise to a stirred solution of 3-benzyloxy-1-propanol (16.6 mg, 0.1 mmol), 1,3-dicyclohexylcarbodiimide (31 mg, 0.15 mmol) and 4-dimethylaminopyridine (14.6 mg, 0.12 mmol) in dry CH2Cl2 (1 mL). The mixture was stirred for 4 h at room temperature and concentrated in vacuo. The residue was chromatographed over silica gel using CH2Cl2/MeOH (50:1, v/v) to give 6 (61.2 mg, 84%) as a yellow liquid. 1H NMR (CDCl3) δ 8.16 (s, 1H, H4), 7.47 (d, 1H, H5, J=8.7 Hz), 7.20-7.45 (m, 11H, H6+2×OCH2Ph), 6.82 (d, 1H, H5′, J=7.8 Hz), 6.76 (d, 1H, H2′, J=1.5 Hz), 6.70 (dd, 1H, H6′, J=1.5, 7.8 Hz), 6.06 (AB, 2H, 3′,4′-OCH2O—, Δδ=9.9 Hz, J=1.5 Hz), 5.84 (AB, 2H, 7,8-OCH2O—, Δδ=4.5 Hz, J=1.5 Hz), 4.65 (s, 2H, OCH2Ph), 4.53 (s, 2H, OCH2Ph), 4.42 (t, 2H, 3-COOCH2(CH2)2OBn, J=6.3 Hz), 4.35 (s, 2H, 2-CH2OBn), 3.62 (t, 2H, 3-COO(CH2)2CH2OBn, J=6.3 Hz), 2.06 (quintet, 2H, 3-COOCH2CH2CH2OBn, J=6.3 Hz); MS (EI) m/z 604 [M]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[C:26]([O:30][C:31](=[O:38])[CH:32]([CH2:36][NH2:37])[CH2:33][CH2:34][CH3:35])([CH3:29])([CH3:28])[CH3:27].C[O-].[Na+]>CO>[C:26]([O:30][C:31](=[O:38])[CH:32]([CH2:36][NH:37][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4])[CH2:33][CH2:34][CH3:35])([CH3:27])([CH3:28])[CH3:29]
Reactant: CCCC(CN)C(=O)OC(C)(C)C
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Yield: 21.6 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (138 mg), 2-aminomethyl-pentanoic acid tert-butyl ester HCl salt (96 mg) and NaOMe in MeOH (0.85 mL, 0.5 M solution) in MeOH (1 mL) was microwaved at 150° C. for 2 h. The mixture was cooled, concentrated with HOAc (0.1 mL), the residue was directly column purified to give the desired product (44 mg). LC MS ESI+: 476 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].O.[CH2:8]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[CH2:8]([O:15][C:16]([CH2:17][CH2:18][NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: NCCC(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)CCNCCC(=O)OCc1ccccc1

Procedure:
3-Aminopropionic acid (5 g, 56 mmol) was added to ethanol (50 mL), and TEA (7.8 ml, 56 mmol) and water (50 mL) were added and the mixture was refluxed under nitrogen. Acrylic acid benzyl ester ((9.1 g, 56 mmol) and more ethanol (50 mL) were added, and the mixture was refluxed for 16 h. The sample was concentrated under vacuum, adding toluene and reevaporating twice to yield 17.5 grams (product plus TEA).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:18])[C:15]([OH:17])=[O:16].[Mg].[CH3:20]I.Cl>CCOCC.C(O)(=O)C>[CH3:20][C:14]([OH:18])([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)C(=O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: CI
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(O)(C(=O)O)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A cooled solution of fluorene-2-glyoxylic acid (4.5 g) in ether (150 ml) is treated dropwise over a 45 minute period with Grignard reagent prepared from magnesium (2.1 g) and methyl iodide (6.5 ml) in ether (145 ml). The mixture is then stirred for 2 hours at room temperature and poured into ice water. The mixture is treated with 250 ml 50% acetic acid and finally acidified to pH 2.0 with 10% HCl. The ether layer is separated, and the aqueous extracted with additional ether. The combined ether extracts are washed with sodium chloride solution and water, dried (MgSO4) and evaporated to give the title compound (3.7 g, mp 164°-168°). Recrystallization from ethvl acetate-hexane raises the mp to 170°-171°, λKBr 3400 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH3:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[CH3:27]>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([CH3:20])[CH:22]=2)=[CH:7][C:6]=1[F:8]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: Cc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1C

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 3,4-dimethylphenylboronic acid (step 1) to give 1,2-difluoro-4-(3,4-dimethylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 125.1-125.8° C.; NMR (CDCl3) δ 2.16 (s, 3H), 2.23 (s, 3H), 3.04 (s, 3H), 6.69 (dd, J=2, 8 Hz, 1H), 6.86 (S, 1H), 6.95 (d, J=8 Hz, 1H), 7.16-7.26 (m, 3H), 7.29 (d, J=9 Hz, 1H), 7.79 (d, J=9 Hz, 2H); MS (FAB) m/z 379 (M+Li)+; HRMS calc'd for M+ 372.0996, found 372.0978. Anal. calc'd for C20H18F2O2S: C, 67.73; H, 4.87; F, 10.20. Found: C, 67.93; H, 4.92; F, 9.82.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:12]([CH:13]=[O:14])=[CH:11][N:10]([CH3:15])[N:9]=1.[CH3:33][Mg]Br.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:12]([CH:13]([OH:14])[CH3:33])=[CH:11][N:10]([CH3:15])[N:9]=1
Reactant: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(COc2nn(C)cc2C(C)O)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carbaldehyde (0.45 g) in tetrahydrofuran (10 mL) was slowly added methylmagnesium bromide (3.0 M diethyl ether solution, 0.5 mL) at 0° C., and the mixture was stirred for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)ethanol (0.38 g, yield 81%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 94-95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2([CH2:13][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:18]=1[C:19](Cl)=[O:20]>C1(C)C=CC=CC=1.ClCCl>[CH2:13]([C:7]1([C:5]2[O:4][N:3]=[C:2]([NH:1][C:19](=[O:20])[C:18]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:17]=3[O:16][CH3:15])[CH:6]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:14]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CCC1(c2cc(N)no2)CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCC1(c2cc(NC(=O)c3c(OC)cccc3OC)no2)CCCCC1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of 14 g of 3-amino-5-(1-ethylcyclohexyl)isoxazole and 14.4 g of 2,6-dimethoxybenzoyl chloride in 100 ml of toluene was heated to reflux and stirred for eighteen hours. The reaction mixture then was cooled to room temperature and the solvent was removed by evaporation under reduced pressure to provide a solid. The solid was dissolved in 200 ml of dichloromethane, washed with dilute sodium hyroxide and with brine, dried, and the solvent was removed by evaporation. The product was crystallized from dichloromethane and diethyl ether to provide 15.5 g of N-[5-(1-ethylcyclohexyl)-3-isoxazolyl]-2,6-dimethoxybenzamide. M.P. 179°-181° C. Yield 60%.
Reaction SMILES: [Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][Si:37]([CH3:44])([CH3:43])[CH2:38][CH2:39][O:40][CH2:41]Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[N:29]([CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:44])([CH3:43])[CH3:36])[C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:34][CH:35]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (1.19 g, 2 mmol) was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (708 μL, 4 mmol) to give 5-{3-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one, which was then treated according to general procedure AD to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([OH:13])[CH3:12].[ClH:14]>C(Cl)Cl>[ClH:14].[CH3:1][C:2]1[C:7]([CH2:8][C:9](=[NH:10])[O:13][CH2:11][CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1CC#N
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)Cc1cccnc1C
Reaction time: 8 h

Procedure:
Through a stirred solution of Example 53A (1.7 g, 12.86 mmol), absolute ethanol (0.89 g, 19.35 mmol) and anhydrous methylene chloride (25 ml) was bubbled with hydrogen chloride gas for 20 min. The mixture was allowed to stand overnight in the refrigerator. The product was precipitated with anhydrous ether and filtered to obtain the title compound, which was immediately used in the next step. MS (ESI+) m/z 180 (M+H)+.
Reaction SMILES: C([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25]([OH:27])=O)=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:40][NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:40][N:41]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1)[C:25]([C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([OH:14])=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:28][C:17]=12)=[O:27]
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reactant: CNc1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2)c1ccccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 7.8 %

Procedure:
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added 2-methylaminopyridine (0.0079 mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Purified by reverse phase HPLC (0.1% TFA, H2O/ACN) to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid methyl-pyridin-2-yl-amide 318 (0.0017 g, 0.003 mmol, 8%.) 1H NMR (CDCl3) δ 9.02 (dd, 1H), 8.50 (d, 1H), 8.18 (d, 1H), 7.65 (dd, 1H), 7.38 (m, 5H), 7.08 (dd, 2H), 4.94 (dd, J=15 Hz, 11Hz, 2H), 4.49 (d, J=17 Hz, 1H), 4.19 (d, J=17 Hz, 1H), 3.61 (s, 3H.) MS: 443 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([OH:16])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([CH3:25])([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[NH2:19]>>[CH3:17][C:18]([NH:19][C:14]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])[N:6]=1)=[O:16])([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[CH3:25]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)F)n1
Product: CC(C)(NC(=O)c1ccc(Br)c(OCC(F)(F)F)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 282a) and α,α-dimethyl-2-thiazolemethanamine (Example 12c) as starting materials, MS (EI): m/e=424.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:35])[CH:3]=1.O1CCOCC1>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:35])[CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)c(-c3ccc(F)cc3C)sc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a 30 mL screw cap vial, (E)-tert-butyl 3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (100 mg, 0.204 mmol) was dissolved in 4M HCl in dioxane (153 μl, 0.612 mmol) and the reaction mixture was stirred for 10 min at room temperature. The reaction mixture was concentrated to dryness to afford (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (88 mg, 0.202 mmol, 99% yield). 1H NMR (400 MHz, CD3OD) δ ppm=2.25 (s, 3 H) 3.78 (s, 3 H) 6.21 (d, J=15.66 Hz, 1 H) 6.68-6.84 (m, 3 H) 6.84-6.92 (m, 2 H) 7.16-7.29 (m, 2 H) 7.31-7.41 (m, 3 H) 7.46 (d, J=16.17 Hz, 1 H).