Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([O:11]CC=C)[C:8]([CH2:15][C:16]#[C:17][CH3:18])=[CH:7][C:6]=1[C:19]1[N:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:27][CH:26]=2)[C:21](=[O:24])[NH:22][N:23]=1)C=C.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO.[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>[CH2:15]([C:8]1[C:9]([OH:11])=[CH:10][C:5]([OH:4])=[C:6]([C:19]2[N:20]([C:25]3[CH:26]=[CH:27][C:28]([CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:29][CH:30]=3)[C:21](=[O:24])[NH:22][N:23]=2)[CH:7]=1)[C:16]#[C:17][CH3:18]
Reactant: C=CCOc1cc(OCC=C)c(-c2n[nH]c(=O)n2-c2ccc(CN3CCOCC3)cc2)cc1CC#CC
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: CC#CCc1cc(-c2n[nH]c(=O)n2-c2ccc(CN3CCOCC3)cc2)c(O)cc1O
Yield: 21.8 %

Procedure:
Under a nitrogen atmosphere crude 5-[2,4-bis-allyloxy-5-(but-2-ynyl)-phenyl]-4-[4-(morpholin-4-ylmethyl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-one(F470-IM12: 208 mg) was dissolved in methanol (10 mL) and mixed with potassium carbonate (348 mg, 2.52 mmol) and tetrakis (triphenylphosphine) palladium (20 mg, 0.016 mmol), and the mixture was heated for 3 hours under reflux. After adding water (5 mL), the reaction mixture was adjusted to pH 6.5 with 2M hydrochloric acid. Silica gel (2.0 g) was added to this mixture and the mixture was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol=30:1-10:1) to obtain the title compound (OH-c02: 38 mg, yield 10.4%, in 4 steps).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[C:13]([C:16]4[O:20][N:19]=[C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:17]=4[C:27]([F:30])([F:29])[F:28])[O:14][N:15]=3)[CH2:8][N:9]([CH3:12])[C:10]=2[CH:11]=1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.[Cl-].[Li+]>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>[CH3:12][N:9]1[C:10]2[CH:11]=[C:2]([CH:31]=[CH2:32])[CH:3]=[CH:4][C:5]=2[C:6]2=[N:15][O:14][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]=3[C:27]([F:29])([F:28])[F:30])=[C:7]2[CH2:8]1
Reactant: CN1Cc2c(noc2-c2onc(-c3ccccc3)c2C(F)(F)F)-c2ccc(Br)cc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)N(C)Cc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 100 °C
Yield: 56 %

Procedure:
To a heterogeneous solution of 7-bromo-5-methyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydroisoxazolo[4,3-c]quinoline (Preparation 77E, 0.040 g, 0.084 mmol) in dioxane (5.0 mL) in a sealed tube was added sequentially tributyl(vinyl)stannane (0.027 mL, 0.092 mmol) and lithium chloride (10.7 mg, 0.252 mmol). The reaction mixture was degassed with nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (9.71 mg, 8.40 μmol) was added, and the stirred reaction mixture was heated in an oil bath at 100° C. for 4 h overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with dichloromethane (10 mL), filtered through a pad of Celite, and rinsed with dichloromethane (10 mL). The filtrate was concentrated, and the solid residue was purified by flash silica gel chromatography using a 5% mixture of ethyl acetate in hexane to give the crude product mixture. The crude mixture was chromatographed using reverse-phase preparative HPLC (Column: LUNA 5 u C18, 21×100 mm:Solvent MeOH(B)—H2O(A), 0.1% TFA: 0% B-100% B, Gradient Time 12 min, Stop Time 20 min, Flow Rate 20 ml/min, Wavelength 220 nM) to give 5-methyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydroisoxazolo[4,3-c]quinoline [0.020 g, 0.047 mmol, 56%] as a viscous, tan film. The product had an HPLC ret. time=3.85 min. (condition B); LC/MS M+1=424.1.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2.CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>C(OCC)C>[N:13]1[C:14]2[C:9](=[CH:8][C:7]([CH:19]=[O:20])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2ncccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: O=Cc1ccc2ncccc2c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
n-Butyl lithium (19.2 mL; 1.5M hexane solution) was added dropwise to a solution of 6-bromoquinoline (5 g, 24.0 mmol) in diethyl ether (20 mL) that had been cooled to −70° C. under nitrogen atmosphere, a solution of N,N-dimethylformamide (3.7 mL, 48.0 mmol) in diethyl ether was further added, and the solution was stirred at −70° C. for 2 hours. The reaction solution was allowed to room temperature, then, an aqueous solution of saturated ammonium chloride was added, the solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and the title compound (320 mg, 8.5%) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:15])[CH:3]=1.[Cl-].[CH3:17][O:18][C:19](=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:6]2[N:5]=[C:4]([NH:15][C:24]([C:23]2[CH:27]=[CH:28][C:20]([C:19]([O:18][CH3:17])=[O:29])=[CH:21][CH:22]=2)=[O:25])[CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1cc(Cl)n2nc(C(F)(F)F)cc2n1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc(Cl)n3nc(C(F)(F)F)cc3n2)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
7-chloro-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-amine (0.5 g, 1.0 equivalent) was suspended in pyridine (0.2 M) in a round bottom flask. At 0° C. was added a solution of terephthalic acid monomethylester chloride (2.0 equivalents) pre-dissolved in pyridine (0.8M), and followed by addition of N,N-dimethylpyridin-4-amine (0.1 equivalent). The mixture was stirred vigorously at 0° C. for 48 h. The reaction was quenched with saturated NaHCO3; pyridine was removed in vacuo and the residue was extracted with EtOAc twice and the combined organic layers were dried over Na2SO4. The organic layers were concentrated in vacuo and the crude mixture was purified using chromatography (SiO2, gradient of 10 to 50% EtOAc/hexanes) to afford the titled compound (10%) as a solid. Melting point (191.0-195.0° C.). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.90 (s, 3H) 7.20 (s, 1H) 8.06-8.11 (m, 2H) 8.12-8.18 (m, 2H) 8.32 (s, 1H) 11.88 (s, 1H); ESI-MS: m/z 399.0 (M+H)+.
Reaction SMILES: C1(C[O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)C=CC=CC=1.Cl>CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: c1ccc(COc2ccc(-c3ccncc3)cc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(-c2ccncc2)cc1
Yield: 87.6 %

Procedure:
A solution 4-[4-(phenylmethoxy)phenyl]pyridine (120 mg, 0.46 mmol), Pd(OH)2/C (20% w/w, 10 mg) and aqueous 1.0 M HCl solution (0.5 mL) in MeOH (20 mL) was stirred under a hydrogen atmosphere (50 psi) for 17 h at 25° C. The catalyst was removed by filtration, Et3N (0.1 mL) was added and the filtrate was concentrated under reduced pressure. The residue was treated with hot THF. The resulting suspension was filtered and the filtrate concentrated under reduced pressure to give the title compound (69 mg, 88% yield) as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:24]2[C:25]([CH3:34])=[N:26][N:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=23)[S:11][C:12]=1[C:13]1[N:17]=[CH:16][N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:14]=1.Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:24]2[C:25]([CH3:34])=[N:26][N:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:29][C:28]=23)[S:11][C:12]=1[C:13]1[N:17]=[CH:16][N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:14]=1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2F)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn2ccc(OCCN3CCCCC3)cc2c1-c1nc(-c2ccccc2F)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A mixture of 3-{4-(2-fluorophenyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}-2-methylpyrazolo[1,5-a]pyridin-5-ol (100 mg, 0.20 mmol) obtained in Example 74-B(vi), 1-(2-chloroethyl)piperidine hydrochloride (112 mg, 0.61 mmol), potassium carbonate (260 mg, 1.9 mmol) and DMF (10 mL) was stirred at 50° C. for 1 h. The mixture was allowed to cool to rt. To the reaction mixture were added water (100 mL) and EtOAc (100 mL), and the mixture was stirred for 30 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (MeOH/EtOAc=0/100→5/95) to give the title compound (112 mg, 95%) as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[I-].C[S+](C)(C)=O.C[C:19](C)([O-:21])C.[K+]>CS(C)=O>[O:21]1[C:2]2([CH2:9][CH2:8][CH2:7][CH2:6][C:5]3([O:1][CH2:10]3)[O:4][CH2:3]2)[CH2:19]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: C1CCC2(CO2)OCC2(C1)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dimethyl sulfoxide (40 mL) solution of 1,4-dioxaspiro[4.5]decan-8-one (6.25 g) was added dropwise to a solution of trimethylsulfoxonium iodide (8.8 g) and potassium t-butoxide (4.5 g) in dimethyl sulfoxide (50 mL). The mixture was stirred at room temperature overnight. The mixture was then poured over ice-water and extracted with diethyl ether (3×200 mL). The combined organic extracts were washed with water and brine, dried over Na2SO4, and filtered. Concentration of the filtrate gave the crude product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:19][N:20]([CH3:32])[C:21]1[CH:31]=[CH:30][CH:29]=[C:23]2[C:24]([O:26][C:27](=O)[C:22]=12)=[O:25]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:27](=[O:26])[C:22]3[C:23](=[CH:29][CH:30]=[CH:31][C:21]=3[N:20]([CH3:19])[CH3:32])[C:24]2=[O:25])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CN(C)c1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N(C)C)c3C2=O)ccc1OC

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisoindoline-1,3-dione was prepared by the procedure of Example 8 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (572 mg, 2.09 mmol) and 3-dimethylaminophthalic anhydride (400 mg, 2.09 mmol) in acetic acid (20 mL). The product was obtained as a yellow solid (740 mg, 80% yield): mp, 94.0-96.0° C.; 1H NMR (CDCl3) δ 1.46 (t, J=7.0 Hz, 3H, CH3), 2.82 (s, 3H, CH3), 3.08 (s, 6H, CH3), 3.76-3.84 (m, 1H, CHH), 3.82 (s, 3H, CH3), 4.11 (q, J=7.0 Hz, 2H, CH2), 4.54 (dd, J=9.9, 14.5 Hz, 1H, CHH), 5.88 (dd, J=4.8, 9.9 Hz, 1H, NCH), 6.81-6.84 (m, 1H, Ar), 7.04-7.15 (m, 3H, Ar), 7.23-7.27 (m, 1H, Ar), 7.48 (dd, J=7.3, 8.3 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.68, 41.47, 43.39, 48.74, 55.20, 55.92, 64.43, 111.34, 112.54, 113.78, 114.41, 120.47, 122.09, 129.97, 134.32, 134.81, 148.46, 149.44, 150.42, 167.06, 168.19; Anal Calcd for C22H26NO6S: C, 59.14; H, 5.91; N, 6.27. Found: C, 59.14; H, 5.91; N, 6.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[C:13](=[O:18])[NH:14][CH:15]=[CH:16][CH:17]=1.[CH3:19]I>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[C:13](=[O:18])[N:14]([CH3:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CI
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccc[nH]c1=O
Product: COc1cc([N+](=O)[O-])ccc1-c1cccn(C)c1=O

Procedure:
350 mg (1.42 mmol) of the product from example 55A are alkylated analogously to example 56A with 242 mg (1.71 mmol) of methyl iodide. This affords 347 mg (88% of theory) of the title compound.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27]([NH:29][CH2:30][C@H:31]([O:107][Si](C(C)(C)C)(C)C)[CH2:32][C@H:33]([NH:99][C:100]([O:102][C:103]([CH3:106])([CH3:105])[CH3:104])=[O:101])[C:34]([NH:36][C@@H:37]([CH2:48][C:49]1[CH:50]=[C:51]([C:63]2[CH:68]=[CH:67][C:66]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)=[C:65]([CH2:77][C@H:78]([NH:88][C:89]([O:91][CH2:92][C:93]3[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=3)=[O:90])[C:79]([O:81]CC[Si](C)(C)C)=[O:80])[CH:64]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=[O:35])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C.Cl>C1COCC1.CN(C=O)C>[CH2:92]([O:91][C:89]([NH:88][C@@H:78]([CH2:77][C:65]1[CH:64]=[C:63]([C:51]2[CH:52]=[CH:53][C:54]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:49]([CH2:48][C@@H:37]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[NH:36][C:34](=[O:35])[C@@H:33]([NH:99][C:100]([O:102][C:103]([CH3:104])([CH3:106])[CH3:105])=[O:101])[CH2:32][C@@H:31]([OH:107])[CH2:30][NH:29][C:27]([O:26][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:28])[CH:50]=2)[CH:68]=[CH:67][C:66]=1[O:69][CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)[C:79]([OH:81])=[O:80])=[O:90])[C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](CNC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C)C(=O)N[C@@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)OCC[Si](C)(C)C)c2)ccc1OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@@H](O)CNC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)c2)ccc1OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
1.8 ml of 1N tetrabutylammonium fluoride in THF are added dropwise to a solution of 800 mg (0.6 mmol) of benzyl 2(S)-[5-benzyloxycarbonylamino-2(S)-tert-butoxycarbonylamino-4(R)-(tert-butyldimethylsilyloxy)pentanoylamino]-3-{4,4′-bisbenzyloxy-3′-[2(S)-benzyloxycarbonylamino-2-(2-trimethylsilylethoxycarbonyl)ethyl]biphenyl-3-yl}propionate (Example 16A) in 26 ml of absolute DMF at RT. After 25 min at RT, the mixture is cooled to 0° C. and a large amount of ice-water is added. Ethyl acetate and a little 1N hydrochloric acid solution are immediately added; the organic phase is dried with magnesium sulfate, concentrated and dried under high vacuum for 1 h. The crude product is reacted without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[S:16]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=3[OH:27])(=[O:18])=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.N(OC(C)(C)C)=O.[N:43]([Si](C)(C)C)=[N+:44]=[N-]>C(#N)C.C1COCC1>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[S:16]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=3[OH:27])(=[O:18])=[O:17])[CH:9]=2)=[CH:6][CH:7]=1)=[N+:43]=[N-:44]
Reactant: Nc1ccc(-c2cccc(CN(Cc3ccc(F)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc(-c2cccc(CN(Cc3ccc(F)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To an ice cold mixture of N-((4′-aminobiphenyl-3-yl)methyl)-3,5-dichloro-N-(4-fluoro-benzyl)-2-hydroxybenzenesulfonamide (0.08 g, 0.15 mmol) in anhydrous acetonitrile (1 mL) and anhydrous THF (1 mL) was added tert-butyl nitrite (0.03 mL, 0.22 mmol) followed by the dropwise addition of azidotrimethylsilane (0.02 mL, 0.17 mmol). The ice bath was removed and the reaction stirred at room temperature. After 1 h, anhydrous THF (0.5 mL) and anhydrous acetonitrile (0.5 mL) were added. After an additional 16 h, the reaction mixture was cooled to 0° C. before tert-butyl nitrite (0.06 mL, 0.44 mmol) and azidotrimethylsilane (0.07 mL, 0.52 mmol) were added. Two hours later, the reaction was quenched with water and extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in CHCl3 then passed through a RediSep normal phase silica flash column (4 g) eluting with hexane, followed by CHCl3. The appropriate fractions were concentrated in vacuo to afford the title compound (0.04 g, 50%) as a brown glass. 1H NMR (DMSO-d6) δ 7.80-7.75 (m, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.56-7.45 (m, 3H), 7.32 (t, J=7.7 Hz, 1H), 7.28-7.18 (m, 5H), 7.15-7.03 (m, 3H), 4.51 (s, 2H), 4.49 (s, 2H). MS (ESI): 555.3 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.Br.Br[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: BrCc1cccnc1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1cc(OCc2cccnc2)ccn1
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 2 g (15.4 mmol) of 2-chloropyridin-4-ol, 3.82 g (15.1 mmol) of 3-(bromomethyl)pyridine hydrobromide, 3 g (75.6 mmol) of sodium hydroxide and 1.39 g (4.3 mmol) of tetrabutylammonium bromide in 90 mL of toluene is refluxed for 12 hours. After cooling to room temperature, the reaction medium is taken up in 300 mL of EtOAc, washed successively with water (2×100 mL), with saturated NaHCO3 solution (100 mL) and with brine (100 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and then purified by chromatography on silica gel, eluting with a 98/2 DCM/MeOH mixture. 2.5 g of 2-chloro-4-(pyridin-3-ylmethoxy)pyridine are obtained in the form of a yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([N:12]1[C@H:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][S:14][CH:13]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:11])=O)(C)(C)C.C(C1N[C@H]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])CS1)C1C=CC=CC=1.C(OC(NCC(O)=O)=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>>[C:46]([O:45][C:43]([CH:9]([NH2:8])[C:10]([N:12]1[C@H:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][S:14][CH:13]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:11])=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(Cc2ccccc2)N1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1C(Cc2ccccc2)SC[C@H]1C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)NCC(=O)O
Product: CC(C)(C)OC(=O)C(N)C(=O)N1C(Cc2ccccc2)SC[C@H]1C(=O)OC(C)(C)C

Procedure:
B tert-Butyl (4R)-3-(2-tert-butoxycarbonylaminoacetyl)-2-benzyl-4-thiazolidinecarboxylate (isomer A) may be prepared in a manner similar to that described in Example 1C, but starting with 25.7 g of tert-butyl (2RS,4R)-2-benzyl-4-thiazolidinecarboxylate, 13.9 g of 2-tert-butoxycarbonylaminoacetic acid and 16.3 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica [eluent: methylene chloride/methanol (99:1 by volume)]. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure at 40° C. 12.1 g of tert-butyl (4R)-3-(2-tert-butoxycarbonyl-aminoacetyl)-2-benzyl-4-thiazolidinecarboxylate (isomer A) are thereby obtained in the form of a cream-coloured foam, which is used in the subsequent syntheses without further treatment.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5](C(OCC[Si](C)(C)C)=O)[CH:4]([CH:17]=[CH2:18])[CH2:3]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH:17]([CH:4]1[CH2:3][C:2](=[O:1])[CH2:7][CH2:6][NH:5]1)=[CH2:18]
Reactant: C=CC1CC(=O)CCN1C(=O)OCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC1CC(=O)CCN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(trimethylsilyl)ethyl 4-oxo-2-vinylpiperidine-1-carboxylate (24.1 g, 89.0 mmol) was dissolved in tetrahydrofuran (90 ml) at 0° C. and added TBAF (268 ml, 268 mmol) dropwise. The solution stirred at 0° C. for 30 min then at rt for an additional three hrs. The solution was quenched with 1N HCl and extracted five times with EtOAc. The organic fractions were combined, dried with Na2SO4, and concentrated. The crude product was not purified.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][N:12]2[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]2=[O:20])=[CH:7][C:6]=1[S:21]([NH2:24])(=[O:23])=[O:22])[CH3:2].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30]([NH:36][C:37](=O)[O:38]C2C=CC=CC=2)[N:29]=1.N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C>[CH3:18][C:15]1[C:16](=[O:17])[N:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:25])=[C:6]([S:21]([NH:24][C:37]([NH:36][C:30]3[N:29]=[C:28]([O:27][CH3:26])[CH:33]=[C:32]([O:34][CH3:35])[N:31]=3)=[O:38])(=[O:23])=[O:22])[CH:7]=2)[C:13](=[O:20])[C:14]=1[CH3:19]
Reactant: CCOC(=O)c1ccc(NN2C(=O)C(C)=C(C)C2=O)cc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(NN2C(=O)C(C)=C(C)C2=O)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At room temperature, 158 mg (0.43 mmol) of ethyl -2-(aminosulfonyl)-4-[(2,5-dihydro-3,4-dimethyl-2,5-dioxo-1H-pyrrol-1-yl)amino]benzoate and 118 mg (0.43 mmol) of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate were dissolved in 1.5 ml of N,N-dimethylacetamide. Then, 73 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene were added, followed by stirring for 5 minutes. The resultant mixture was allowed to stand for 15 hours. Thereafter, 0.2 ml of 35% hydrochloric acid was added to 20 ml of ice water, followed by the addition of the reaction mixture in 0.2 ml portions under stirring. After the reaction mixture was stirred for 20 minutes, the resulting precipitate was collected by filtration and dried in air. Using dichloromethane as an eluent, the crude product was purified by chromatography on a column of silica gel ("WAKO GEL C-300", trade name; product of Wako Pure Chemical Industries, Ltd.). Yield: 162 mg (58%). Melting point: 121°-123 ° C. (decomposed). Its physicochemical properties are shown in Table 4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[S:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[S:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: FC(F)(F)c1ccc(Br)s1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(C(F)(F)F)s2)C1=O
Yield: 65 %

Procedure:
1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643 mmol) was reacted with 2-bromo-5-trifluoromethyl-thiophene (136.9 mg, 0.5925 mmol), 1,4-dioxane (10 mL), copper iodide (10.75 mg, 0.0564 mmol), trans-1,2-diamino cyclohexane (20.4 mL, 0.1693 mmol) and potassium phosphate (360 mg, 1.693 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 120 mg of the product (65% yield).