Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([Sn:35]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:31][CH2:32][CH2:33][CH3:34])[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(Cl)cc3)cc(C(F)(F)F)n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
To a stirred solution of 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example E.70) (0.45 g, 1.0 mmol) in THF (5 mL) was added at 0° C. iso-propylmagnesium chloride lithium chloride (1M in THF, 1.22 mL, 1.22 mmol). The reaction mixture was allowed to stir for 15 min at 0° C., tributyltin chloride (0.43 g, 1.33 mmol) was added, the reaction mixture was stirred at room temperature for 16 h, poured into saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (ethylacetate/heptane) to yield the title compound (0.29 g, 47%) as a light yellow oil. MS (ISP) 615.3 [(M+H)+].
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CS(C)=O>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1
Reactant: CNC(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Reaction time: 68 h
Yield: 65.6 %

Procedure:
To a solution of 4-fluoro-N-methylbenzamide (6 g, 39.2 mmol) in DMSO (24.0 mL) was added piperazine (16.87 g, 196 mmol) at 23° C. The reaction was stirred at 120° C. for 68 hr. The reaction mixture was poured into ice (261 g) and the reaction vessel was rinsed with H2O (˜50 mL). Next, Celite (30 g) was added to aid the filtration. The resulting suspension was warmed to 100° C., cooled to ˜40° C., filtered, and rinsed with warm H2O (4×50 mL). The resulting solid was dried in vacuo. The filtrate was stirred at room temperature overnight affording a suspension. The suspension was filtered, rinsed with H2O (3×25 mL), and the resulting solid was dried in vacuo. The cloudy filtrate was filtered once again through a medium fritted funnel and rinsed with H2O (3×10 mL). Added NaCl (200.1 g) to the filtrate, cooled on ice, filtered, rinsed with cold H2O (3×25 mL), and dried the resulting solid in vacuo. Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C., filtered, rinsed with H2O (3×5 mL), and dried the resulting solid in vacuo. The purified product was re-suspended in ACN (25 mL), agitated for 10 min, and dried in vacuo. This procedure was repeated three times to provide the title compound as a white solid (5.64 g, 25.7 mmol, 65.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (br. s., 1H) 2.74 (d, J=4.55 Hz, 3H) 2.77-2.86 (m, 4H) 3.08-3.18 (m, 4H) 6.91 (m, 2H) 7.69 (m, 2H) 8.13 (q, J=4.04 Hz, 1H). ESI-MS: m/z 220.2 (M+H)+. mp=153.9-156.5° C.
Reaction SMILES: Br[CH2:2]Br.[F:4][C:5]1[C:6]([O:14][CH3:15])=[C:7]([C:11](=O)[CH3:12])[CH:8]=[CH:9][CH:10]=1.Cl>C1COCC1.ClCCl.C(OCC)C.[Zn].[Ti](Cl)(Cl)(Cl)Cl.[Pb](Cl)Cl>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[CH2:2])[CH3:12])[C:6]=1[O:14][CH3:15]
Reactant: COc1c(F)cccc1C(C)=O
Reactant: BrCBr
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: Cl[Pb]Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)c1cccc(F)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
41.8 g (639 mmol) of zinc dust and 874 mg (3.1 mmol) of lead(II) chloride are suspended in 557 ml of THF and at room temperature 39 ml (556 mmol) of dibromomethane are added. The mixture is stirred for a further 30 minutes and at 0° C. 68.8 ml (68.8 mmol) of a 1 M titanium(IV) chloride solution in dichloromethane are added dropwise. The cooling bath is removed and after 30 minutes at room temperature 13.6 g (80.8 mmol) of 1-(3-fluoro-2-methoxyphenyl)ethan-1-one (Chem. Commun. 2000, 14, 1323-4) in 139 ml of THF are added dropwise. The reaction mixture is stirred for a further 1.5 hours at room temperature. It is diluted with diethyl ether and cautiously poured onto a mixture of 4 M hydrochloric acid and ice. The phases are separated and subjected to extraction with diethyl ether, the extracts are washed with water and dried over sodium sulphate and the solvent is removed. The crude product is purified by column chromatography on silica gel (hexane/isopropyl ether 0-5%) to give 9.5 g of 2-fluoro-6-(1-methyleneethyl)anisole.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[OH-].[Na+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([O-:16])=[O:15].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].NC(N)=O>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].C(O)(=O)C.CCOCC.ClCCl>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([CH2:4][N+:1]([O-:3])=[O:2])(=[O:16])=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: O=S([O-])c1ccccc1Br
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: NC(N)=O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])CS(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.9 %

Procedure:
Nitromethane (4.6 ml, 82.3 mmol) was added to a stirred solution of sodium hydroxide (7.9 g, 197.5 mmol) in water (50 ml). A solution of sodium 2-bromobenzenesulphinate (20 g, 82.5 mmol) in water (100 ml) was added, followed by dichloromethane (50 ml). The reaction mixture was cooled in an ice bath and a solution of potassium ferricyanide (3 g, 9.1 mmol) in water (20 ml) was added, followed by solid sodium persulphate (12 g, 50.4 mmol). The resultant deep orange solution was allowed to stir for one hour at ambient temperature. Ether (25 ml) was added, followed by urea (5 g), and the pH of the reaction mixture was then adjusted to pH 6 with 20% aqueous acetic acid solution. The organic phase was separated and the aqueous phase was extracted with ether (150 ml×bb 3). The combined organic phases were dried (MgSO4), and the solvent was removed by evaporation. The resultant brown solid was purified by MPLC, eluting with dichloromethane, to give (2-bromophenylsulphonyl)nitromethane as a pale yellow solid (0.197 g), m.p. 74°-76° C.; microanalysis, found: C,29.7; H,2.1; N,4.9%; C7H6BrNO4S requires: C,30.0; H,2.1; N,5.0%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11].N1CCCCC1.[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24].[Cl-].[Na+]>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.[Cu]I.C1(C)C=CC=CC=1>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([C:24]#[C:23][C:22]([CH3:26])([CH3:25])[CH3:21])=[CH:13][C:6]=1[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)NCc1cc(Br)ccc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)NCc1cc(C#CC(C)(C)C)ccc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
In a nitrogen atmosphere, 1.00 g of methyl N-(5-bromo-2-chlorobenzyl)carbamate, 0.20 g of tetrakis(triphenylphosphine)palladium, 0.07 g of copper(I) iodide and 10 ml of piperidine were added to 40 ml of toluene. To this mixed solution, 0.60 g of 3,3-dimethyl-1-butyne was added at 90° C., followed by stirring at 90° C. for 1 hour. The reaction solution was poured into a saturated sodium chloride aqueous solution and extracted with ethyl acetate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.80 g of methyl N-[2-chloro-5-(3,3-dimethyl-1-butynyl)benzyl]carbamate as colorless crystals.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:27][CH:28]([NH2:30])[CH3:29].C(N(CC)C(C)C)(C)C>ClCCl>[CH:28]([NH:30][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3])([CH3:29])[CH3:27]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Reactant: CC(C)N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC(C)C)c1)=N2
Yield: 59.1 %

Procedure:
To a stirred solution of methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (393 mg, 1.0 mmol) in dichloromethane (4 mL) was added propan-2-amine (60 mg, 1.0 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol). The resultant mixture was stirred overnight. The mixture was purified on preparative Thin layer chromatography to afford 245 mg of methyl 2-(3-(N-isopropylsulfamoyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]=[C:12]=[O:13])[CH2:8]2.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:15]>CCOCC>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([NH:11][CH:2]1[CH:1]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]1[CH2:4]3)[CH2:8]2)=[O:13])[CH3:15]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Solvent: CCOCC
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
2-Adamantyl-isocyanate (CAS 71189-14-5, made from 2-aminoadamantane according to Eur. J. Med. Chem. 28 (1), 1993, 37-45, 500 mg) and commercially available benzylamino-acetic acid ethyl ester (572 mg) were dissolved in absolute ether (25 mL) under argon and stirred at RT for 12 hours. A colorless precipitate was formed. The reaction mixture was concentrated in vacuo and the residue was triturated with hexanes (30 mL) for one hour. The suspension was filtered and the solid was dried in vacuo to give (3-adamantan-2-yl-1-benzyl-ureido)-acetic acid ethyl ester (823 mg). MS (ESI): 371.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[N+:17]([CH3:19])[CH3:18].FC(F)(F)C1C=CC=CC=1C=O.CNC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]([N:17]([CH3:19])[CH3:18])[C:15]1[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=1[C:13]([F:12])([F:24])[F:25]
Reactant: C[N+](C)=Cc1ccccc1C(F)(F)F
Reactant: Clc1ccc2[nH]ccc2c1
Agent: CNC
Agent: O=Cc1ccccc1C(F)(F)F
Agent: [Cl-]
Product: CN(C)C(c1ccccc1C(F)(F)F)c1c[nH]c2ccc(Cl)cc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-chloro-1H-indole and (2-trifluoromethyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-trifluoromethyl-benzaldehyde and dimethylamine.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])=[CH:32][CH:33]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A solution of 4-[(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methyl)amino]benzoic acid (355 mg) synthesized in Example 276 (2), ethyl 3-(methylamino)propanoate (118 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (173 mg), hydroxybenzotriazole monohydrate (138 mg) and triethylamine (125 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (1.5 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (384 mg, 92%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6]O.[NH:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1.O>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: OC[C@H]1CCCO1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NN(C[C@H]1CCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 205.7 %

Procedure:
To (R)-(tetrahydrofuran-2-yl)methanol (4.0 g, 39.2 mmol), di-tert-butyl hydrazine-1,2-dicarboxylate (3.64 g, 15.67 mmol) and triphenylphosphine (15.41 g, 58.7 mmol) in THF (100 mL) was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (13.5 g, 5.87 mmol). The mixture was stirred at ambient temperature for 3 h then diluted with water and extracted with EtOAc (100 mL×2). The organic extract was washed with brine and concentrated. Purification by flash chromatography (silica gel, 5-30% EtOAc/hexane) afforded 10.2 g (82%) of (R)-di-tert-butyl 1-((tetrahydrofuran-2-yl)-methyl)-hydrazine-1,2-dicarboxylate, which was dissolved in a solution of 4M HCl in dioxane (40 mL) and stirred at ambient temperature overnight. The solvent was removed under reduced pressure and ethyl acetate (20 mL) was added with stirring. The solid precipitate was filtered, washed with ether (10 mL) and dried under vacuum to yield 7.8 g (97%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.48-1.63 (m, 1H), 1.73-1.88 (m, 2H), 1.90-2.02 (m, 1H), 2.84-3.01 (m, 2H), 3.61-3.71 (m, 1H), 3.72-3.83 (m, 1H), 3.97-4.08 (m, 1H), 5.76 (br, 5H); MS (ESI) m/z 117 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=3)[NH2:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:21]1[C:34]2[C:25](=[CH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=1.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.C1(C)C=CC=CC=1>[CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([NH:17][C:26]4[C:27]5[C:32]([CH:33]=[C:34]6[C:25]=4[CH:24]=[CH:23][CH:22]=[CH:21]6)=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:18]=[CH:19][CH:20]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(-n2c3ccccc3c3ccccc32)c1
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1cc(Nc2c3ccccc3cc3ccccc23)cc(-n2c3ccccc3c3ccccc32)c1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Take 1.3 g of the carbazole from step (1c) above (0.005M) in glove box and add 2.3 g anthracene from step (a) above (0.005M). Add 0.05 g Pd2DBA3 (0.05 mM), 0.022 g P(t-Bu)3 (0.11 mM) and 0.55 g t-BuONa and dissolve all into 25 mL toluene. Upon addition of catalyst materials, there is a mild exotherm. Heat in glove box in mantle at 80 C. under nitrogen for 2 hr as a dark brown solution (thick). Cool and work up by basic-alumina chromatography eluting with DCM and collect dark yellow solution with bright purple/blue PL. Evap to a very dark oily solid. Wash with methanol to give a nice powdery yellow solid. Rinse recovered solid with methanol to give ˜1.8 g of yellow solid. The structure was confirmed by 1-H nmr spectroscopy.
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[S:18])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]#[N:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]1([C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([S:18][CH2:20][C:21]#[N:22])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: S=C1NN=C(c2ccccc2)C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCSc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of 3,4-diphenyl-1H-pyrazole-5(4H)-thione (0.5 g, 1.981 mmol) in DMF (5 mL), were added 2-bromoacetonitrile (0.238 g, 1.981 mmol) and K2CO3 (0.274 g, 1.981 mmol) at room temperature. After stirring at the same temperature for 1 h, the reaction was extracted with ethyl acetate, which was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.38 g). LCMS m/z=292.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.20 (s, 2H), 7.35-7.45 (m, 10H), 13.7 (s, 1H).
Reaction SMILES: [CH:1]1([C:7]2([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[CH:17]1([C:7]2([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:11]3[CH2:12][N:13]([C:32]([NH:31][C:25]4[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=4[F:23])=[O:33])[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: O=C1OC(C2CCCCC2)(C2CCCCC2)C2CNCCN12
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)cc1F)N1CCN2C(=O)OC(C3CCCCC3)(C3CCCCC3)C2C1
Temperature: 60 °C
Reaction time: 14 h
Yield: 61.9 %

Procedure:
1,1-Dicyclohexyl-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.13 g, 0.42 mmol) was dissolved in toluene (1.5 mL). 2,4-Difluorophenyl isocyanate (0.10 g, 0.64 mmol) was added thereto, and the mixture was stirred at 60° C. for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:2) and crystallized from hexane to obtain the title compound (0.12 g, yield 59%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]2[C:27](=[O:28])[NH:26][N:25]=[CH:24][C:13]3=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][C:16]([CH:17]=1)=[C:12]23.[CH3:29][CH:30]1[CH2:32][CH:31]1[C:33](O)=[O:34].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:28]=[C:27]1[C:11]2[C:12]3[C:13](=[C:14]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:15][C:16]=3[CH:17]=[C:9]([NH:8][C:33]([CH:31]3[CH2:32][CH:30]3[CH3:29])=[O:34])[CH:10]=2)[CH:24]=[N:25][NH:26]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC1CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CC1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reaction time: 8 h
Yield: 37 %

Procedure:
Triethylamine (0.030 mL, 0.22 mmol), the title compound of Example 7 (15mg, 0.054 mmol) and 2-methyl-cyclopropanecarboxylic acid (6 mg, 0.062 mmol) were stirred in N,N-dimethylformamide (1.0 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) was added and the reaction was stirred overnight at which point the volatile components were removed under vacuum. The resulting mixture was purified on silica gel, eluting with 3:2 hexane:ethyl acetate. The purest fractions were combined and after solvent removal, the resulting solids were triturated with diethyl ether to give the title compound (7 mg, 0.020 mmol) as yellow powder in 36% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:21]>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([C:14](=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)Cc1nc(NC(=O)OC(C)(C)C)cs1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)c1nc(NC(=O)OC(C)(C)C)cs1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 78.5 %

Procedure:
Ethyl 2-(4-tert-butoxycarbonylaminothiazol-2-yl)acetate (5.1 g) was added to a solution of selenium dioxide (2.96 g) in dioxane (60 ml) and water (2 ml) at 110° C. and stirred for 4.5 hours at 110° C. The mixture was evaporated and the residue was dissolved in ethyl acetate and water. The separated ethyl acetate layer was washed with an aqueous sodium chloride and dried over magnesium sulfate. After removing the solvent, the residue was subjected to column chromatography on silica gel and eluted with methylene chloride. The fraction containing an object compound was evaporated to give ethyl (4-tert-butoxycarbonylaminothiazol-2-yl)glyoxylate (4.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=N[N:14]([CH3:16])[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N1C=CC=C(B(O)O)[CH:18]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:15]=[N:14][CH:16]=[CH:18][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Reactant: OB(O)c1cccnc1
Product: Cc1ccc(-c2cccnc2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using pyridin-3-ylboronic acid. ESI-MS (m/z): 214 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(N)cc2)cc1
Yield: 100.7 %

Procedure:
Combine {2-[4-(4-nitro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.3 g), 5% Pd/C (100 mg), and methanol (50 mL) then hydrogenated at 40 PSIG at room temperature for 2 hours. Filter off catalyst then concentrate on a rotary evaporator to yield {2-[4-(4-Amino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.2 g): 1H NMR (CDCl3, 300.00 MHz): 7.12 (d, 2H, J=8.4 Hz), 6.89 (d, 4H, J=8.8 Hz), 6.72 (d, 2H, J=8.8 Hz), 4.61 (s, 1H), 3.42-3.32 (m, 2H), 2.77 (t, 2H, J=7.0 Hz), 1.46 (s, 9H). Step 4 {2-[4-(4-Acetylamino-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester