Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[CH:8]=2)[CH2:24][CH2:23]1
Reactant: Fc1ccc(-c2cncc(CCl)c2)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CC#N
Product: Fc1ccc(-c2cncc(CN3CCN(c4ncccn4)CC3)c2)cc1

Procedure:
Starting from 1.10 g of 3-chloromethyl-5-(4-fluorophenyl)pyridine (“B”) [obtainable, for example, by radical chlorination of 3-methyl-5-(4-fluorophenyl)-pyridine], reaction with 0.82 g of 1-(2-pyrimidinyl)piperazine in 200 ml of acetonitrile at room temperature analogously to Example 1 gives 1-(2-pyrimidinyl)-4-[(5-(4-fluorophenyl)-3-pyridyl)methyl]piperazine, m.p. 97-98°, after customary work-up.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1(C)C=CC(S(N[CH2:20][CH2:21][O:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])(=O)=O)=CC=1>>[C:29]1([CH3:32])[CH:30]=[CH:31][C:26]([S:23]([O:22][CH2:21][CH2:20][N:1]2[CH2:9][CH2:8][N:7]([CH2:20][CH2:21][O:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:6][CH2:5][N:4]([CH2:20][CH2:21][O:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:24])=[O:25])[CH2:3][CH2:2]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)NCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: C1CNCCNCCN1
Product: Cc1ccc(S(=O)(=O)OCCN2CCN(CCOS(=O)(=O)c3ccc(C)cc3)CCN(CCOS(=O)(=O)c3ccc(C)cc3)CC2)cc1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), 2-(p-toluenesulfonylamino)-1-(p-toluenesulfonyloxy)ethane (1.1.16) and base.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[NH2:10][C:11]1[N:12]([OH:24])[C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([Br:23])[CH:14]=2.N.CO>C(#N)C>[NH2:5][C:3]([NH:10][C:11]1[N:12]([OH:24])[C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([Br:23])[CH:14]=2)=[O:4]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: NC(=O)c1c(N)n(O)c2cc(Br)ccc12
Agent: N
Solvent: CO
Solvent: CC#N
Product: NC(=O)Nc1c(C(N)=O)c2ccc(Br)cc2n1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.5 %

Procedure:
Trichloroacetyl isocyanate (0.10 mL, 0.85 mmol) was added to a solution of 2-amino-6-bromo-1-hydroxyindole-3-carboxamide (Reference compound 2-1, 180 mg, 0.71 mmol) in acetonitrile (5 mL), and the mixture was stirred at room temperature for 5 hours. 2.0 M Ammonia in methanol solution (4.5 mL, 9.0 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, 1 N hydrochloric acid (6 mL) and water (25 mL) was added to the residue and the whole was extracted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL) and brine (20 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with diethyl ether (10 mL), and dried under reduced pressure to give the title compound (90 mg) as a slightly brown solid (yield 42%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10]([CH3:18])([CH3:17])[CH2:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:41][N:42]([CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:43](=[O:58])[C@H:44]([NH:56][CH3:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C:10]([CH3:18])([CH3:17])[CH2:11]/[CH:12]=[CH:13]/[C:14](=[O:16])[N:56]([CH3:57])[C@@H:44]([C:43](=[O:58])[N:42]([CH3:41])[CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C/C=C/C(=O)O
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCc1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
(2E)-5-(N-(tert-Butoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid (122 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml). 1-Hydroxy-7-azabenzotriazole (65 mg, 0.48 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of (2R)-2-(methylamino)-3-(2-naphthyl)propionic acid N-methyl-N-phenethylamide (165 mg, 0.48 mmol) in dichloromethane (2 ml) and ethyldiisopropylamine (0.083 ml, 0.48 mmol) were added successively. The solution was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (50 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (50 ml). The aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (50 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane 1:1 as eluent to give 204 mg of N-methyl-N-((3E)-4-(N-methyl-N-((1R)-1-(N-methyl-N-phenethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>>[CH3:14][C:15]1[N:16]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH:17]=[CH:18][N:19]=1
Reactant: N#Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1ccc(C#N)cc1C(F)(F)F

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-chloro-3-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH) and 2-methyl-imidazole (Fluka, Buchs, Switzerland), with a reaction temperature of 145° C. for 38 hours.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.[C:31]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)(=[O:33])[CH3:32]>C1COCC1>[OH:33][C:31]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)([C:7]1[CH:8]=[N:9][N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)[CH3:32]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-BuLi (1.65 mL, 4 mmol) was added dropwise to a mixture of 4-bromo-1-trityl-1H-pyrazole (1.5 g, 3.8 mmol) in THF (15 mL) cooled to −78° C. Then the mixture was stirred at −78° C. for 1 hour. After methyl 4-acetylbenzoate (0.71 g, 3.8 mmol) in THF (1 mL) was added, the mixture was stirred at −78° C. for 2 hours, and then quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by chromatography on silica gel to afford methyl 4-[1-hydroxy-1-(1-trityl-1H-pyrazol-4-yl)ethyl]benzoate. MS ESI calc'd. for C32H29N2O3 [M+H]+ 489. found 489.
Reaction SMILES: [Li+].[F:2][C:3]([F:30])([F:29])[C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O-:26])=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[CH3:65][O:66][C:67]1[CH:68]=[C:69]([NH:76][CH:77]2[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]2)[CH:70]=[CH:71][C:72]=1[N+:73]([O-:75])=[O:74]>CN(C)C=O.ClCCl.O1CCCC1>[CH3:65][O:66][C:67]1[CH:68]=[C:69]([NH:76][CH:77]2[CH2:82][CH2:81][N:80]([C:24](=[O:26])[CH2:23][CH2:22][N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:7]5[CH:27]=[CH:28][C:4]([C:3]([F:2])([F:29])[F:30])=[CH:5][CH:6]=5)=[CH:11][CH:12]=4)[CH2:21][CH2:20]3)[CH2:79][CH2:78]2)[CH:70]=[CH:71][C:72]=1[N+:73]([O-:75])=[O:74]
Reactant: COc1cc(NC2CCNCC2)ccc1[N+](=O)[O-]
Reactant: O=C([O-])CCN1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC2CCN(C(=O)CCN3CCN(c4ccc(OCc5ccc(C(F)(F)F)cc5)cc4)CC3)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
3-{4-[4-(4-Trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-propionic acid lithium salt (160 mg; 0.39 mmol, prepared in accordance with Example 37), diisopropylethyl amine (134 μL; 0.77 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (127 mg; 0.39 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution (3-methoxy-4-nitro-phenyl)-piperidin-4-yl-amine hydrochloride (100 mg; 0.35 mmol, prepared in accordance with Example 39) in dimethylformamide (0.5 mL) is added and the reaction is stirred for 3 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (2×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (29.5 mg; 0.05 mmol). The structure was confirmed using Protocol II-A. Calculated mass=642; observed mass=642; HPLC retention time=3.68 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH3:34])(=[O:33])=[O:32])[C:6]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[N:7]2.[C:35]([Zn]C#N)#[N:36]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[C@H:12]([C:6]1[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:32])=[O:33])=[N:4][C:3]2[C:2]([C:35]#[N:36])=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1)[CH3:13]
Reactant: C[C@@H](c1nc2cccc(Cl)c2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Reactant: N#C[Zn]C#N
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Product: C[C@@H](c1nc2cccc(C#N)c2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
A 5 L three-necked round-bottomed flask equipped with a condenser, nitrogen inlet, overhead stirrer and thermocouple was charged with 2-((1S)-1-(5-chloro-3-(2-(methylsulfonyl)phenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione (400 g, 813 mmol), dicyanozinc (143 g, 1.22 mol) and 1,4-dioxane (4.0 L). The solution was stirred vigorously and degassed with Ar for 1 h. To the solution was then added XPhos precatalyst (66.1 g, 89 mmol). The mixture was then degassed with Ar for 1 h and heated to 90° C. The reaction was monitored by LC, and deemed complete after 8 h. The reaction was cooled to rt (20-21° C.) and divided into two batches. For each batch, EtOAc (2.0 L), NaHCO3 (400 mL) and water (400 mL) were added. The mixture was stirred for 10 min and a precipitate formed. The precipitates were filtered to afford the pure product as a white solid 201.5 g. The mother liquor was washed with brine (800 mL) and the organic layer concentrated to afford the crude product ˜400 g. The crude material was then slurried in EtOAc (1.2 L) for 30 min at rt. The solid was filtered, washed with EtOAc (2×400 mL) and dried to afford the product as a tan solid 220 g. All the solids were combined, dried on a glass frit under mild vacuum and a stream of N2 for 2 days to afford the product as white solid 378 g with 99.6% LC purity and 96% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47-8.68 (m, 2H), 7.66-8.19 (m, 7H), 7.52 (dd, J=5.5, 3.0 Hz, 1H), 7.22-7.40 (m, 1H), 5.61-5.95 (m, 1H), 3.11-3.27 (m, 3H), 1.68-1.93 (m, 3H) Mass Spectrum (ESI) m/z=483.0 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:27]3[CH:28]=[CH:29][C:30]([O:35][CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][CH:41]([CH3:44])[CH2:40][CH2:39]4)=[C:31]([CH:34]=3)[CH:32]=O)=[N:23][CH:24]=2)=[CH:15][CH:14]=1>C(#N)C.CCO.O>[CH3:2][O:3][N:4]=[CH:32][C:31]1[CH:34]=[C:27]([C:26]#[C:25][C:22]2[CH:21]=[CH:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=3)=[CH:24][N:23]=2)[CH:28]=[CH:29][C:30]=1[O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH:41]([CH3:44])[CH2:40][CH2:39]1
Reactant: CON
Reactant: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2C=O)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: CON=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCC(C)CC1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
22 mg (0.257 mmol) of O-methylhydroxylamine hydrochloride and 36 μL (0.257 mmol) of triethylamine were added to a solution of 85 mg (0.185 mmol) of 5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-methylpiperidin-1-yl)ethoxy]benzaldehyde (Example 14.1c) in 2 mL of acetonitrile/EtOH (1:1) and the mixture was stirred for 16 hours at 75° C. The reaction mixture was diluted with water and the aqueous phase exhaustively extracted with DCM. The combined organic phases were dried over magnesium sulfate and evaporated down in vacuo. Yield: 40 mg (44% of theoretical); C29H30ClNO3O2 (M=488.020); calc.: molpeak (M+H)+: 488/490 (Cl); found: molpeak (M+H)+: 488/490 (Cl); HPLC-MS: 6.04 minutes (method A).
Reaction SMILES: [CH2:1]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH:21]=O>>[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH:21]=[C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][CH2:1][C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: COc1ccc(C=O)c(OC)c1
Product: COc1ccc(C=C2c3ccccc3CCc3ccccc32)c(OC)c1
Yield: 6.6 %

Procedure:
Following procedures essentially as described in Preparation 5 and Example 28, above, and using dibenzosuberone (2.00 g, 10.29 mmol) and 2,4-dimethoxybenzaldehyde (1.71 g, 10.29 mmol) affords 231 mg (7%) ofthe title compound as awhite foam. 1H-NMR (CDCl3) δ 2.70-3.67 (br m, 4H), 3.73 (s, 3H), 3.84 (s, 3H), 6.15 (dd, 1H), 6.41 (d, 1H), 6.61 (d, 1H), 6.9-7.27 (m, 8H), 7.56 (dd, 1H); HPLC shows 98% purity.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[CH:5]1)(=O)C.[CH3:15]I.O>C(#N)C>[CH3:15][N:6]1[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][N:4]=[CH:5]1
Reactant: CI
Reactant: CC(=O)n1cnc(-c2ccccc2)c1
Solvent: O
Solvent: CC#N
Product: Cn1cncc1-c1ccccc1

Procedure:
To 2.88 g of 1-acetyl-4-phenylimidazole in 50 ml of acetonitrile was added 5.8 ml of methyl iodide and the reaction mixture sealed in a flask over a weekend. The reaction mixture was poured into water and then decanted from insoluble oil. The pH of the decanted solution was adjusted to 9 with sodium carbonate and the solution extracted with chloroform. The extracts were combined, dried over magnesium sulfate and concentrated to give 1.02 g of crude product which was chromatographed on 50 g of silica gel using 30% ethyl acetate in chloroform as the eluent, 640 mg.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]1[C:30]2=[CH:31][CH:32]=[CH:33][C:29]2=[CH:28][CH:27]=[C:26]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1/[CH:40]=[CH:41]/S(O)(=O)=O>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:25]1[C:30]2=[CH:31][CH:32]=[CH:33][C:29]2=[CH:28][CH:27]=[C:26]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1/[CH:40]=[CH:41]/[S:1]([Cl:5])(=[O:3])=[O:2]
Reactant: O=S(=O)(O)/C=C/c1ccccc1-c1ccc2cccc-2o1
Reactant: O=S(=O)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(Cl)/C=C/c1ccccc1-c1ccc2cccc-2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
Sulfurylchloride (0.21 mL, 2.6 mmol) was added to a solution of triphenylphosphine (0.68 g, 2.5 mmol) in CH2Cl2 (10 mL) at 0° C. The ice-bath was then removed and (E)-2-(4-benzofuran-2-ylphenyl)ethenesulfonic acid (0.38 g, 1.18 mmol) was added and the resulting mixture was stirred for 6 h at RT. A catalytic amount of tetrabutyl ammonium iodide was added and the reaction was stirred for an additional 12 h. The mixture was then filtered and the filtrate was concentrated in vacuo and the product was purified by column chromatography eluting with 20% EtOAc/hexanes to give the product as a yellow solid (0.27 g, 73%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[C:24]([C:39](OCC)=[O:40])=[CH:23]2.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:38])[F:37])[CH:30]=1)[C:24]([C:39](=[O:40])[CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:23]2
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of LHMDS (13 mL, 1.0 M in THF, 13.0 mmol) in THF (13 mL) was added tert-butyl acetate (1.76 mL, 13.0 mmol), dropwise. After 30 min, a solution of the title compound of Example 9 Step A (1.60 g, 4.36 mmol) in THF (4 mL) was added, and the mixture was held at −78° C. for 30 min, then was placed in a 0° C. bath. After 1.5 h, the reaction mixture was poured into sat. aq. NaHCO3 and extracted twice with ethyl acetate. The combined organic phases were concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30%, then 30 to 100% hexanes in ethyl acetate) afforded the title compound: LCMS C, tr=2.99 min, m/z 382.1 [M−tBu+H]+; 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J=2.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.38 (s, 1H), 7.29 (dd, J=9.0, 2.0 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 3.83 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1I.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][C:14]=2[F:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)c(F)c1
Reactant: Sc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Fc1ccc(Sc2ccc(Br)cc2)c(F)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 2,4-difluoroiodobenzene (0.63 g, 2.64 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-(4-bromo-phenylsulfanyl)-2,4-difluorobenzene (0.56 g). MS calcd. for C12H8BrF2S [(M+H)+] 302, obsd. 302.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[CH3:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[CH3:35].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:31]1[CH:32]=[CH:33][C:34]([CH3:35])=[C:29]([CH3:28])[CH:30]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1ccc(C)c(C)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 3,4-dimethylphenylboronic acid (82.5 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3,4-dimethyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a slight yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[NH:28][CH2:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:27][C:26]([CH3:32])([CH3:25])[O:30][C:29]4=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1(C)CNC(=O)O1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3F)CC2)c(C)c1
Yield: 32.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (574 mg) described in Preparation Example 65 and 5,5-dimethyloxazolidin-2-one (265 mg) described in Preparation Example 43, the title compound (203 mg) was obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1)([O:3][CH3:4])=[O:2].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C([O-])(O)=O.[Na+]>[CH2:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][NH:6][CH:5]([C:1]([O:3][CH3:4])=[O:2])[CH2:10]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCN1

Procedure:
2-Carbomethoxypiperazine was treated with benzyl chloroformate (1.0 eq) in aqueous NaHCO3 to give 1-benzyloxycarbonyl-3-carbomethoxypiperazine. This material was treated with di-tert-butyldicarbonate (1.1 eq) and triethylamine (1.0 eq) in THF to produce 1-tert-butyoxycarbonyl-4-benzyloxycarbonyl-2-carbomethoxypiperazine. Hydrogenation of this compound in methanol using 10% Pd—C gives the title compound after filtration and solvent removal.