Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[C:20]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[N:19]=2)[CH2:14][CH2:13]1>>[CH3:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:23]([NH:24][C:8]([C:6]3[O:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[O:10])=[CH:22][CH:21]=[C:20]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[N:19]=2)[CH2:16][CH2:17]1
Reactant: N#Cc1ccc(C(=O)O)o1
Reactant: CC1CCN(c2nc(N3CCN(C)CC3)ccc2N)CC1
Product: CC1CCN(c2nc(N3CCN(C)CC3)ccc2NC(=O)c2ccc(C#N)o2)CC1

Procedure:
The title compound was prepared according to the procedure from Example 4, step (c) using 2-cyano-5-furancarboxylic acid (as prepared in Example 1) and 4-methyl-6′-(4-methyl-piperazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine (as prepared in the previous step). Purification of the resulting residue by silica gel preparative TLC eluting with 10% methanol in dichloromethane afforded the title compound in 50% as a yellow glass. 1H-NMR (400 MHz, CDCl3): δ 8.76 (br s, 1H), 8.410 (d, 1H, J=8.8 Hz), 7.24 (d, 1H, J=3.7 Hz), 7.21 (d, 1H, J=3.7 Hz), 6.37 (d, 1H, J=8.8 Hz), 3.53 (m, 4H), 3.21-3.18 (m, 2H), 2.85 (m, 2H), 2.52 (m, 4H), 2.34 (s, 3H), 1.82-1.79 (m, 2H), 1.57 (m, 1H), 1.47-1.37 (m, 2H) 1.05 (d, 3H, J=6.5 Hz). NOE 1H-NMR experiments confirmed the correct regiochemical assignment. LC-MS (ESI, m/z): Calcd. for C22H29N6O2, 409.2 (M+H); found: 409.2.
Reaction SMILES: Br[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[C:16]1([NH:22][CH2:23][CH2:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3][CH:2]([NH:25][CH2:24][CH2:23][NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Reactant: NCCNc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(NCCNc2ccccc2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 409.3 %

Procedure:
A solution of 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (0.75 g, 2.82 mmole, from Example 8, part B) and N-phenylethylenediamine (8.84 g, 10 eq.) containing NaHCO3 (2.40 g, 5 eq.) in N,N-dimethylformamide (15 ml) was stirred for 48 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and distilled H2O. The organic phase was washed with distilled H2O, saturated NaCl solution, dried over Na2SO4 and evaporated in vacuo to obtain 3.71 g of an orange gum. The crude product was chromatographed on silica eluting with 3:2 hexane/ethyl acetate to obtain 0.36 g (40%) of the title compound as a colorless gum which solidified upon standing. 1H NMR (CDCl3) δ 7.91 (s. 1H), 7.38 (dd, J=2.34 and 8.79 Hz, 1H), 7.19 (m, 2H), 6.79 (d, J=8.21 Hz, 1H), 6.70 (m, 3H), 3.87 (dd, J=5.86 and 11.14 Hz, 1H), 3.26 (m, 2H), 3.10 (m, 1H), 2.86 (m, 1H), 2.20 (dd, J=5.87 and 12.90 Hz, 1H), 1.58 (d, J=12.30 Hz, 1H), 1.45 (s, 3H), 1.27 (s, 3H); 13C NMR (CDCl3) δ 157.63, 148.16, 132.40, 132.09, 129.21, 125.32, 119.56, 118.09, 117.52, 112.97, 102.89, 76.83, 49.24, 44.89, 44.00, 39.25, 29.69, 24.96; MS: (M+H)+ @322.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH2:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:12][CH3:13].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][S:14]([CH2:11][CH2:12][CH3:13])(=[O:16])=[O:15])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Br)c1F
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(Br)c1F

Procedure:
A solution of 3-bromo-2,4-difluoroaniline (4.16 g, 20 mmol, EP184384), n-propanesulfonyl chloride (4.6 ml, 40 mmol), pyridine (8 ml), DMAP (97 mg), and DCM (100 ml) was stirred at rt for 16 h. Aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and brine. The crude product was purified by silica gel chromatography (8:1 to 3:1 hexanes/ethyl acetate eluant) to give the title compound. MS m/z 313.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:6]([NH:21][C:22](=[O:24])[CH3:23])[CH:5]=1.[CH:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:6]([NH:21][C:22](=[O:24])[CH3:23])[CH:5]=1
Reactant: C#CCCCCC
Reactant: COC(=O)c1ccc(OS(=O)(=O)c2ccc(C)cc2)c(NC(C)=O)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC#Cc1ccc(C(=O)OC)cc1NC(C)=O

Procedure:
This product was prepared from 3-acetylamino-4-(toluene-4-sulfonyloxy)-benzoic acid methyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (80 mg, 55%); 1H NMR δ (CDCl3): 8.96 (d, J=1.51 Hz, 1H), 7.92 (br s, 1H), 7.66 (dd, J=1.57, J=8.33 Hz, 1H), 7.38 (d, J=8.15 Hz, 1H), 3.89 (s, 3H), 2.53 (t, J=7.09 Hz, 2H), 2.21 (s, 3H), 1.63 (p, J=7.16 Hz, 2H), 1.48-1.3 (m, 4H), 0.92 (t, J=7.26 Hz, 3H); LCMS m/z: 287.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35]>>[O:22]=[C:10]1[NH:11][C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[CH:15]=[CH:16][C:17]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:24]=3)(=[O:36])=[O:35])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:23]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4ccc5ccccc5c4)c2)c1=O)CCCC3
Yield: 19 %

Procedure:
4-(3-Aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (30 mg, 0.097 mmol) and 2-naphthalenesulfonyl chloride (33 mg, 0.146 mmol) were used in a process similar to Example 9 to give the titled compound (a white crystal, 9 mg, yield 19%).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]1[O:17][C@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[C@H:14]([OH:15])[C@H:12]1[OH:13]>C(N(CC)CC)C.C(Cl)Cl>[C:2]([O:13][C@@H:12]1[C@@H:14]([O:15][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[C@@H:16]([C@@H:18]([CH2:20][O:21][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[O:19][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[O:17][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC[C@@H](OC(=O)c1cccnc1)[C@H]1OC[C@H](OC(=O)c2cccnc2)[C@H]1OC(=O)c1cccnc1)c1cccnc1

Procedure:
23.8 g of nicotinoyl chloride-hydrochloride are added in portions in the course of 15 minutes to a suspension of 5.0 g of 1,4-anhydro-D-glucitol (Arlitan) in 30 g of triethylamine and 100 ml of methylene chloride, at 40°, whilst stirring and with the exclusion of atmospheric moisture. After the reaction mixture has been allowed to react for a further 30 minutes, it is filtered and the bulk of the methylene chloride is distilled off from the filtrate. The residue which is thus formed from the filtrate is dissolved in methylene chloride and the solution is washed with water. After drying over sodium sulphate, evaporating under a waterpump vacuum and degassing the residue under a high vacuum, pure 2,3,5,6-tetra-O-nicotinoyl-1,4-anhydro-D-glucitol is obtained as a viscous, brownish oil which has an optical rotation [α]D20 = + 16° ± 1° (c = 1.099 in chloroform), IR: carbonyl band at 1,730 cm-1, and a Rf value of 0.26 on silica gel thin layer plates in the system: methylene chloride/ethyl acetate (85:15).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:6]1.[CH3:34][O:35][CH2:36][C:37]#[CH:38]>CCN(CC)CC.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>[C:14]([O:13][C:11]([N:10]([C:7]1[O:8][CH2:9][C:5]2([N:6]=1)[C:25]1([CH2:26][O:27][CH2:28]1)[CH2:29][O:30][C:31]1[C:4]2=[CH:3][C:2]([C:38]#[C:37][CH2:36][O:35][CH3:34])=[CH:33][CH:32]=1)[C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: C#CCOC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OCC21COC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc2c(c1)C1(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1)C1(COC1)CO2
Yield: 23.6 %

Procedure:
A mixture of di-tert-butyl (6′-bromodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (150 mg, 0.286 mmol) and 3-methoxyprop-1-yne (0.072 mL, 0.86 mmol) in Et3N (1.5 mL) was purged with argon. To the mixture was added Pd(PPh3)4 (13 mg, 0.011 mmol) and CuBr (4.9 mg, 0.034 mmol), and the mixture was refluxed for 3 hours under an argon atmosphere. The mixture was partitioned between CHCl3 and brine, and filtered through celite. The organic layer of the filtrate was dried over MgSO4, filtered off, and the filtrate was evaporated. Silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 25%) afforded di-tert-butyl[6′-(3-methoxyprop-1-yn-1-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (34.7 mg).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[CH3:50][CH:51]([C:53]1[N:58]=[C:57]([NH2:59])[CH:56]=[CH:55][CH:54]=1)C>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([NH:59][C:57]3[CH:56]=[CH:55][CH:54]=[C:53]([CH2:51][CH3:50])[N:58]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)c1cccc(N)n1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)OC(C)(C)C)CC2CCCC2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.29 mL, 2.6 mmol). The reaction was stirred for 2 hours at 0° C., and then 6-(1-methylethyl)-2-pyridinamine (177 mg, 1.30 mmol) was added to the reaction. The mixture was allowed to warm to room temperature and was stirred for 3 hours. The solvent was removed under reduced pressure, and then water (5 mL) and DCM (15 mL) were added. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organics were dried over sodium sulfate and concentrated. The resulting residue was purified by Combiflash silica gel chromatography (0-100% EtOAc in hex) to give 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (368 mg, 0.81 mmol, 81% yield) as a yellow oil. MS: 457 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(CCc2ccccc2)c1
Temperature: 77.5 °C
Yield: 84.9 %

Procedure:
To a solution of 42 (80.0 mg; 0.17 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL) was added aqueous sodium hydroxide (4 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a clear oil (64.0 mg).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]>[Pd].C(O)(=O)C>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4]1
Reactant: CCOC(=O)C1COc2ccccc2C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1COc2ccccc2C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 4-oxochromane-3-carboxylic acid, ethyl ester (4.0 g, 18 mmol) and 10% palladium on carbon (0.4 g) in 100 mL of acetic acid was degassed and filled with hydrogen using a balloon. After stirring at 70° C. overnight, the reaction mixture was filtered through CELITE diatomaceous earth, and the CELITE cake was washed with ethyl acetate (200 mL). The filtrate was washer with water (2×200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.2-7.0 (m, 2H), 6.84 (t, 1H), 6.74 (d, 1H), 4.36 (dd, 1H), 4.21-4.13 (m, 3H), 3.03 (m, 3H), 1.26 (t, 3H).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(S)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(S)cc1

Procedure:
To a solution of 4-mercaptobenzoic acid (Apin, 1.72 g, 11.17 mmol) in anhydrous methyl alcohol (20.0 mL) was added concentrated sulfuric acid (0.43 mL). The reaction mixture is then warmed to reflux for 16 h, concentrated in vacuo, diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (2×100 mL). The organic phase is then separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 712 mg (Y: 38%) of the title product; 1H-NMR (CDCl3): δ 7.89 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 3.90 (s, 3H), 3.60 (s, 1H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1>>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])=[CH:18][CH:19]=1
Reactant: Cc1ccc(C)cc1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Product: Cc1ccc(CON2C(C)(C)CC(O)CC2(C)C)cc1
Yield: 28.8 %

Procedure:
A mixture of 8.60 g (0.05 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 106.17 g (1.0 mol) of p-xylene under a nitrogen atmosphere is heated at reflux for 48 hours. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate is washed with 10 w/v % ascorbic acid (1×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from heptane to give 4.00 g (59% yield) of a white solid melting at 92.5-93° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[C:6]([CH2:8]O)[CH:7]=1.FC(OC1C=CC(F)=CC=1C[Br:50])(F)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=CC=1>>[Br:50][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19]
Reactant: OCc1cc(F)ccc1OCc1ccccc1C(F)(F)F
Reactant: Fc1ccc(OC(F)(F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(CBr)c1
Product: Fc1ccc(OCc2ccccc2C(F)(F)F)c(CBr)c1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield from (5-fluoro-2-{[2-(trifluoromethyl)benzyl]oxy}-phenyl)methanol (Example 48A) in analogy to 2-(bromomethyl)-4-fluorophenyl difluoro[4′-(trifluoromethyl)biphenyl-4-yl]methyl ether (Example 41A).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5](I)=[N:4][C:3]=1[C:24]([O:26][CH3:27])=[O:25].[C:28]([Cu])#[N:29].C(Cl)Cl>CN(C=O)C>[C:28]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:7]=2)[C:2]([OH:1])=[C:3]([C:24]([O:26][CH3:27])=[O:25])[N:4]=1)#[N:29]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(I)c2cc(Oc3cccc4ccccc34)ccc2c1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2cc(Oc3cccc4ccccc34)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
Methyl 4-hydroxy-1-iodo-7-(naphthalen-1-yloxy)isoquinoline-3-carboxylate (130 mg, 0.28 mmol) and CuCN (49 mg, 0.55 mmol) were suspended in DMF (1.1 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 87 mg. MS: (−) m/z 369.31 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:14][C:15]1[CH:22]=[C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:20]=[CH:19][C:16]=1[CH2:17][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(N2CCOCC2)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2F)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.8 %

Procedure:
A 50 mL round-bottom flask, equipped with a magnetic stir bar, was charged with tert-butyl-1-piperazine carboxylate (445 mg, 2.39 mmol) under nitrogen. The solid was dissolved in 10 mL dichloromethane (anhydrous) and stirred at room temperature. 2-Fluoro-4-morpholinobenzaldehyde (500 mg, 2.39 mmol) was added followed by molecular sieves (440 mg, 8-12 mesh beads). The reaction was allowed to continue to stir at room temperature for 1 h. At that point, sodium triacetoxyborohydride (557 mg, 2.63 mmol, 1.10 equiv) was added. The reaction was monitored for disappearance of aldehyde by thin layer chromatography. After 15 h, the reaction was quenched with saturated sodium bicarbonate (15 mL). After the addition of dichloromethane (15 mL), the mixture was partitioned into two phases. The aqueous phase was extracted twice with dichloromethane (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude mixture was applied to a chromatography column containing 24 g silica and dichloromethane. A gradient solvent was used from 100% dichloromethane to 10% methanol in dichloromethane to provide 833 mg (92%) of tert-butyl 4-(2-fluoro-4-morpholinobenzyl)piperazine-1-carboxylate as a pale yellow solid. 1H NMR 400 MHz (CDCl3) δ 7.22 (t, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.57 (d, J=13.0 Hz, 1H), 3.90-3.85 (m, 4H), 3.53 (s, 2H), 3.43 (bs, 4H), 3.20-3.15 (m, 4H), 2.41 (bs, 4H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[N:18]([CH3:22])[CH:19]=[N:20][CH:21]=2)=[N:10][S:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[F:23])#[N:2].[CH3:24][Mg+].[Br-]>C1COCC1.CCOCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:10][S:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])([C:17]2[N:18]([CH3:22])[CH:19]=[N:20][CH:21]=2)[CH3:24])=[CH:5][C:4]=1[F:23])#[N:2]
Reactant: CC(C)CS(=O)N=C(c1ccc(C#N)c(F)c1)c1cncn1C
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CS(=O)NC(C)(c1ccc(C#N)c(F)c1)c1cncn1C

Procedure:
N-[(4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide (as described above in Step B) (1.50 g, 4.51 mmol) was dissolved in anhydrous THF (30 mL) at 0° C. to which a 3.0M solution of MeMgBr (4.50 mL, 13.5 mmol) in Et2O was added. The reaction was quenched with aq. NH4Cl solution, diluted with saturated NaHCO3 solution and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, concentrated, and recrystallized from 95% EtOAc/Hexane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:13](O)=[O:14]>>[NH:11]1[CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH:13]=[O:14])=[CH:7][CH:6]=2)[N:9]=[CH:10]1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: O=CO
Product: O=CNc1ccc(-c2c[nH]cn2)cc1

Procedure:
A solution of 4-(4-aminophenyl)-1-H-imidazole (10 g) in formic acid (100 ml) was refluxed for 4 hours and evaporated to dryness. The residue was dissolved in water, and the solution was filtered through charcoal and made basic to give 10 g of N-[4-(imidazol-4-yl)-phenyl]-formamide, M.p. 108°-109° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[CH2:7][CH2:6]1)=[O:4])[C:25](=[O:30])[CH2:24]2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)CN3C(=O)Cc4cc(Cl)ccc43)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 5-chloro-1,3-dihydro-indol-2-one (116 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL N-methylpyrrolidinone (NMP). A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 5-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-indol-2-one (2): HPLC retention time, 2.47 minutes, (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 434.3, found, 434.4.