Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH:48]1[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:57])([CH3:56])[CH3:55])[CH2:49]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:48]2[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:57])([CH3:56])[CH3:55])[CH2:49]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CC(C)(O)C1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC(C(C)(C)O)C2)cc1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to 2-piperidin-3-ylpropan-2-ol hydrochloride (9 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z calcd for C19H24N2O3: 328.1787, found 328.1787.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([Br:15])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Br:15][C:13]1[CH:12]=[CH:11][C:9]2=[N:10][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[N:7]=[C:8]2[CH:14]=1
Reactant: CC(N)(C#N)Cn1nc2ccc(Br)cc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2ccc(Br)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-bromo-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 25, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.45 g, 87%). Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z [M+H]=484. 1H NMR: (400 MHz, DMSO-d6): 1.74 (s, 3H), 5.36-5.53 (m, 2H), 7.58 (dd, J=9.1, 1.8 Hz, 1H), 7.84-7.92 (m, 4H), 7.95 (dd, J=9.1, 0.5 Hz, 1H), 8.29 (dd, J=1.7, 0.6 Hz, 1H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.93 (s, 3F).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(O)(=O)C>CCO>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:19]([C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=2)[N:20]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of 4,4-dimethyl-3-oxopentanenitrile (20.4 g, 163 mmol) and 4-nitrophenylhydrazine (25.0 g, 163 mmol) in anhydrous EtOH (300 mL) was added acetic acid (3.4 mL, 60 mL) dropwise. The reaction was stirred at reflux under N2 for 18 h. The reaction mixture was cooled to room temperature and concentrated at reduced pressure. The residue was partitioned between EtOAc (500 mL) and aqueous saturated NaHCO3 solution (300 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The crude residue was purified by MPLC (eluting with 80:20 hexanes/EtOAc) to give 36.0 g (85%) of the desired product. 1H-NMR (DMSO-d6) δ 8.28 (d, J=6.9 Hz, 2H), 7.93 (d, J=6.9 Hz, 2H), 5.55 (s, 2H), 5.46 (s, 1H), 1.20 (s, 9H); MS LC-MS [M+H]+=261, RT=2.74 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[CH:16]=[C:15]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[N:14]=1>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][C:20]=1[O:23][CH3:24])[C:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)=[N:14][C:15]([NH:27][C:28]1[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=1)=[CH:16]2
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccc(NC(C)=O)cc3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[6,7-dimethoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 434(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].[Br:19]Br.[OH-].[Na+]>CC(OC)(C)C.C(O)(=O)C>[Br:19][CH2:17][C:16]([C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[Cl:1])=[O:18]
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[2-chloro-4-(4-chlorophenoxy)phenyl]ethanone (1000 g) was dissolved in MTBE (5000 mL) and a solution of bromine (563 g) in glacial acetic acid (400 mL) was added dropwise at room temperature. After completion of the addition the mixture was stirred for 1 h at room temperature and the pH was adjusted to 7-8 by addition of 10% NaOH solution. The organic layer was separated, extracted twice with MTBE and the combined organic phases were washed with sat. NaHCO3 solution (1×) and brine (2×). The solvent was evaporated and the crude product was used directly in the next step.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[OH:22])=[O:14])[CH:4]=1)=O.[Cl-].[C:24]([C:26]1([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH2+:29][CH2:28][CH2:27]1)#[N:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClC(Cl)C>[C:24]([C:26]1([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][N:29]([CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:5]([C:13]([NH:15][C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]3[OH:22])=[O:14])[CH:4]=2)[CH2:28][CH2:27]1)#[N:25]
Reactant: O=Cc1cc(C(=O)N[C@H]2CCCC[C@@H]2O)nc2ccccc12
Reactant: N#CC1(c2ccncc2)CC[NH2+]CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: N#CC1(c2ccncc2)CCN(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (0.035 g, 0.117 mmol) in 0.50 mL dichloroethane was added 4-cyano-4-(pyridin-4-yl)piperidinium chloride (0.032 g, 0.141 mmol), sodium triacetoxyborohydride (0.037 g, 0.176 mmol), and triethylamine (0.016 mL, 0.117 mmol). The reaction mixture was stirred at room temperature overnight and concentrated. The resultant residue was subjected to purification via reverse phase HPLC. The isolated material was then purified via preparative TLC (7% MeOH/CH2Cl2) to afford the titled compound that gave a mass ion (ES+) of 470.2551 for M+H+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([C:12]1[CH:17]=[C:16]([SH:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:11])[CH3:10].[CH:24]([CH:26]=[CH2:27])=[O:25]>CO>[CH3:11][C:9]([C:12]1[CH:17]=[C:16]([S:18][CH2:27][CH2:26][CH:24]=[O:25])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:8])[CH3:10]
Reactant: C=CC=O
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
Triethylamine (1.1 ml, 0.0076 mole) was added to a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (18.2 g, 0.076 mole) in methyl alcohol (200 ml) and stirred for 30 minutes. Freshly distilled acrolein (12.8 g, 0.23 mole) was added and the solution stirred at room temperature. The product was purified by chromatography on silica and characterized by its NMR and IR spectra and m.p. ca. 75° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]2=[N:12][C:13]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N:20]([CH3:27])[C:19]4[C:14]=3[C:15]([CH:16]=[CH:17][CH:18]=4)=[C:8]2[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]2=[N:12][C:13]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N:20]([CH3:27])[C:19]4[C:14]=3[C:15]([CH:16]=[CH:17][CH:18]=4)=[C:8]2[CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1ccc2nc3c4c(cccc4c2c1)N(C)c1ccccc1-3
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc2nc3c4c(cccc4c2c1)N(C)c1ccccc1-3
Yield: 70 %

Procedure:
(Method N) (E)-3-(8-Methyl-8H-quino[4,3,2-kl]acridin-3-yl)-acrylic acid methyl ester, 40 (50 mg, 0.14 mmol) was suspended in ethyl acetate (150 mL) and shaken under pressure of hydrogen (40 psi) with 10% palladium on carbon (100 mg) for 2 days. The mixture was filtered through celite, the solvent evaporated under reduced pressure, the product adsorbed onto silica and purified by column chromatography (1:4 EtOAc:hexane) to give the title compound (36 mg, 0.098 mmol, 70%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(Cl)(Cl)[Cl:13].C(=O)([O-])[O-].[Na+].[Na+]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:4][CH:3]=[C:2]([CH3:1])[C:10]=12
Reactant: ClC(Cl)Cl
Reactant: Cc1c[nH]c2c1ccc[n+]2[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c[nH]c2nccc(Cl)c12
Temperature: 25 °C

Procedure:
1.00 g (6.75 mmol) of 3-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide (from example XXXVII) is suspended in 5 ml of phosphoryl chloride. 2 ml of chloroform are then added, and the mixture is heated under reflux overnight. The mixture is allowed to cool to RT and poured into ethyl acetate/ice water. Solid sodium carbonate is then added. The phases are separated and the aqueous phase is washed with ethyl acetate. The organic phases are dried over sodium sulfate and concentrated. The residue is purified by column chromatography (silica gel 60, mobile phase: cyclohexane:methanol=4:1).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[CH2:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:47])=[CH:42][C:41]=1[N+:54]([O-])=O)[CH3:38]>>[NH2:54][C:41]1[CH:42]=[C:43]([S:46]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:47])[CH:44]=[CH:45][C:40]=1[NH:39][CH2:37][CH3:38]
Reactant: CCNc1ccc(S(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: CCNc1ccc(S(=O)c2ccccc2)cc1N
Yield: 93 %

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (4-ethylamino-3-nitrophenyl)-phenyl sulfoxide, the title compound is obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH:20]1([NH:23][CH2:24][C@@H:25]2[C@H:29]([F:30])[CH2:28][NH:27][CH2:26]2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][CH2:24][C@@H:25]2[C@H:29]([F:30])[CH2:28][N:27]([C:10]3[C:11]([F:13])=[C:12]4[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:8][C:9]=3[F:15])[CH2:26]2)[CH2:22][CH2:21]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)c21
Yield: 46.4 %

Procedure:
Using 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (200 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (128 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a pale yellow crystal (140 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N+:13]=[N-:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[C:15]([N:12]=[N+:13]=[N-:14])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: COc1ccc(C=O)cc1Br
Product: COC(=O)C(=Cc1ccc(OC)c(Br)c1)N=[N+]=[N-]

Procedure:
Following the general procedure of PREPARATION 61 and making non-critical variations but starting with 3-bromo-4-methoxybenzaldehyde (5.0 g) and methyl azidoacetate (10.7 g), the title compound is obtained, NMR (300 MHz, CDCl3) 8.10, 7.73, 6.89, 6.79, 3.94 and 3.90 δ.
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][NH:10][CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=O.Cl.[OH-].[Na+]>O.C(O)=O>[C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][N:10]([CH3:16])[CH2:9][CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C23CCCC2CNCC3)cc1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CN1CCC2(c3ccccc3)CCCC2C1
Temperature: 95 °C

Procedure:
A solution of 3.0 g. of 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine in 10 ml. of 88% formic acid was stirred at 20° C. while 10 ml. of 38% formaldehyde was added dropwise over fifteen minutes. The reaction mixture was then heated at 95° C. for eight hours. After cooling the reaction mixture to 25° C. 100 ml. of 4 N hydrochloric acid was added dropwise over thirty minutes. The aqueous acidic reaction mixture was concentrated under reduced pressure to provide an oily residue. The oil was then dissolved in 100 ml. of water, and the aqueous solution was made basic by the addition of 50 percent aqueous sodium hydroxide solution. The product precipitated out of the aqueous alkaline solution, and was extracted into diethyl ether. The ethereal extracts were combined, washed with water, dried, and the solvent was evaporated under reduced pressure to provide 4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine as an oil. The oil so formed was dissolved in 150 ml. of diethyl ether. The ethereal solution was stirred at 25° C. while a solution of 10 ml. of 48 percent hydrobromic acid in 10 ml. of ethanol was added dropwise over ten minutes. The product precipitated out of solution and was recovered by filtration. The solid precipitate was recrystallized from diisopropyl ether and isopropanol to afford 2.7 g. of 4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindinium bromide. M.P. 209°-210° C.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][OH:15])=[CH:6][CH:5]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:15][CH2:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH:2]([F:16])[F:1])=[CH:5][CH:6]=1)(=[O:20])=[O:19]
Reactant: OCc1ccc(OC(F)F)c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(OC(F)F)c2ccccc12

Procedure:
Prepared by reacting (4-difluoromethoxy-naphthalen-1-yl)-methanol with methanesulphonic acid chloride in methylene chloride in the presence of triethylamine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[F:26][C:27]1[CH:32]=[C:31]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:30]=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[CH:32]=[C:31]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Reactant: CS(=O)(=O)c1ccc(B(O)O)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3O1)C2

Procedure:
The title compound is prepared from 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] and 2-fluoro-4-methylsulfonyl-phenylboronic acid following a procedure analogous to that described for Example 2; PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex is the preferred catalyst used. LC (method 1): tR=1.30 min; Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:19]=1[C:20]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=1)=[O:21]
Reactant: Cc1cccc(C)c1C(=O)Cl
Reactant: CC(=O)c1cccc(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1cccc(OC(=O)c2c(C)cccc2C)c1
Reaction time: 16 h

Procedure:
To a stirred solution of 3′-Hydroxyacetophenone (4.84 g, 35.5 mmol) in anhydrous CH2Cl2 (50 ml) was added at room temperature pyridine (25 ml) followed by addition of 2,6-Dimethylbenzoyl chloride (Step A, 6 g, 35 mmol) in anhydrous CH2Cl2 (10 ml) under argon. The reaction mixture was stirred for 16 hours, concentrated under reduced pressure, diluted with CH2Cl2, and washed with 0.1M HCl, water and brine. The organic layer was dried over Na2SO4, concentrated and purified by flash chromatography eluted with ethyl acetate:hexane (1:2) to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:26][CH2:25][CH2:23][OH:24])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: NCCO
Product: OCCNCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 6, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and ethanolamine were converted to yield 2-{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butylamino}-ethanol as white solid, MS: 421(MH+, 1Br).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[I:25][C:26]1[C:27](CO)=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2>C(Cl)Cl>[Br:24][CH2:20][C:27]1[C:26]([I:25])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc2ccccc2cc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc2ccccc2cc1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of triphenylphosphine (469 mg, 1.79 mmol) in dry CH2Cl2 (2 mL) was added dropwise to a stirred solution of carbon tetrabromide (592 mg, 1.79 mmol) and (3-iodo-2-naphthyl)methanol (423 mg, 1.49 mmol) in dry CH2Cl2 (11 mL) at room temperature under N2. The reaction was stirred for 4 h at room temperature and was concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient) to afford 2-(bromomethyl)-3-iodonaphthalene, as a colorless solid. Rf=0.84 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 8.39 (s, 1H); 7.94 (s, 1H); 7.78-7.76 (m, 1H); 7.71-7.69 (m, 1H); 7.52-7.48 (m, 2H); 4.76 (s, 2H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[NH:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.CO>C(Cl)Cl>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:5][CH:6]=2)=[O:22])=[CH:17][CH:16]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 89.1 %

Procedure:
Into a round bottom flask was added aluminum trichloride (16.0 g, 0.12 mol) and methylene chloride (100.0 mL) under an atmosphere of nitrogen. Into the reaction mixture, was added 1H-Pyrrolo[2,3-b]pyridine 1 (3.2 g, 0.027 mol) in methylene dichloride (20.0 mL). The reaction was stirred at room temperature for 70.0 minutes, and then 6-Chloropyridine-3-carbonyl chloride 8 (5.4 g, 0.031 mol) in methylene chloride (10.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. Methanol (10 mL) was added to the reaction mixture and the solvent was evaporated in vacuo. The residue was poured into water, and the precipitated product was removed by filtration. The aqueous layer was extracted with ethyl acetate, and then the organic layer was dried and concentrated and combined with the solid isolated by filtration to give 7 (6.2 g, yield 88.6%) as a white solid (M+1=258).
Reaction SMILES: O[C:2]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C>[Si:13]([C:2]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C=O)c(O)c1Br
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c([Si](C)(C)C(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Diiospropylethylamine (3.0 ml) was added to a stirred solution (under argon) of 2-hydroxy-3-bromo- -4-methoxybenzaldehyde (1.96, 8.5 mmole) in DMF (15 ml) followed by t-butyldimethlsilyl chloride (TBSCl, 1.91 g, 12.8 mmole). The reaction mixture was stirred at room temperature for 30 min and Ice (20 g) was added to the mixture. The mixture was then extracted with ether (3×25 ml). The ethereal solution was washed with water (25 ml) and saturated NaHCO3 solution (2×15 ml). The solvent evaporated to yield 2-(t-butyldimethylsilyl)-3-bromo-4-methoxy benzaldehyde as an oil (2.54 g, 7.06 mmole, 83.1%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[S:14][C:15]([CH2:19]O)=[C:16]([CH3:18])[N:17]=1.S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+].Cl.O>C(Cl)(Cl)Cl>[Cl:23][CH2:19][C:15]1[S:14][C:13]([C:3]2[CH:4]=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[C:7]([F:8])[C:2]=2[F:1])=[N:17][C:16]=1[CH3:18]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2F)sc1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of [2-(2,3-difluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-methanol (45 mg, 150 μmol) in chloroform (3 ml) was added thionyl chloride (20 μl, 290 μmol) at −10° C. under an argon atmosphere. The reaction mixture was stirred for 30 min, saturated aqueous sodium bicarbonate solution/ice water 1/1 was added and the layers were separated. The aqueous layer was extracted two times with dichloromethane. The combined organic layers were washed with ice water/brine 1/1 and dried over sodium sulfate. The solvent was evaporated in vacuo to give the title compound (44 mg, 134 μmol, 90%) as yellow oil which was used in the next step without further purification.