Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:18](=[O:19])[C:14]3([CH2:17][CH2:16][CH2:15]3)[N:13]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26]OS(C)(=O)=O)=[CH:22][CH:21]=3)[C:12]2=[S:32])=[CH:7][C:6]=1[C:33]([F:36])([F:35])[F:34])#[N:4]>C1COCC1>[CH3:1][NH:2][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([N:13]2[C:12](=[S:32])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[C:6]([C:33]([F:36])([F:34])[F:35])[CH:7]=3)[C:18](=[O:19])[C:14]32[CH2:17][CH2:16][CH2:15]3)=[CH:25][CH:24]=1
Reactant: CN
Reactant: CS(=O)(=O)OCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Solvent: C1CCOC1
Product: CNCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: -78 °C
Yield: 82 %

Procedure:
Methylamine (0.5 ml) was bubbled into a mixture of Methanesulfonic acid 4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]phenylmethyl ester (50a) (0.059 g, 0.115 mmol) in THF (3 ml) cooled to −78° C. After 1 hour of reaction at −78° C., the mixture was concentrated and chromatographed (dichloromethane:acetone, 95:5; methanol) to yield 4-[5-(4-methylaminomethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-7-yl]-2-trifluoromethylbenzonitrile (50b) [RD155] (0.042 g, 0.095 mmol, 82%), the structure of which is illustrated in Formula 23, as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](COCC[Si](C)(C)C)[CH:6]=[CH:5]2.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:24]1[CH:25]=[CH:20][N:21]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:23]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(F)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4ccc(F)cc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole (prepared by SEM protection of 5-fluoro-1H-indole using standard procedures) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM protecting group with TBAF.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[NH:15][N:16]=[C:17]([C:22](=[O:26])[CH2:23][O:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19].[CH3:27]OC(OC)N(C)C>>[F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH:27]=[C:23]([O:24][CH3:25])[C:22](=[O:26])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[N:16]1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1ccc(N2CCOCC2)c(F)c1F)C(=O)OC
Product: COC(=O)c1nn(-c2ccc(N3CCOCC3)c(F)c2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of methyl 2-[(2,3-difluoro-4-morpholin-4-ylphenyl)hydrazono]-4-methoxy-3-oxobutanoate (4.7 g, 13 mmol) in N,N-dimethylformamide dimethyl acetal (20 mL) was stirred at 100° C. for 80 min. After cooling to room temperature, the precipitate was collected by filtration and washed with iPr2O to give the title compound (4.1 g, 84% yield) as a brown powder: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.13 (4H, dt, J=4.4, 2.5 Hz), 3.49-4.05 (10H, m), 7.03 (1H, td, J=8.8, 2.5 Hz), 7.51 (1H, td, J=8.5, 2.3 Hz), 8.53 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 382 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][NH:5][C:6]=1[CH3:7].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[I:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][N:5]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[C:6]=1[CH3:7]
Reactant: CCOC(=O)c1n[nH]c(C)c1I
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(C2CCCCO2)c(C)c1I
Yield: 94 %

Procedure:
A solution of ethyl 4-iodo-5-methyl-1H-pyrazole-3-carboxylate (3.6 g, 12.85 mmol, 1.00 equiv), 3,4-dihydro-2H-pyran (3.24 g, 38.52 mmol, 3.00 equiv) and p-toluenesulfonic acid (222 mg, 1.29 mmol, 0.10 equiv) in tetrahydrofuran (150 mL) was stirred at 80° C. for 8 h. The resulting mixture was concentrated under vacuum and the residue was mixed with 100 mL of H2O. The resulting mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-30% of ethyl acetate in petroleum ether to yield 4.4 g (94%) of (R/S) ethyl 4-iodo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 5.43 (dd, J=9.9 Hz, 2.7 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.05-4.00 (m, 1H), 3.67-3.60 (m, 1H), 2.43 (s, 3H), 2.12-2.10 (m, 1H), 1.96-1.95 (m, 1H), 1.69-1.58 (m, 4H), 1.40 (t, J=7.2 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.53 min, m/z=365.0 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](CCN)=[CH:21][CH:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])=[CH:21][CH:20]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Solvent: CN(C)C=O
Product: S=C(NCCc1ccc(Cl)cc1)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl]imidazole (1.04 g, 4 mmol) and 2-(4-chlorophenyl)ethylamine (0.63 g, 4 mmol) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.89 g (64%) of the title product:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=3)[S:18][C:11]=12)[NH2:5].FC1C=CC=CC=1NC(=O)CC(O)=O.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50](=[O:55])[CH2:51][C:52](O)=[O:53]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:52](=[O:53])[CH2:51][C:50]([NH:49][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][CH3:41])=[O:55])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=3)[S:18][C:11]=12
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: CC(C)n1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: O=C(O)CC(=O)Nc1ccccc1F
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(C(C)C)cn4)sc23)c(F)c1

Procedure:
Title compound 126 (scheme 36) was obtained similarly to the compound 122 (example 45, scheme 36) starting from the amine 125 and replacing the acid 29 with the acid 27. 1H NMR (DMSO-d6). δ (ppm): 10.58 (s, 1H), 9.64 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.07 (dd, J=1.6 and 7.2 Hz, 1H), 8.05 (d, J=1.2 Hz, 1H), 7.87 (dd, J=2.4 and 12.8 Hz, 1H), 7.84 (d, J=1.2 Hz, 1H), 7.67 (s, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.43 (dd, J=1.6 and 8.8 Hz, 1H), 7.12-7.04 (m, 2H), 6.92 (ddd, J=2.4, 7.2 and 8.8 Hz, 1H), 6.58 (d, J=5.6 Hz, 1H), 4.48 (quin, J=6.4 Hz, 1H), 3.86 (s, 3H), 3.64 (s, 2H), 1.46 (d, J=6.8 Hz, 6H). MS (m/z): 559.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)C(C)C)(C)C.[CH3:20][O:21][CH2:22]Cl.[C:24]([O:27][CH2:28]C)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.Cl>[CH3:20][O:21][CH2:22][O:1][C:2]1[C:9]([O:10][CH2:24][O:27][CH3:28])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCOC(C)=O
Reactant: COCCl
Reactant: O=Cc1cccc(O)c1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(C=O)c1OCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
2,3-Dihydroxybenzaldehyde (300 mg, 2.17 mmol) was placed in a 20 mL reaction vessel, and dissolved in 6.5 mL of dry dichloromethane. To the solution were added N,N-diisopropylethylamine (1.1 mL, 6.3 mmol), 4-dimethylaminopyridine (13 mg, 0.11 mmol), and chloromethyl methyl ether (412 μL, 5.43 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with 100 mL of ethyl acetate and 20 mL of 1N HCl, and extracted. The extract was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a colorless oil (400 mg, 81%).
Reaction SMILES: C([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:20]2[NH:29][C:23]3=[N:24][CH:25]=[C:26]([F:28])[CH:27]=[C:22]3[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1)(C)(C)C.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH:15]1([CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]#[N:5])=[CH:8][CH:9]=2)[C:20]2[NH:29][C:23]3=[N:24][CH:25]=[C:26]([F:28])[CH:27]=[C:22]3[CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)NC(=O)c1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a stirred solution of N-tert-butyl-4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-benzamide (250 mg, 0.61 mmol) in chloroform (6 mL) at room temperature was added phosphorus oxychloride (0.32 mL, 3.15 mmol). The mixture was heated at 80° C. and stirred for 3 h. The resulting mixture was concentrated in vacuo and the residue was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-benzonitrile (120 mg, 58.8%) as a white solid: LC/MS m/e calcd for C21H20FN3 [M+H]+ 334.41, observed 334.1; 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (s, 1H), 7.63-7.70 (m, 3H), 7.53 (d, J=8.3 Hz, 2H), 6.39 (s, 1H), 4.28 (t, J=7.8 Hz, 1H), 2.23-2.31 (m, 1H), 2.03-2.13 (m, 1H), 1.61-1.87 (m, 5H), 1.51 (dd, J=7.3, 4.0 Hz, 2H), 1.17-1.35 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1([C:13]2[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[C:23]1[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=1>COCCOC.O.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>[CH:7]1([C:13]2[CH:18]=[CH:17][C:16]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
A mixture of 2M aqueous sodium carbonate solution (0.396 mL), tetrakis(triphenylphosphine)palladium(0) (30.5 mg), 4-cyclohexylphenylboronic acid (140 mg) and 3-bromopyridin-2-amine (91 mg) in 1,2-dimethoxyethane (20 mL) and water (5 mL) was stirred overnight under a nitrogen atmosphere at 80° C. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (57.4 mg) as a pale-yellow solid.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)[NH2:2].[CH3:16][C:17](=O)[CH2:18][CH2:19][C:20](=O)[CH3:21]>C(O)(=O)C>[CH3:21][C:20]1[N:2]([NH:1][C:3]2[N:4]=[N:5][C:6]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:7][CH:8]=2)[C:17]([CH3:16])=[CH:18][CH:19]=1
Reactant: CN1CCN(c2ccc(NN)nn2)CC1
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(C)n1Nc1ccc(N2CCN(C)CC2)nn1
Temperature: 70 °C

Procedure:
A mixture of 7 g (35 m moles) of 3-hydrazino-6-(4-methyl-1-piperazinyl)-pyridazine and 4.1 g (36 m moles) of 2,5-hexanedione in 100 ml of acetic acid is heated for 3 hours at 70° C. The solvent is evaporated off under vacuum and the oily residue is dissolved in water and made alkaline with 10% sodium hydroxyde. The mixture is extracted with ethyl acetate and the organic layer is evaporated to dryness in vacuo. The solid residue is crystallized first from ethyl ether and then from ethyl acetate yielding 2.6 g (26%) of the product of the title which melts at 181°-182° C.
Reaction SMILES: [CH3:1][CH:2]([C:15]1([O:20][CH2:19]1)[C:16](O)=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:21]([N:23](CC)[CH2:24]C)C.ClC(OCC)=O.N(CC)(CC)CC.Cl.CNC>O1CCCC1>[CH3:21][N:23]([CH3:24])[C:16](=[O:17])[C:15]1([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1])[O:20][CH2:19]1
Reactant: CCCCCCCCCCCCC(C)C1(C(=O)O)CO1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(C)C1(C(=O)N(C)C)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
To a solution of 1.42 g (0.005 mole) of 2-tetradecylglycidic acid in 10 ml of tetrahydrofuran (THF) at 0° C. (ice-water bath) with stirring is added 0.50 g (0.005 mole) of triethylamine in a small amount of THF. The solution is stirred at 0° C. for 30 minutes and 0.51 g (0.005 mole) of ethyl chloroformate is added. The mixture is stirred at about 0° C. (ice-water bath) for 3 hours (ppt. of Et3N.HCl observed). At the end of 3 hours 0.429 g (0.015 mole) of dimethyl amine in THF is added and the mixture stirred overnight (16 hours) at room temperature. The THF solvent is concentrated to about 1/3 its volume, water is added and the mixture extracted with ether. The ether extract is dried over Na2SO4 and the ether solvent removed. A crude oily residue is obtained which is purified by column chromatography on silica gel. A 37.8% yield of pure N,N-dimethyl-2-tetradecylglycidamide is obtained, m.p. 40°-42° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:17]([CH:19]1[CH2:21][CH2:20]1)=[O:18])=[C:10]2O>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:17]([CH:19]1[CH2:21][CH2:20]1)=[O:18])=[C:10]2[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1cnc2ccc(Br)cc2c1O)C1CC1
Product: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
Phosphoryl chloride (50 mL, 0.547 mol) was cooled to 0° C. and (6-bromo-4-hydroxyquinolin-3-yl)(cyclopropyl)methanone (21 g, 67.7 mmol) was added. The reaction mixture was stirred at 0° C. for 2 h, at room temperature for 2 h and concentrated. The residue was dissolved in methylene chloride and poured into cold 30% aq. ammonium hydroxide. The aqueous layer was separated and extracted with methylene chloride. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by a silica plug to afford the desired product (5.8 g, 22%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 8.91 (s, J=6.4 Hz, 1H), 8.55-8.49 (m, 1H), 8.07-7.97 (m, 1H), 7.91 (dd, J=8.9, 2.1 Hz, 1H), 2.69-2.54 (m, 1H), 1.50-1.40 (m, 2H), 1.28-1.19 (m, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([SiH2:17][O:18][C:19]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:20]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:21]=1[S:22][C:23]1[C:24]([CH2:40]O)=[CH:25][CH:26]=[CH:27][C:28]=1[N:29]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH3:16])([CH3:15])[CH3:14].[C:54]1(=[O:64])[NH:58][C:57](=[O:59])[C:56]2=[CH:60][CH:61]=[CH:62][CH:63]=[C:55]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([SiH2:17][O:18][C:19]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:20]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:21]=1[S:22][C:23]1[C:24]([CH2:40][N:58]3[C:54](=[O:64])[C:55]4[C:56](=[CH:60][CH:61]=[CH:62][CH:63]=4)[C:57]3=[O:59])=[CH:25][CH:26]=[CH:27][C:28]=1[N:29]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCCCCCN1c2cccc(CO)c2Sc2c1cccc2C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCN1c2cccc(CN3C(=O)c4ccccc4C3=O)c2Sc2c1cccc2C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
0.68 ml (4.36 mmol) of diethyl azodicarboxylate was slowly added dropwise under argon and while cooling with ice to a solution of 1.95 g (3.35 mmol) of [6-(tert-butyl-diphenyl-silanyloxymethyl)-10-hexyl-phenothiazin-4-yl]-methanol, 876 mg (5.03 mmol) of phthalimide and 968 mg (3.69 mmol) of triphenylphosphine in 25 ml of tetrahydrofuran. The reaction mixture was stirred at 0° for 2 hours and at room temperature for 20 minutes and then worked up analogously to that described in Example 2.1.1 ea. The residue was chromatographed on 250 g of silica gel with diethyl ether/hexane (1:3), whereupon, after precipitation from hexane, 1.74 g (73.1%) of 2-[6-(tert-butyl-diphenyl-silanyloxymethyl)-10-hexyl-phenothiazin-4-ylmethyl]-2,3-dihydro-1H-isoindole-1,3-dione were obtained as a light yellowish amorphous solid. MS: 710 (M+, 100), 653(61), 506(16), 370(36), 308(41), 268(40), 224(21), 160(34), 130(45), 43(43).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:29]=[C:30](I)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[O:40]1[C:44]2[CH:45]=[CH:46][C:47](B(O)O)=[CH:48][C:43]=2[O:42][CH2:41]1>>[O:40]1[C:44]2[CH:45]=[CH:46][C:47]([C:30]3[CH:31]=[C:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]4[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[C:7]([CH:15]=[CH:16][CH:17]=4)[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:27]=[C:28]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)[CH:29]=3)=[CH:48][C:43]=2[O:42][CH2:41]1
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3cccc(F)c3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)O
Yield: 62 %

Procedure:
A similar procedure as described in Example 5, step 2 was used, starting from 4-{2-(2-carboxy-ethyl)-3-[6-(3′-fluoro-5-iodo-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (1.2 g, 1.85 mmol) and benzo[1,3]dioxol-5-yl-boronic acid (614 mg, 3.7 mmol) to obtain 4-{3-[6-(5-benzo[1,3]dioxol-5-yl-3′-fluoro-biphenyl-3-yloxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy}-butyric acid (737 mg, 62%) as an amorphous white solid: ES(+)-HRMS m/e calculated for C38H39FO8 (M+Na)+ 665.2521, found 665.2520.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26]Cl)[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]([O-:48])(=[O:47])[CH3:46].[Na+]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26][O:48][C:45](=[O:47])[CH3:46])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCOC(C)=O)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 40 °C
Reaction time: 17 h
Yield: 32.4 %

Procedure:
To the product of Example 145 (21 mg, 32 μmol) in acetone (2 mL) was added tetra-n-butylammonium iodide (24 mg, 65 μmol). The solution was stirred at 40° C. for 17 h prior to the addition of sodium acetate (50 mg, 0.64 mmol). The reaction solution was heated at 75° C. for 48 h. After cooling the solution was diluted with EtOAc (25 mL), washed with satd NaHCO3 (20 mL) and water (2×20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude sample was chromatographed (silica gel, DCM) to provide the title compound (7 mg, 33%). 1H-NMR (CDCl3) δ 7.87 (1H, s), 7.60 (1H, dd), 7.30-7.35 (3H, m), 7.17-7.22 (3H, m), 6.60 (1H, dd), 6.48 (1H, d), 5.27 (2H, s), 4.72 (1H, s), 4.39 (2H, t), 4.16 (2H, t), 3.69 (2H, q), 3.16 (2H, s), 3.08 (3H, s), 2.43 (6H, s), 2.06 (3H, s), 0.91 (3H, t); MS(ESI): 675 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26]C)[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]#[N:31])[C:10]=2[CH:9]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]#[N:31])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC#N)C(=O)NC3=O
Solvent: CO
Product: N#CCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Yield: 89.3 %

Procedure:
Demethylation of nitrile (237) (0.15 g, 0.35 mmol) prepared as described in example 97 employing The procedure described in example 80, followed by trituration from methanol, gave phenol (238) (0.13 g, 89%) as an orange/yellow powder, mp 332–336° C. 1H NMR δ [(CD3)2SO] 11.10 (br s, 1H), 9.42 (br s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.96 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.58 (m, 1H), 7.48 (m, 3H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 4.82 (t, J=6.7 Hz, 2H), 3.02 (t, J=6.7 Hz, 2H). Found: C, 66.24; H, 3.66; N, 9.93. C23H14ClN3O3 requires: C, 66.43; H, 3.39; N, 10.10.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[NH:7][C:6]=1[CH3:15].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Cl:35][C:36]1[CH:37]=[C:38]([S:43](Cl)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[Cl:42]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[N:7]([S:43]([C:38]2[CH:39]=[CH:40][C:41]([Cl:42])=[C:36]([Cl:35])[CH:37]=2)(=[O:45])=[O:44])[C:6]=1[CH3:15]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cc1c(C)[nH]c2nccc(Cl)c12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2nccc(Cl)c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (58 mg, 0.24 mmol) in DMF (1.2 mL) is added BEMP (113 μL, 0.39 mmol). The reaction mixture is stirred at ambient temperature for 40 minutes. 3,4-Dichloro-benzenesulfonyl chloride (60 μL, 0.39 mmol) is added and the reaction mixture is stirred for 10 minutes at ambient temperature. The reaction mixture is poured into ice cold water, extracted with EtOAc, washed with brine, dried (Na2SO4) and evaporated. The crude product is purified by column chromatography on silica gel using 1:8 EtOAc/iso-hexane as the eluent, furnishing [4-chloro-1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl]-acetic acid methyl ester; MH+=449.