Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[CH2:18][C:19]([OH:21])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45][OH:46])=[CH:39][CH:38]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:46][CH2:45][CH2:44][CH2:43][C:40]1[CH:39]=[CH:38][C:37]([NH:36][C:19](=[O:21])[CH2:18][CH:3]2[C:2](=[O:1])[NH:7][CH:6]=[CH:5][N:4]2[S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:42][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)O)cc1
Reactant: Nc1ccc(CCCO)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)Nc2ccc(CCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL vial was added [3-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-pyrazin-2-yl]-acetic acid (500 mg, 1.61 mmol), EDC (Aldrich, 464 mg, 2.42 mmol), HOBt (Aldrich, 195 mg, 1.45 mmol), CH2Cl2 (5 mL), 3-(4-amino-phenyl)-propan-1-ol (731 mg, 4.84 mmol) and (iPr)2NEt (Aldrich, 0.56 mL, 3.22 mmol). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2 (60 mL). The organic phase was washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chomatography (6%-8% MeOH—CH2Cl2) to afford the title compound. MS (ESI): 444 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:24])([F:23])[CH:13]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:14][OH:15]>>[F:24][C:12]([F:11])([F:23])[CH:13]([CH2:14][O:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: OCC(OC1CCCCO1)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(OCC(OC2CCCCO2)C(F)(F)F)cc1

Procedure:
On reaction of 1-fluoro-4-nitro-benzene and 3,3,3-trifluoro-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol according to the procedure described in example 33 i) there was obtained 2-[2,2,2-trifluoro-1-(4-nitro-phenoxymethyl)-ethoxy]-tetrahydro-pyran. This compound was then treated with THF/1N HCl (20 min RT) to take off the tetrahydropyranyl protecting group and alkylated with methyl iodide in DMF and with NaH as a base at RT (2 h) to give 1-nitro-4-(3,3,3-trifluoro-2-methoxy-propoxy)-benzene, which was then hydrogenated as described in example 33 ii) to give the desired compound, (rac)-4-(3,3,3-trifluoro-2-methoxy-propoxy)-phenylamine.
Reaction SMILES: [NH4+].Cl[C:3]1[N:8]=[C:7]([OH:9])[C:6]([F:10])=[C:5]([CH2:11][CH3:12])[N:4]=1.C(O)C>[Pd].O>[CH2:11]([C:5]1[N:4]=[CH:3][N:8]=[C:7]([OH:9])[C:6]=1[F:10])[CH3:12]
Reactant: CCc1nc(Cl)nc(O)c1F
Agent: [Pd]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCc1ncnc(O)c1F
Temperature: 4 °C

Procedure:
To a mixture of the compound of part (iii) (34 kg), ethanol (170 L) and water (5 kg) was added 5% w/w palladium-on-carbon (50% w/w water content) (3.4 kg) and the mixture hydrogenated at 50° C. and 345 kPa (50 psi) until completion of the reaction. Water (10.5 L) was added and the catalyst removed by filtration. The filtrate was concentrated under reduced pressure to a small volume and extracted with dichloromethane (2×58 L). The combined organic extracts were concentrated under reduced pressure and toluene (150 L) added. The mixture was concentrated under reduced pressure to 50 L in volume, toluene (50 L) added and cooled to 4° C. for 4 hours. The precipitated product was collected by filtration, washed with toluene (10 L) and dried (Yield=20 kg), m.p. 112-4° C.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)CCC.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:22]=1)[CH:20]=[O:21]>C1COCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:20]([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[OH:21])[CH:22]=1
Reactant: Ic1cnccn1
Reactant: O=Cc1cc(Br)ccc1F
Agent: CCCC[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cnccn1)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an oven-dried flask was added anhydrous THF (60 mL) and 2-iodopyrazine (3 mL, 20 mmol). The flask was cooled to 0° C., and 2M n-butylmagnesium chloride in THF (11 mL) was then added dropwise over several minutes. The mixture was stirred at 0° C. for 30 minutes, and then 5-bromo-2-fluorobenzaldehyde (2.4 mL, 20 mmol) was added. After stirring for 2 hours at 0° C., the reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc, dried over MgSO4, and purified by column chromatography (gradient 0 to 50% EtOAc in hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.55 (s, 2H), 7.59 (dd, J=6.4, 2.5 Hz, 1H), 7.46-7.35 (m, 1H), 6.98 (t, J=9.2 Hz, 1H), 6.17 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>O1CCCC1>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][O:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2cccc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.31 g, 83 mmol) was added to an ice-cooled solution of 1-tert-butoxycarbonyl-4-hydroxy-piperidine (16.64 g, 83 mmol) in tetrahydrofuran (200 mL) and the mixture was stirred at 0° C. for 30 minutes. 3-Bromobenzyl bromide (20.66 g, 83 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction was then quenched with water (50 mL) and concentrated in vacuo. The aqueous residue was extracted with ethyl acetate (2×100 mL) and the combined organic phases were washed with brine (100 mL), dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 90:10 to 80:20, to afford the title compound as a colourless oil in 61% yield, 18.64 g.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH2:16][C@H:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19].Cl.[NH:30]([C:42]([O:44][CH2:45][CH:46]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[C@H:31]([C:39](O)=[O:40])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:38])[NH2:37].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:30]([C:42]([O:44][CH2:45][CH:46]1[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:53]2[C:58]1=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:43])[C@H:31]([C:39]([NH:16][C@H:17]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:40])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:37])[NH2:38]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Reactant: N=C(N)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C

Procedure:
2.2 g of DCC are added, at 0° C., to a stirred solution of 2.23 g of H-Ile-OtBu.HCl, 4 g (10 mmol) of Fmoc-Arg-OH and 1.35 g of HOBt in 80 ml of dimethylformamide. The working-up is carried out in analogy to Example 2b.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]1([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:34](=[O:35])[CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 64 h

Procedure:
A solution of 1.00 g (3.78 mmole) of (S)-4-(benzyloxycarbonyl)piperazine-2-carboxylic acid (from Example 7, Step A) in 10 ml of DMF at 25° C. was treated with 0.755 g. (7.46 mmole) of triethylamine. The solution was cooled to 0° C. and 0.95 g (4.12 mmole) of diphenylacetyl chloride was added in Portions over 2 hours. The solution was stirred at 25° C. for 64 hours, concentrated in vacuo and partitioned between 60 ml. of 1N HCl and 60 ml of ethyl acetate. The ethyl acetate was dried over sodium sulfate, concentrated in vacuo and chromatographed in two portions over an 85×2.5 cm LH-20 column with 11 ml fractions of methanol. Fractions 38-41 from both columns were combined and concentrated in vacuo to 785 mg (44%) of oil which was homogeneous by TLC (80:20:2 chloroform-methanol-ammonia water, Rf =0.40).
Reaction SMILES: C(C1C=C(C(C2N(C)N=C(C3C=CC=CC=3)N=2)O)C=CC=1)C.[CH3:23][N:24]1[CH:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]1.[F:35][C:36]1[CH:43]=[C:42]([F:44])[C:41]([O:45][CH3:46])=[CH:40][C:37]=1[CH:38]=[O:39]>>[F:35][C:36]1[CH:43]=[C:42]([F:44])[C:41]([O:45][CH3:46])=[CH:40][C:37]=1[CH:38]([C:28]1[N:24]([CH3:23])[N:25]=[C:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:27]=1)[OH:39]
Reactant: Cn1cnc(-c2ccccc2)n1
Reactant: COc1cc(C=O)c(F)cc1F
Agent: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Product: COc1cc(C(O)c2nc(-c3ccccc3)nn2C)c(F)cc1F
Yield: 74.1 %

Procedure:
According to the procedure for Intermediate 370.2, 1-methyl-3-phenyl-1H-1,2,4-triazole (70 mg, 0.44 mmol) and Intermediate 391.1 (80 mg, 0.48 mmol) afforded 108 mg of Intermediate 391.2 as a white solid. LCMS 332.28 (M+H).
Reaction SMILES: [N:1]([C:4]1[N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([O:21][C:22]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([Cl:30])[CH:23]=3)[C:15]=2[F:31])=[O:11])=[C:7]([Br:9])[N:8]=1)=[N+]=[N-]>C1COCC1.[Pd]>[NH2:1][C:4]1[N:5]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([O:21][C:22]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([Cl:30])[CH:23]=3)[C:15]=2[F:31])=[O:11])=[C:7]([Br:9])[N:8]=1
Reactant: C[Si](C)(C)CCOCn1c(N=[N+]=[N-])nc(Br)c1C(=O)NCc1ccc(Br)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: [Pd]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(N)nc(Br)c1C(=O)NCc1ccc(Br)c(Oc2cc(Cl)cc(C#N)c2)c1F
Yield: 0.1 %

Procedure:
A solution of 2-azido-4-bromo-N-({4-bromo-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.030 g, 0.043 mmol) and catalytic palladium on Ca2CO3 (poisoned with lead) in THF (1 mL) was stirred under atmospheric hydrogen pressure overnight. The reaction mixture was filtered through celite and evaporated to give the title compound (0.029 mg, quant.) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.43 (dd, J=8.47, 1.42 Hz, 1H) 7.31-7.37 (m, 1H) 7.21-7.26 (m, 1H) 7.11-7.17 (m, 1H) 7.06 (t, J=6.00 Hz, 1H) 7.01 (s, 1H) 5.69 (s, 2H) 4.85 (br. s., 2H) 4.63 (d, J=6.04 Hz, 2H) 3.59-3.68 (m, 2H) 0.86-0.94 (m, 2H) −0.03 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:13])[CH3:12].[OH-].[Na+].Br[CH:17](Br)[CH3:18]>C(#N)C.ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][CH2:18][CH2:17][N:10]([C:11](=[O:13])[CH3:12])[C:3]=2[CH:4]=1
Reactant: CC(Br)Br
Reactant: COc1ccc(O)c(NC(C)=O)c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc2c(c1)N(C(C)=O)CCO2
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Under anhydrous conditions, the compound obtained in Step B (1 g; 5.52 mmol) is dissolved in an acetonitrile/dichloromethane mixture (4/6). Sodium hydroxide (4 eq.; 22.1 mmol; 883 mg) that has been ground beforehand, dibromoethane (4 eq.; 22.1 mmol; 1.96 mmol) and Aliquat 336 (catalytic amount) are added to the solution. The whole is stirred for 24 hours at 30° C., under argon, and then 220 mg (1 eq.) of sodium hydroxide are added to terminate the reaction. The solution is filtered through fritted glass, and the brown solid is rinsed with ether. The red filtrate is recovered, and the solvents are removed under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (eluant: PE/AcOEt (1/1)). The title product is obtained in the form of a red solid.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH2:7]([OH:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1.CCCCC>[CH:1]1([C:4]([O:19][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:5])[CH2:3][CH2:2]1
Reactant: CCCCCCCCCCCCO
Reactant: O=C(Cl)C1CC1
Solvent: CCCCC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCOC(=O)C1CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 2.25 g. of cyclopropane carboxylic acid chloride in dry benzene, under nitrogen, is added 8 g. of 1-dodecanol. The mixture is stirred overnight and then diluted with pentane. The reaction mixture is worked up by washing with water and brine and then removing the solvent to yield dodecyl cyclopropanecarboxylate, b.p. 99°-100° (bath) at 0.03 mm. (I; p" is zero, R is n-dodecyl).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[CH2:3]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C=O)C.CCN(CC)CC.CCOC(C)=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>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: C#CCN1CC[C@H](O)C1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CC[C@H](O)C3)c21

Procedure:
Using Method C above, (S)-3-hydroxy-1-prop-2-ynyl-pyrrolidine (60 mg, 0.48 mmol) (Example 96A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P)4Pd (18 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-[3-(3-hydroxy-pyrrolidin-1-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 42 mg, 71%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH2:5][OH:6].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:6][CH2:5][C:4]1[CH:7]=[C:8]([OH:10])[CH:9]=[C:2]([O:1][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH:3]=1
Reactant: OCc1cc(O)cc(O)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1cc(O)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 20.8 %

Procedure:
3,5-Dihydroxybenzyl alcohol (5.0 g, 40 mmol), 2-chloro-5-trifluoromethyl-pyridine (7.13 g, 39.2 mmol) and potassium carbonate (6.16 g, 44.6 mmol) were suspended in dimethylformamide (100 mL) and heated to 100° C. After stirring for 16 h, the reaction was cooled to room temperature and partitioned between water (500 mL) and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-75%, EtOAc:heptane) to afford the title compound (2.32 g, 20% yield) as a thick oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([O-])([O-:18])=[O:17].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[OH:15])([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1ccccc1OCc1ccccc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(OCc2ccccc2)c1O
Reaction time: 24 h
Yield: 42.4 %

Procedure:
2-Benzyloxyphenol (5.00 g, 25.0 mmol) was dissolved in methylene chloride (40 mL) followed by the addition of sodium nitrate (2.30 g, 27.5 mmol). The addition of sulfuric acid (31 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product (2.6 g, 43%). 1H NMR (CD3COCD3): δ7.70 (d,1H), 7.50-7.28 (m, 5H), 7.14 (d, 1H), 6.92 (t, 1H), 5.21 (s, 2H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C[Si]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](O[Si](C(C)(C)C)(C)C)[C:31]=1[CH:44]1[CH2:49][CH2:48][C:47](=[CH2:50])[CH2:46][CH2:45]1)(C(C)C)C)(C)(C)C.[O:51]1CCCC1>>[CH2:50]=[C:47]1[CH2:48][CH2:49][CH:44]([C:31]2[CH:32]=[CH:33][C:34]([OH:51])=[CH:35][C:30]=2[OH:29])[CH2:45][CH2:46]1
Reactant: C1CCOC1
Reactant: C=C1CCC(c2c(O[Si](C)(CC(C)(C)C)C(C)C)cccc2O[Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C=C1CCC(c2ccc(O)cc2O)CC1
Reaction time: 24 h
Yield: 90 %

Procedure:
Tetrabutylammonium fluoride (230 μl) was added to a stirred solution of tert-butyl-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methylenecyclohexyl)phenoxy](isopropyl)dimethylsilane (40 mg) in tetrahydrofuran (2 ml) at room temperature. After 24 hr, further tetrabutylammonium fluoride (50 μl) was added, and after 2 hr the solvent was removed under reduced pressure. The residue was partitioned between water (20 ml) and ethyl acetate (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 2:3 v/v) to give the title compound as a white solid (17 mg, 90%). δH (CD3OD) 1.25-1.40 (2H, m), 1.75-1.82 (2H, m), 2.04-2.15 (2H, m), 2.22-2.30 (2H, m), 2.86 (1H, tt), 3.20 (1H, m), 4.50 (2H, s), 6.10-6.16 (2H, m), 6.72 (1H, d); m/z (ES+) 205 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][CH:10]=[C:9](Cl)[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH2:8].[Cl:14]C1C=CC=C(Cl)C=1O.ClC1C=CC(O)=CC=1>>[Cl:14][C:11]1[CH:10]=[CH:9][C:3]([O:4][CH2:5][CH2:6][CH2:7][NH2:8])=[CH:2][CH:12]=1
Reactant: NCCCOc1c(Cl)cccc1Cl
Reactant: Oc1c(Cl)cccc1Cl
Agent: Oc1ccc(Cl)cc1
Product: NCCCOc1ccc(Cl)cc1
Yield: 85 %

Procedure:
Intermediate 11 (150 mg, 0.808 mmol, 85% yield) was prepared as a white powder following the procedure described for Intermediate 9 replacing 2,6-dichlorophenol with 4-chlorophenol as starting material. LC-MS (ESI) 186 (M+H), RT=1.41 min (Method B).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=O.[CH:10]([NH2:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>C(Cl)Cl.CO.N>[CH:10]([NH:13][C:7]([C@@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]1[NH2:1])=[O:9])([CH3:12])[CH3:11]
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)NC(=O)[C@@H]1CCC[C@@H]1N
Reaction time: 16 h

Procedure:
55 mg (0.43 mmol) cis-(±)-2-amino-cyclopentanecarboxylic acid are suspended in 900 μL (25 eq) isopropylamine and 205 mg (0.064 mmol, 1.5 eq) TBTU and 550 μL DMF are added. The mixture is stirred for 16 h and the reaction mixture is taken up in DCM/MeOH/NH3(aq) 9/1/0.1 and combined with 7 mL silica gel. After all the volatile constituents have been eliminated in vacuo the residue is chromatographed (silica gel DCM/MeOH/NH3 9/1/0.1). 63 mg of the title compound are obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].C(N(C(C)C)CC)(C)C>CN(C=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.[Cu]I>[CH3:18][Si:17]([C:15]#[C:16][C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(C#C[Si](C)(C)C)s1
Temperature: 50 °C
Yield: 86 %

Procedure:
A mixture of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate (2.79 g, 10 mmol), ethynyltrimethylsilane (1.27 g, 13 mmol), Pd(PPh3)4 (578 mg, 0.5 mmol), CuI (143 mg, 0.75 mmol), and diisopropylethylamine (1.94 g, 15 mmol) in DMF (10 mL) was heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 20% EtOAc/hexanes) to give a yellow solid (2.55 g, 86%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:17]2[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][C:14](=[O:23])[CH:13]=1)(C)(C)C.Cl.O1CCOCC1>>[ClH:22].[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:17]2[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][C:14](=[O:23])[CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1cc(=O)oc2cccc(Cl)c12
Agent: Cl
Solvent: C1COCCO1
Product: NCCCOc1cc(=O)oc2cccc(Cl)c12
Yield: 71.4 %

Procedure:
[3-(5-Chloro-2-oxo-2H-1-benzopyran-4-yloxy)-propyl]-carbamic acid tert-butyl ester (24a) (0.079 g, 0.22 mmol) is treated with 4N HCl/dioxane for several minutes during which time a precipitate is formed. The solventVHCl is removed under reduced pressure. The residue is recrystallized from MeOH/EtOAc followed by a second recrystallization from EtOH to afford the title compound as the hydrochloric acid salt (22.8 mg, 41%). 1H NMR (DMSO-d6, 300 MHz) δ 7.94 (3H, brs), 7.62 (1H, t, J=8.25 Hz), 7.43 (2H, m), 5.94 (1H, s), 4.29 (2H, t, J=5.75 Hz), 3.04 (2H, t, J=7 Hz), 2.14 (2H, m); MS (ESI, Pos.) calcd for C12H12ClNO3 m/z [M+H]=254.0, found 254.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH2:18]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH:32]=O)[CH:22]=1)[CH2:19][CH3:20]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH2:32][C:23]2[CH:22]=[C:21]([CH2:18][CH2:19][CH3:20])[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:24]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Product: CCCc1cc(CNCCN2CCN(c3ccc(C)cc3C)CC2)nn1-c1ccccc1
Yield: 73.6 %

Procedure:
Compound 27 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.