Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:34])[CH2:3]1.Br[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[N:38]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:49]([O:48][C:46]([N:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]([CH2:36][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[N:38]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a stirring solution of 597.8 mg (1.3 mmol) 2-(2,4-Dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 48, in 15 mL DMF at 0° C. is added 3.13 mL (1.57 mmol, 1.2 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The reaction is allowed to warm to RT over 20 min, then is cooled back to 0° C., and 445.4 mg (1.43 mmol, 1.1 equiv) of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole is added in one portion. The reaction is allowed to warm to RT., and after 20 min is concentrated in vacuo. The residue is taken up in water-ethyl acetate, and is poured into a separatory funnel containing water and ethyl acetate. The layers were separated, and the aqueous layer is extracted with ethyl acetate. The combined organics were dried (Na2SO4) filtered and concentrated in vacuo to afford an amber oil, which is purified by silica gel flash column chromatography to afford 561 mg of the title compound as a viscous, glassy oil: 1H NMR (CDCl3, 400 MHz) δ8.52 (d, br, 2H, J=18.8), 8.01 (d, 1H, J=8.4), 7.78 (m, 2H), 7.46 (t, 1H, J=20), 7.36-7.23 (m, 6H), 7.13 (m, 2H), 6.93 (m, 2H), 4.95 (m, 1H), 4.41 (d, br, 1H), 4.34 (dd, 1H, J=5.2, 8.4), 3.83 (s, 3H), 3.83 (dd, 1H), 3.55 (dd, 1H, J=5.1, 16.6), 1.64 (s, 9H), 1.03 (dd, 6H, J=2.0, 6.5); low resolution MS (FAB)m/e 689 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:15]1[C:20]2[CH2:21][CH2:22][CH2:23][C:19]=2[C:18]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:39])[CH2:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:27][CH:26]=2)=[N:17][CH:16]=1>CC(C)=O>[N:15]1[C:20]2[CH2:21][CH2:22][CH2:23][C:19]=2[C:18]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31](=[O:39])[CH2:32][CH:33]3[CH2:34][CH2:35][N:36]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:37][CH2:38]3)=[CH:29][CH:30]=2)=[N:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C(CC1CCNCC1)c1ccc(Nc2ncnc3c2CCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
50 ml of acetone, 1.14 g of potassium carbonate and 0.4 ml of benzyl bromide were added to 1.34 g of N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(piperidin-4-yl)acetyl]aniline, and the mixture was stirred at room temperature for 4 hours. After separating the solid by filtration and removing the solvent by distillation under reduced pressure, the obtained residue was applied to silica gel column chromatography to obtain 1.05 g of the title compound as yellowish white powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:14]([N:13]([CH3:12])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccc(OCCBr)cc1
Reactant: CNCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CCOc1ccc(O)cc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
Compound 8a (0.25 g, 1.15 mmol) and N-methyl-1-phenylmethanamine (0.18 g, 1.38 mmol) were stirred in acetonitrile (12.0 mL) for 20 mins before diisopropylethylamine was added (0.40 mL, 2.30 mmol) dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours and monitored by TLC. The reaction mixture was concentrated, purified by column chromatography to isolate the compound 8 as a brownish oil (0.20 g, 0.77 mmol, 67% yield). MS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.15, found: 257.98. 1H NMR (CDCl3, 400 MHz) δ 7.30-7.37 (m, 4H), 6.74-6.82 (m, 5H), 4.05 (t, J=6 Hz, 2H), 3.78 (s, 1H), 3.645 (s, 2H), 2.83 (t, J=6.0 Hz, 2H).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][OH:19])[CH3:15]>CN(C=O)C>[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][O:19][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13])[CH3:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCN(CC)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.92 g (19.2 mmol) of sodium hydride (50% in oil) is added at 0° C. under an argon atmosphere to a solution of 2.70 g (17.4 mmol) of 2-fluoro-5-nitrotoluene and 2.54 mL (19.2 mmol) of 2-diethylaminoethanol in 50 mL of DMF and the mixture is stirred for 2 hours at 0° C. and for 1 hour at ambient temperature. The solvent is removed, the residue is taken up in ethyl acetate, and extracted with water. The organic phase is dried over sodium sulfate and evaporated down in vacuo. Then it is purified by silica gel column chromatography with dichloromethane/methanol (9:1) as eluant. Yield: 3.1 g (71% of theory); C13H20N2O3 (M=252.31); calc.: molecular ion peak (M+H)+: 253; found: molecular ion peak (M+H)+: 253; Rf value: 0.60 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:25]#[C:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([O:16][CH3:15])=[O:26])[CH:19]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(I)ccc1O
Reactant: C#Cc1cccc(C(=O)OC)c1
Product: COC(=O)CCc1nc(C#Cc2cccc(C(=O)OC)c2)ccc1O
Yield: 46.2 %

Procedure:
Under the conditions of example 5A, 9.2 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester is reacted with 4.8 g of 3-ethinylbenzoic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-20% ethyl acetate. 4.7 g of 3-{3-hydroxy-6-[2-(3-methoxycarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester of melting point 125°-127° C. is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:6])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)(Cl)Cl>[CH3:3][C:2]([CH3:15])([O:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:12][CH:13]=1)=[O:6])[CH3:1]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 102.8 %

Procedure:
To a 500 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(1,1-dimethylethoxycarbonylamino)phenol (8.20 g, 39.19 mmol), Cs2CO3 (25.54 g, 78.38 mmol), DMF (75 mL), and ethyl bromoacetate (4.78 mL, 43.11 mmol). This heterogeneous mixture was stirred at ambient temperature for 3.5 h. The mixture was diluted with a little CHCl3 and filtered through a frit to remove the salts. The DMF was removed under high vacuum and the residue was suspended in 500 mL of EtOAc. This mixture was washed with H2O (3×), and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo, gave an oil. This material was chromatographed on 400 g of silica gel using 20% EtOAc-hexane as eluant. There was obtained 11.9 g (100%) of ethyl (4-(1,1-dimethylethoxycarbonylamino)phenoxy)acetate as an oil.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:8][N:9]1[C:13]2[N:14]=[CH:15][NH:16][C:17](=O)[C:12]=2[CH:11]=[N:10]1>>[Cl:3][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:9]([CH:8]=[CH:7][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=[CH:11][C:12]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c1cnn2CC(O)c1ccccc1
Product: Clc1ncnc2c1cnn2C=Cc1ccccc1
Temperature: 25 °C

Procedure:
POCl3 (14 g, 91 mmol) was added to 10 (2.56 g, 10 mmol) and the mixture was refluxed for 12 h and then cooled to room temperature.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.CC(C)([O-])C.[K+]>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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccco2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (100 mg, 0.22 mmol) and 2-furanylboronic acid (50 mg, 0.45 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E109). MS (ES+) m/e 442 [M+H]+.
Reaction SMILES: [I-:1].[Na+].[C:3]1([C:9]2([CH:14](C)S([O-])(=O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(C(C)=O)C(C)C>[C:3]1([C:9]2([CH2:14][I:1])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: CC(C1(c2ccccc2)CCCC1)S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: ICC1(c2ccccc2)CCCC1
Yield: 44.8 %

Procedure:
5.00 g (33.3 mmol) of sodium iodide were added to a solution of 1.00 g (3.93 mmol) of (1-phenylcyclopentyl)-methylmethanesulfonate [prepared as described in step (ii) above] in 10 ml of methyl isobutyl ketone, and the resulting mixture was heated under reflux for 18 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was partitioned between diethyl ether and water. The organic phase was washed with water, with a saturated aqueous solution of sodium hydorgencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel, using a 1: 1 by volume mixture of methylene chloride and hexane as the eluent, to give 504 mg (yield 45%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH3:16]>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:16][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: N
Reactant: FC(F)(F)c1cc(Cl)cc(C(F)(F)F)n1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
A mixture of 4-chloro-2,6-bis(trifluoromethyl)pyridine (50 g, 0.20 mole) in concentrated ammonia (250 ml, density 0.88) and ethanol (250 ml) containing copper sulphate (ca. 0.5 g) was stirred and heated in a pressure vessel at 100°-120° C. for 5 hours. The mixture was cooled, extracted with methylene chloride and dried over MgSO4. The solvent was removed under reduced pressure leaving the title compound as a cream solid. The produt was recovered in a yield of 26 g, (56% of theoretical), m.p. 147°-149° C.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12]Cl)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH:25]([CH3:29])[C:26]([OH:28])=[O:27])[CH:19]=[CH:18]2>>[CH3:29][CH:25]([C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH2:12][C:10]3[N:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:8][CH:9]=3)[CH:16]=2)[CH:21]=1)[C:26]([OH:28])=[O:27]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Product: CC(C(=O)O)c1ccc2cc(OCc3csc(-c4ccccc4)n3)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 2-phenyl-4-(chloromethyl)thiazole and racemic 6-hydroxy-α-methyl-2-naphthaleneacetic acid. White crystals are obtained having a melting point of 163°-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[CH:3]=1.[CH2:11]([S:13](Cl)(=[O:15])=[O:14])[CH3:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:13]([CH2:11][CH3:12])(=[O:15])=[O:14])=[C:4]([F:10])[CH:3]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)NCc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4-Bromo-2-fluorophenyl)methanamine (924 mg, 4.53 mmol) was dissolved in pyridine and ethane sulfonyl chloride (0.82 mL, 8.60 mmol) was added to the solution at 0° C. The mixture was stirred for 1 h at 0° C. Then, the mixture was quenched with 1N HCl and extracted with ethyl acetate. Drying over magnesium sulfate and evaporation of the ethyl acetate and purified by column chromatography gave N-(4-bromo-2-fluorobenzyl)-ethanesulfonamide in pure form (1.06 g, 79%).
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN([CH:42]=[O:43])C>C1COCC1.C1CCCCC1>[C:1]([Si:5]([CH3:33])([CH3:32])[O:6][C:7]1[CH:8]=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]([F:13])=[C:11]([CH:12]=1)[CH:42]=[O:43])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(C=O)c(F)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: -78 °C

Procedure:
A solution of 55.0 g of 4-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-diphenyl-silanyloxy)-fluorobenzene described in example 3.1 in 120 ml THF was cooled to −78° C. Within 30 min 97 ml of an 1.3 M solution of sec-butyllithium in cyclohexane was added dropwise. After stirring at −78° C. for an hour, 9.7 DMF in 18.3 ml THF was added within 20 min. The mixture was stirred at −78° C. for 1 hr, then warmed to r.t. within 90 min and quenched with 300 ml ice-cold water. The product was isolated by extraction with Et2O to yield 60.6 g 5-(tert-butyl-dimethyl-silanyloxy)-3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-benzaldehyde as yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([N+:33]([O-])=O)[CH:27]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].CO>[NH2:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[OH:32])[CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[C:10]2[CH:36]=[C:37]([F:41])[C:38]([F:40])=[CH:39][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A mixture of the resulting 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(4-hydroxy-3-nitrobenzyl)piperidine with a 10% palladium carbon (45 mg) and methanol (5 mL) was stirred at room temperature under a hydrogen atmosphere for 4 hours. The palladium catalyst was removed by filtration, and the filtrate was concentrated to provide 1-(3-amino-4-hydroxybenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (100 mg, 60%).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]([NH2:20])=O)=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)Cl>CN(C=O)C>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]#[N:20])=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C(N)=O)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: C=CCn1c(C#N)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Yield: 109.7 %

Procedure:
A solution of 1,3-dibutyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carboxamide (300 mg) in anhydrous DMF (7 ml) at 0° C. was treated dropwise with POCl3 (237 uL). The ice-bath was removed and after 2 hours the mixture was partitioned between water and Et2O. The aqueous layer was re-extracted with Et2O and the combined extracts separated, washed with water (x2), brine, then dried (MgSO4) and concentrated, giving a yellow oil (312 mg). The oil was taken up in cyclohexane and purified by SPE (Si, 10 g) eluting with EtOAc/cyclohexane mixtures. Concentration of the product fractions gave the title compound as a colourless oil (150 mg, 53%). m/z. 330.3[MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:33])[CH2:14][CH2:15][CH2:16][S:17]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH:37]([CH3:39])[CH3:38]>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:33])[CH2:14][CH2:15][CH2:16][S:17]([N:20]([CH:37]([CH3:39])[CH3:38])[C:21]2[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=2)(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)Br
Reactant: COc1ccc(CCN(C)CCCS(=O)(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCS(=O)(=O)N(c2cc(OC)c(OC)c(OC)c2)C(C)C)cc1OC
Yield: 46.6 %

Procedure:
3-[[2-(3,4-Dimethoxyphenyl)ethyl]methylamino]-N-(3,4,5-trimethoxyphenyl)-1-propanesulfonamide (6.7 g, 0.0139 mol) in dry dimethylformamide (100 mL) was treated with sodium hydride, 60% in mineral oil, (0.555 g, 0.0139 mol) and the reaction stirred 1 hour at which point 2-bromopropane (1.71 g, 0.0139 mol) was added and the solution warmed overnight. The reaction was then stripped, dissolved in methylene chloride, filtered and evaporated to a gum. Preparative high pressure chromatography provided the title compound (3.40 g).
Reaction SMILES: C([Li])CCC.[C:6]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:51]=[CH:50][C:40]([CH2:41]P(=O)(OCC)OCC)=[CH:39][CH:38]=1>CCCCCC.O1CCCC1>[O:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:38]=[CH:39][C:40]([CH:41]=[C:28]2[CH2:27][CH2:26][N:25]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)=[CH:50][CH:51]=1
Reactant: CCOP(=O)(Cc1ccc(C2=NCCO2)cc1)OCC
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C(=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)c1ccc(C2=NCCO2)cc1
Temperature: -60 °C
Reaction time: 0.42 h

Procedure:
6.25 ml of a 1.6M solution of n-butyllithium in hexane followed, after stirring for 20 minutes, by 3.4 g of N-trityl-4-piperidone (prepared from 4-piperidone hydrochloride hydrate and trityl chloride) in 20 ml of tetrahydrofuran are added dropwise at -60° C. to 2.97 g of diethyl 4-(2-oxazolin-2-yl)benzylphosphonate. The mixture is stirred at -60° C. for 25 minutes. The reaction solution is then allowed to warm to ambient temperature and is stirred for a further 1.5 hours at this temperature. The reaction solution is then stirred into 150 ml of ice-water, the mixture is extracted three times with 150 ml of ethyl acetate, and the organic phase is dried and evaporated down. The residue is purified by column chromatography on Silica gel (petroleum ether/ethyl acetate=1:1, v/v). 1.7 g of the title compound of melting point 110°-115° C. are obtained.
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH:12]=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4].C([O-])(=O)C.[Na+].Cl.[CH3:20][NH:21][OH:22]>O1CCOCC1.O>[CH3:20][N:21]1[O:22][CH:3]([CH3:4])[CH:2]2[CH:12]1[CH2:11][N:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH2:1]2
Reactant: CC=CCN(CC=O)C(=O)OCC
Reactant: CNO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)N1CC2C(C)ON(C)C2C1

Procedure:
18.4 g (0.1 mol) of ethyl N-(but-2-enyl)-N-(2-oxoethyl)-carbamate are dissolved in 100 ml of dioxane, and 9 g of anhydrous sodium acetate and 9 g (0.108 mol) of N-methylhydroxylamine hydrochloride in 10 ml of water are added. The mixture is heated under reflux overnight and cooled and the salts are filtered off with suction and washed with dioxane. The filtrate is concentrated, the residue is taken up in 100 ml of water and K2CO3 is added. The mixture is extracted with CHCl3, the extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:16]([Cl:17])=[N:15][S:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CCO>[Cl:17][C:16]1[C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[N:13][S:14][N:15]=1
Reactant: CCOC(=O)C1CCN(c2nsnc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(c2nsnc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid ethyl ester (12.3 g, 45 mmol) was dissolved in EtOH (70 mL) to which was added 5N NaOH (15 mL). The mixture was stirred at room temperature for 2 h, then concentrated in vacuo. The resulting aqueous solution was further diluted with H2O, washed with EtOAc (3×) and acidified to pH 2.0 with conc'd HCl. The resulting precipitate was filtered, washed with H2O and dried under high vacuum to give 8.44 g (77%) of 1-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid. 1H NMR (CDCl3) 3.97-3.92 (m, 2H), 3.03 (m, 2H), 2.59 (m, 1H), 2.06 (m, 2H), 1.93 (m, 2H) ppm. LC-MS (M−)=246.