Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[K+].CN(C)C(=O)C.Cl[C:22]1[N:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[OH-].[Na+]>ClC1C=CC=CC=1.O>[NH2:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:22]2[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=[CH:31][N:32]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(N)Cc1ccc(O)cc1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cccnc1Oc1ccc(CC(C)(C)N)cc1
Temperature: 50 °C
Yield: 89 %

Procedure:
4-(2-Amino-2-methylpropyl)phenol (55.18 grams, 244.9 mmol) was added to 5.05 N KOH (97.2 mmol, 2.0 equiv). The mixture was warmed to 50° C. to give a homogeneous yellow solution. Chlorobenzene (1104 mL) and N,N-dimethylacetamide (10.7 grams, 122 mmol) were added and the mixture was heated to reflux (ca. 100° C.). The water was removed azeotropically via a Dean-Stark trap. At ca. 125° C. a solid began to form. When the pot temperature reached132° C. the water had been removed and the reaction mixture was a thick but stirrable slurry (mechanical stirring required). The Dean-Stark trap was removed and an additional 100 mL of chlorobenzene was removed and discarded. Dry chlorobenzene (50 mL) was added to the slurry, followed by ethyl 2-chloronicotinate (50.0 grams, 269 mmol) in chlorobenzene (50 mL). The slurry was heated at reflux until the reaction was complete (ca. 24, hours). As the reaction progressed the slurry thinned and became beige in color. After cooling to room temperature, water (385 mL) and 1 N NaOH (25 mL, 0.1 equiv) were added to the mixture and the phases were separated. The organic phase was washed with water (285 mL) and the solution was concentrated to a net weight of 700 grams (9.83% potency by HPLC, 89% yield) for use in the next reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]#[C:9][CH:10]([OH:13])[CH2:11][CH3:12]>C(N(CC)CC)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.CSC.[Cu]Br>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:8]#[C:9][CH:10]([OH:13])[CH2:11][CH3:12])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CC(O)CC
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CSC
Product: CCC(O)C#Cc1cccnc1
Temperature: 70 °C
Yield: 100.1 %

Procedure:
To a solution of 3-bromopyridine (12.0 g, 75.6 mmol) and 1-pentyn-3-ol (7.0 mL, 83.2 mmol) in triethylamine (150 mL) were added Pd(PPh3)4 (88 mg, 0.076 mmol) and copper(I) bromide dimethylsulfide (31 mg, 0.15 mmol). The mixture was heated at 70° C. for 5 hr, cooled to room temperature and filtered. The filter cake was washed with EtOAc (30 mL). The combined filtrate was concentrated to give 1-(3-pyridinyl)-1-pentyn-3-ol (12.2 g, 99%) as a dark oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2C=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:9]2)[N:5]=[CH:4][N:3]=1.[NH4+:27].[OH-]>>[NH2:27][C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:8]2[C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:11][C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:9]2)[CH:7]=1
Reactant: [NH4+]
Reactant: Fc1ccc(C2=CN(c3cc(Cl)ncn3)NC(c3ccccc3)=N2)cc1
Agent: [OH-]
Product: Nc1cc(-n2nc(-c3ccccc3)nc2-c2ccc(F)cc2)ncn1
Temperature: 120 °C

Procedure:
A mixture of 1-(4-chloropyrimidin-6-yl)-3-phenyl-5-(4-fluorophenyl)-1,2,4-triazine (0.080 g, 0.23 mmol) and concentrated NH4OH was heated to 120° C. for 18 h in a sealed reaction vessel. After cooling the reaction to ambient temperature, the precipitate which had formed was collected and washed with water, air-dried and dried in vacuo at 40° C. to afford the title compound as a white solid; yield 0.030 g (39%): ES MS m/z=333 (MH+).
Reaction SMILES: Cl.Cl[C:3]1[C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[N:6]=[CH:7][N:8]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH:16]([C:3]1[C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[N:6]=[CH:7][N:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2c1[nH]c1ccccc12
Agent: Cl
Solvent: CCO
Product: c1ccc(Nc2ncnc3c2[nH]c2ccccc23)cc1
Yield: 105.3 %

Procedure:
A solution of 4-chloroindolo[3,2-d]pyrimidinehydrochloride (240 mg, 1.0 mmol) [Monge, A.; Palop, J. A.; Goni, T.; Martinez-Crespo, F.; Recalde, I. J. Het. Chem., 1986, 23, 647-9.], and aniline (0.273 mL, 3 mmol) in ethanol (1 mL) is heated at reflux for 3 h, during which time the reaction becomes a thick suspension. After cooling to 25 C. and diluting with ethanol (4 ml) the mixture is filtered, and the crude product washed with water (15 mL), and ethanol (15 mL), giving 274 mg tan solid, which is recrystallized from DMF/water affording pure 4-anilinoindolo[3,2-d]pyrimidine hydrochloride (82 mg, 27%). 1H NMR (DMSO): δ12.79 (1H, brs), 11.04 (1H, brs), 8.94 (1H, s), 8.27 (1H, d, J=8.2 Hz), 7.96 (2H, d, J=7.5 Hz), 7.85 (1H, d, J=8.4 Hz), 7.71 (1H, t, J=7.7 Hz), 7.49 (2H, t, J=8.0 Hz), 7.41 (1H, t, J=7.6 Hz), 7.24 (1H, t, J=7.4 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1.NC1C=CC=CC=1.[C:30]([C:32]1[O:36][C:35]([C:37](O)=[O:38])=[CH:34][CH:33]=1)#[N:31].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd].CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:37]([C:35]3[O:36][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[O:38])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCCCC3)c2)CC1
Reactant: N#Cc1ccc(C(=O)O)o1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(NC(=O)c3ccc(C#N)o3)c(N3CCCCC3)c2)CC1

Procedure:
The procedure of Example 4, step (c) was followed using 304 mg (1.00 mmol) 1-methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine (as prepared in the previous step) and 304 mg of 10% palladium on carbon (50% by weight water) to prepare the intermediate aniline (4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine) along with 140 mg (1.02 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 178 μL (2.04 mmol) of oxalyl chloride, 10 μL of anh DMF, and 267 μL (1.53 mmol) of DIEA to perform the amide coupling. The resulting residue was chromatographed on a 20-g silica SPE column with 2-5% EtOH-dichloromethane to afford, after slow concentration from EtOAc-hexane (1:1), 232 mg (59%) of the title compound as a yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.53 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz), 7.25 (d, 1H, J=3.7 Hz, partially obscured by CHCl3 peak), 7.21 (d, 1H, J=3.7 Hz), 6.80 (d, 1H, J=2.7 Hz), 6.73 (dd, 1H, J=8.9, 2.7 Hz), 3.20 (m, 4H), 2.85 (m, 4H), 2.59 (m, 4H), 2.36 (s, 3H), 1.80 (m, 4H), and 1.65 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. for C22H27N5O2, 394.2 (M+H), found 394.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:11])=[C:4]([N+:12]([O-])=O)[C:3]=1[CH3:15].C(OCC)(=O)C>C(O)(=O)C.[Zn]>[NH2:12][C:4]1[C:3]([CH3:15])=[C:2]([Cl:1])[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[C:5]=1[OH:11]
Reactant: Cc1c(Cl)cc(C(C)C)c(O)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cc(C(C)C)c(O)c1N
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Zinc (6.4 g, 98 mmol) was added little by little to a solution of the nitro compound (1.88 g, 8.18 mmol) in acetic acid (30 ml) with ice cooling. After stirring for 1 hour, the reaction solution was diluted by adding ethyl acetate thereto and the mixture was filtered off. The filtrate was neutralized with an aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over magnesium sulfate and the solvent was evaporated therefrom to provide 1.63 g (yield 99%) of 2-amino-4-chloro-6-isopropyl-3-methylphenol as pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:13].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1B(O)O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=2[F:13])[CH:24]=1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: CCS(=O)(=O)c1ccc(Br)c(F)c1
Product: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2OCc2ccccc2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (ii) and the product from example 16 step (ii). Yield 0.55 g
Reaction SMILES: O[Li].O.O.C([O:9][C:10]([C:12]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2([C:33]([O:35]CCCC)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])CCC>CCO>[C:33]([C:28]1([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22](=[O:40])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:12]2([C:10]([OH:11])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:29][CH2:30][CH2:31][CH2:32]1)([OH:35])=[O:34]
Reactant: CCCCOC(=O)C1(CCCCCC(=O)CCCCCC2(C(=O)OCCCC)CCCC2)CCCC1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: O=C(CCCCCC1(C(=O)O)CCCC1)CCCCCC1(C(=O)O)CCCC1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
LiOH.H2O (7.83 g, 187 mmol) and H2O (100 mL) were added to a solution of butyl 1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxylate (21.03 g, 90% pure by 1H NMR, 37.3 mmol) in EtOH (300 mL) and the resulting mixture was stirred at reflux temperature for 2 d, allowed to cool to rt and concentrated in vacuo to a smaller volume. H2O (100 mL) was added and the resulting mixture was extracted with Et2O (100 mL), acidified with conc aqueous HCl (25 mL) and extracted with Et2O (3×150 mL). The latter organic layers were combined, dried (Na2SO4; To avoid loss of material, a minimal amount of Na2SO4 was used, with the desiccant becoming a white, oily paste. The organic layer was decanted from the desiccant.) and evaporated in vacuo. The remaining residue was purified by recrystallization from a mixture of iPr2O and heptane to give 1-[11-(1-carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxylic acid (12.15 g, 83%) as white granules. mp=78–85° C. 1H NMR (CDCl3): δ=2.37 (t, J=7.4 Hz, 4H), 2.18–2.10 (m, 4H), 1.65–1.45 (m, 20H), 1.29–1.25 (m, 8H). 13C NMR (CDCl3): δ=211.5, 184.4 (2×), 54.0 (2×), 42.4 (2×), 38.9 (2×), 35.9 (4×), 29.2 (2×), 25.5 (2×), 24.9 (4×), 23.5 (2×). Anal. calcd for C23H38O5: C, 70.02; H, 9.71, found: C, 70.37; H, 9.72.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][NH2:21]>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:21][CH2:20][C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1ccco1
Reactant: N#Cc1c(N)nc2ccccc2c1Cl
Solvent: O
Product: N#Cc1c(N)nc2ccccc2c1NCc1ccco1

Procedure:
5 g of 2-amino-3-cyano-4-chloroquinoline, prepared as described in Example 1 are stirred with 1 ml of 2-furylmethylamine (furfurylamine) at 130° C. for 3 hours. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water. The pale yellow material is recrystallized from 20 ml of ethanol to obtain 4.8 g of the title compound, mp.: 208° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:31]=[C:32]([N:47]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:48](=[O:51])[O:49][CH3:50])[CH:33]=[C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH:43]3[CH2:46][O:45][CH2:44]3)[CH2:39][CH2:38]2)[C:35]=1[F:36].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:14]([C:13]1[N:9]2[C:10]([C:5]([N:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:6][C:7]([NH:29][C:30]3[CH:31]=[C:32]([N:47]([CH2:52][C:53]4[CH:54]=[CH:55][C:56]([O:59][CH3:60])=[CH:57][CH:58]=4)[C:48](=[O:51])[O:49][CH3:50])[CH:33]=[C:34]([N:37]4[CH2:38][CH2:39][N:40]([CH:43]5[CH2:46][O:45][CH2:44]5)[CH2:41][CH2:42]4)[C:35]=3[F:36])=[N:8]2)=[N:11][CH:12]=1)#[N:15]
Reactant: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCN(C3COC3)CC2)c1
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(Nc2nc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)c(F)c(N2CCN(C3COC3)CC2)c1
Temperature: 45 °C
Reaction time: 16 h
Yield: 179.8 %

Procedure:
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 3) (58.4 mg, 0.146 mmol), methyl (3-amino-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (62 mg, 0.098 mmol) and Cs2CO3 (95 mg, 0.293 mmol) in DMF (1 ml) were heated at 70° C. for 80 minutes. Additional 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (58.4 mg, 0.146 mmol) and Cs2CO3 (95 mg, 0.293 mmol) were added and the mixture stirred at 45° C. for 16 hours. The mixture was partitioned between EtOAc and dilute aq. NH4Cl solution. The organic layer was washed twice with dilute NaHCO3 solution, once with brine, then dried over MgSO4, filtered and evaporated to dryness to give methyl (3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4 methoxybenzyl)carbamate (134.4 mg). The material was used in the following reaction without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.ClC[CH:12]([O:15]C(CCl)CCl)CCl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:12]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)=[O:15]
Reactant: c1ccc2c(c1)CCO2
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 9.4 ml (83.4 mmole) 2,3-dihydrobenzofuran in 250 ml methylene dichloride was cooled under nitrogen to 0° to -5° C. and 18 ml (167 mmole)titanium tetrachloride was added dropwise at 0° C. The resulting brown mixture was stirred 10 minutes and 8.3 ml (91.6 mmole) 1,1-dichloromethyl methylether was then added dropwise at 0° C. During this addition the reaction mixture became dark red. The mixture was allowed to warm to room temperature, stirred for two hours and poured slowly into a 2 liter beaker containing 700 ml saturated aqueous sodium bicarbonate solution. The resulting mixture was filtered through diatomaceous earth and the solids washed with methylene dichloride. The separated organic layer was dried (Na2SO4) and the solvent evaporated to afford a residual oil, log (81%) of which appeared homogeneous on silica gel TLC, eluting with an ethyl acetate/hexane/5% acetic acid 1:5:5 by volume. Mass spectrum (m/e): 148 (M+), 147, 119.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:50]([O:54][C:55]([NH:57][C@H:58]([C:60](O)=[O:61])[CH3:59])=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([NH:57][C@H:58]([C:60]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:61])[CH3:59])=[O:56])([CH3:52])([CH3:53])[CH3:51]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 79 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-L-alanine. Yield 79%. [α]D =+12.1° (c=0.87, tetrahydrofuran).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([F:35])=[C:30]([OH:36])[CH:29]=[CH:28]2>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([F:35])=[C:30]([O:36][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=1)[CH:29]=[CH:28]2
Reactant: Oc1ccc2cc(Br)ccc2c1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc4cc(Br)ccc4c3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline (prepared as described in WO 03/33472) (0.465 mg, 1.93 mmol), 6-bromo-1-fluoro-naphthalen-2-ol (Example 3a) (0.65 mg, 1.93 mmol) and DMAP (0.235 mg, 1.93 mmol, Aldrich) in toluene (in a microwave tube) was heated in a microwave oven (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with brine (2×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (40% to 100% EtOAc in hexanes) to give the title compound as an orange foam. MS (ESI, pos. ion) m/z: 541.1 (M+1). Mass Calc'd for C27H26BrFN2O4: 540.11.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:8]([F:11])=[CH:9][CH:10]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:23]([CH2:22][C:13]1[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:12]=1[C:7]1[C:8]([F:11])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:29])[CH:6]=1)[CH2:24][C:25]([F:28])([F:27])[F:26])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1
Product: CC(=O)N(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1F)CC(F)(F)F

Procedure:
Prepared according to the procedure described in Example 1, Step 6 and Step 7, using the following starting materials: {6-fluoro-2′-[(2,2,2-trifluoro-ethylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[O:7]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CI>CN(C)C=O>[CH3:1][N:23]([S:20]([C:17]1[CH:18]=[CH:19][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1)(=[O:22])=[O:21])[CH:24]([CH2:25][OH:26])[CH2:27][OH:28]
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(NC(CO)CO)c1ccc(Oc2ccccc2)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(CO)CO)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
After potassium carbonate (45.39 g, 328.4 mmol) was added to a solution of N-(4-phenoxybenzenesulfonyl)serinol (10.62 g, 32.84 mmol), the product of (1) above, in N,N-dimethylformamide (250 ml), methyl iodide (5.12 g, 36.12 mmol) was added dropwise to the mixture. After stirring it at room temperature for 2 hours, the same amount of methyl iodide was further added to this mixture and stirred for 1 hour. The solvent of the reaction mixture was evaporated under reduced pressure, ice-water was added to the resulting residue and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the desired compound (8.32 g, yield 75%) as a white powder.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:15][C:16]([C:18]1[S:19][C:20]([C:23]2[C:24]3[C@H:31]([CH3:32])[CH2:30][C@@H:29]([OH:33])[C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:21][CH:22]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:15][C:16]([C:18]1[S:19][C:20]([C:23]2[C:24]3[C@H:31]([CH3:32])[CH2:30][C@@H:29]([OH:33])[C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:21][CH:22]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)N[C@H](CN=[N+]=[N-])Cc4ccc(Cl)cc4Cl)s3)c21
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)N[C@H](CN)Cc4ccc(Cl)cc4Cl)s3)c21
Reaction time: 2 h
Yield: 96.9 %

Procedure:
10% w/w Pd/C (1 mg) was added to a solution of N-((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide (4.0 mg, 0.008 mmol) in MeOH (0.5 mL). The solution was put under vacuum and purged with H2 (3×). The reaction mixture was then stirred under a hydrogen atmosphere for 2 hours. LC-MS analysis of the reaction mixture showed no more starting material. The reaction mixture was filtered and then concentrated to yield N-((S)-1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide as a solid (3.7 mg, 98%). m/z 477 (M+). 1H NMR (DMSO d6) δ (ppm) 8.91 (s, 1H), 8.58-8.56 (m, 1H), 7.90 (br s, 2H), 7.84 (d, 1H, J=4.3 Hz), 7.78 (d, 1H, J=4.1 Hz), 7.60 (m, 1H), 7.39-7.33 (m, 2H), 5.22-5.17 (m, 1H), 4.59-4.50 (m, 1H), 3.87-3.77 (m, 1H), 3.19-2.84 (m, 5H), 2.33-2.26 (m, 1H), 1.88-1.82 (m, 1H), 1.13 (d, 3H, J=6.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][C:16]3[O:17][C:18]4[C:23]([C:24](=[O:32])[C:25]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:9]=[C:10]([C:11]#[C:12][CH2:13][OH:14])[C:3]=12.ClCCl>CO.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][C:16]3[O:17][C:18]4[C:23]([C:24](=[O:32])[C:25]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[C:3]=12
Reactant: Nc1ncnc2c1c(C#CCO)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnc2c1c(CCCO)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Reaction time: 48 h
Yield: 42 %

Procedure:
To a solution of example 59 (0.170 g, 0.401 mmoles) in methanol (4 ml), palladium on charcoal 1 (10%, 0.050 g) was added and hydrogenated at 5 kg/cm2 for 48 h. The reaction mixture filtered through celite pad and washed with methanol. The filtrate was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.072 g, 42% yield). MP: 182-184° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.11 (s, 1H), 8.05 (dd, J=8.0, 1.6 Hz, 1H), 7.76 (m, 1H), 7.49 (t, J=7.1 Hz, 1H), 7.39-7.20 (m, 8H), 4.62 (t, J=4.6 Hz, 1H), 3.45 (q, J=6.1 Hz, 2H), 2.92 (t, J=7.4 Hz, 2H), 1.78 (m, 2H). Mass: 427.87 (M+).