Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)=[N:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cnc(Nc2cccc3c2CC(=O)CC3)o1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: CC(C)(C)c1cnc(Nc2cccc3c2CC(O)CC3)o1

Procedure:
The title compound was prepared using the procedure as described in Example 2, substituting the product of Example 17C for the product of Example 1I. 1H NMR (DMSO-d6) δ 8.66 (s, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.44 (s, 1H), 4.76 (d, J=3.7 Hz, 1H), 3.94 (m, 1H), 2.61-2.99 (m, 4H), 1.84 (m, 1H), 1.60 (m, 1H), 1.22 (s, 9H); MS (ESI+) m/z 287 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([NH:10][C:11](=[O:33])[C@@H:12]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]=[CH2:24])=[CH:16][CH:15]=1)[CH2:5][CH:6]([CH2:8]C)[CH3:7].[OH-].[Na+].CO>C1COCC1.O>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:12]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:11]([NH:10][C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:34])=[O:2])=[O:33])=[CH:19][CH:18]=1)[CH2:22][CH:23]=[CH2:24]
Reactant: C=CCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)CC)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl ester 20 (2.30 g, 4.97 mmol) was dissolved in THF (30 mL) and NaOH (0.298 g, 7.46 mmol) dissolved in water (10 mL) was added. Methanol (10 mL) was added to obtain a homogenous solution and this was stirred at rt for 18 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted twice more with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a white solid, 2.14 g, 96%. m.p. 68-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[N:25]([CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1.[ClH:36]>O1CCCC1>[ClH:1].[ClH:36].[NH2:28][CH2:27][CH2:26][N:25]1[C:18]2[C:17]([NH:16][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:22][CH:21]=[N:20][C:19]=2[CH:23]=[CH:24]1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(Cl)c4)c(Cl)c3)c21
Agent: Cl
Solvent: C1CCOC1
Product: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(Cl)c4)c(Cl)c3)c21
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethylcarbamate (1.69 g) in tetrahydrofuran (32 mL) was added 2N hydrochloric acid (16 mL). The reaction mixture was stirred at 65° C. for 18 hrs and concentrated. Ethanol was added, and the mixture was concentrated again. Ethyl acetate and diisopropyl ether were added to the residue, and the precipitate was collected by filtration and washed with diisopropyl ether to give the title compound (1.50 g) as crystals.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NC[CH2:47][CH2:48][N:49]([CH3:51])[CH3:50].CN(CCO)C.CC#N.Cl.O1CCOCC1>C(Cl)Cl>[CH3:51][N:49]([CH3:50])[CH2:48][CH2:47][O:13][C:11](=[O:12])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH2:17])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:2][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)CCO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)CCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.03 h

Procedure:
(2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (125 mg, 302 μmol), HOBt (240 mg, 1.8 mmol), and EDCI (320 μL, 1.8 mmol) were dissolved in DCM and stirred for 2 minutes. N,N-Dimethylaminoethanol (304 μL, 3.0 mmol) was added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution. The organic layer was separated, dried, concentrated, then purified (Interchim reverse phase chromatography column; 5-70% MeCN in water with 0.5% TFA). The purified material was combined with MeCN (3.0 mL, 58 mmol) and 4 M HCl in dioxane (0.3 mL, 1.2 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed and azeotroped with toluene (2×) to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-dimethylamino-ethyl ester.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=4)[C:20](=[O:43])[C:19]=3[C:18]=2[O:44][CH3:45])=[O:16])[CH2:10][CH2:9]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO.O>C1COCC1.C(=O)([O-])O.[Na+]>[OH:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:41])([F:42])[F:40])[CH:33]=4)[C:20](=[O:43])[C:19]=3[C:18]=2[O:44][CH3:45])=[O:16])[CH2:10][CH2:9]1)=[O:7]
Reactant: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(Cc1cccc(OC(F)(F)F)c1)c1ccccc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(=O)NC2CCN(C(=O)CO)CC2)n(C)c2c1c(=O)n(Cc1cccc(OC(F)(F)F)c1)c1ccccc21
Yield: 35.2 %

Procedure:
A solution of 2-{4-[({3-methoxy-1-methyl-4-oxo-5-[3-(trifluoromethoxy)benzyl]-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-2-yl}carbonyl)amino]piperidin-1-yl}-2-oxoethyl acetate (70 mg) and potassium carbonate (77 mg, 0.55 mmol) in THF (2 mL)-methanol (1 mL)-water (1 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (23 mg, 4%) as white crystals.
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6]([C:8]1[C:9]2[C:17]([NH2:18])=[C:16]([C:19](=[O:21])[NH2:20])[S:15][C:10]=2[N:11]=[C:12]([CH3:14])[CH:13]=1)=O)C.C1COCC1>CO>[NH2:18][C:17]1[C:9]2[C:10](=[N:11][C:12]([CH3:14])=[CH:13][C:8]=2[CH2:6][OH:5])[S:15][C:16]=1[C:19]([NH2:20])=[O:21]
Reactant: CCOC(=O)c1cc(C)nc2sc(C(N)=O)c(N)c12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(CO)c2c(N)c(C(N)=O)sc2n1
Reaction time: 2 h
Yield: 71 %

Procedure:
LiBH4 (62 mg, 2.04 mmol) was added to a solution of 3-Amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid ethyl ester (205 mg, 0.73 mmol) in 10:1 THF:MeOH (15 mL) at room temperature. After stirring for 2 h, the reaction was quenched by addition of 1M HCl. The mixture was buffered to a pH≈7, diluted with EtOAc, washed sequentially with H2O, brine, dried over Na2SO4, concentrated, and triturated with 50% EtOAc/hexane giving 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (123 mg, 71%) as a yellow solid, m.p. >210° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH:5][CH:6]=[C:7]([C:21]#[N:22])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=1[Cl:20])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:23]([C:8]([NH:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=3[Cl:20])=[C:7]([C:21]#[N:22])[CH:6]=[N:5]2)=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1cc(NC(=O)C(C#N)=CNc2ccc(OC)c(Br)c2)c(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc(Nc2c(C#N)cnc3cc(Br)c(OC)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A suspension of 3-bromo-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (4.00 g, 8.50 mmol) in 200 mL of acetonitrile was heated to reflux and phosphorous oxychloride (5.0 mL) was added dropwise, via syringe. The reaction mixture was heated at reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue was cooled to 0° C. and saturated aqueous sodium bicarbonate was added. The mixture was stirred for 1 hour and then extracted with a large volume of ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and filtered. The filtrate was reduced in volume until solids appeared. The solids were collected by filtration, washed with diethyl ether and hexanes to provide 1.73 g of 7-bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile as a light tan solid, mp >250° C. 1H NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 4.04 (s, 3H), 7.41 (s, 1H), 7.78 (s, 1H), 7.99(s, 1H), 8.22 (s, 1H), 8.48 (s, 1H), 9.93 (s, 1H); MS (ES) m/z449.9, 451.9, 453.9 (M−H)−
Reaction SMILES: [C:1]([C@H:4]([NH:12]C1C(C(O)=O)=CC2C(=CC=C(Cl)C=2)N=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:3])=[O:2].N[C@@H](C(O)=O)CC1C=CC=CC=1>>[NH2:12][CH:4]([C:1]([OH:3])=[O:2])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@H](Cc1ccccc1)C(=O)O
Agent: N[C@H](Cc1ccccc1)C(=O)O
Product: NC(Cc1ccccc1)C(=O)O

Procedure:
Analysis of the sample enriched by (2%) substance obtained according to the procedure described in Example 6 (2-((R)-1-Carboxy-2-phenyl-ethylamino)-6-chloro-quinoline-3-carboxylic acid, obtained using D-phenylalanine as a starting material) resulted in an increase of peak with Rt 39.32 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[Si]([C:14]([F:17])([F:16])[F:15])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cccc(Br)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cccc(Br)n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
6-Bromopyridine-2-carbaldehyde (1.0 g, 5.38 mmol) was dissolved in 35 mL THF and cooled to 0° C. TMSCF3 (1.0 mL, 6.45 mmol) was added followed by tetrabutylammonium fluoride (6.45 mL of 1.0M in THF). The ice bath was removed and the reaction was stirred for 4.5 hours at room temperature. The reaction was then diluted with water and brine and extracted with ethyl acetate three times. The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-40% ethyl acetate/hexanes) afforded the title compound. 1H NMR (600 MHz, d6-DMSO) δ 7.83 (m, 1H), 7.67 (d, 1H), 7.63 (d, 1H), 7.15 (d, 1H), 5.11 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:14])[C:4]=2[CH2:3]1.[C:16]([O:19][CH2:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=1Br)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[C:16]([O:19][CH2:20][C:21]1[C:22]([N:8]2[CH2:7][CH2:6][N:5]3[C:10](=[CH:11][C:12]4[CH2:13][C:2]([CH3:15])([CH3:1])[CH2:3][C:4]=43)[C:9]2=[O:14])=[CH:23][C:24]([F:28])=[CH:25][C:26]=1[Br:27])(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Reactant: CC1(C)Cc2cc3n(c2C1)CCNC3=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 56.3 %

Procedure:
A sealed tube was equipped with a magnetic stirrer and charged with 103e (740 mg, 3.6 mmol), 2,6-dibromo-4-fluorobenzyl acetate 101c (2.4 g, 7.2 mmol) and cesium carbonate (2.6 g, 7.9 mmol) in 1,4-dioxane (36 mL). After bubbling nitrogen through the solution for 30 min, Xantphos (250 mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium(0) (260 mg, 0.29 mmol) were added, and the reaction mixture was heated to 100° C. for 16 h. After this time, H2O (50 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. The resulting residue was purified by column chromatography eluting with a gradient of 100% hexanes-100% Ethyl acetate to afford a 56% yield (910 mg) of 103f.
Reaction SMILES: ClCCl.[N+:4]([O-:18])([O:6][CH2:7][C@H:8]([O:14][N+:15]([O-:17])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[O:5].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.O>[N+:4]([O-:18])([O:6][CH2:7][C@H:8]([O:14][N+:15]([O-:17])=[O:16])[CH2:9][CH2:10][CH2:11][CH:12]=[O:13])=[O:5]
Reactant: O=[N+]([O-])OC[C@@H](CCCCO)O[N+](=O)[O-]
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: ClCCl
Product: O=CCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrapropylammonium perruthenate (16 mg, 0.05 mmol) was added to a dichloromethane (5 mL) solution of (2R)-6-hydroxyhexane-1,2-diyl dinitrate (intermediate 2, 105 mg, 0.49 mmol) and 4-methylmorpholine N-oxide (137 mg, 1.17 mmol). The solution was stirred at room temperature for 30 minutes. Water was added and the solution was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica eluting with ethyl acetate/hexanes afforded the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 9.79 (s, 1H), 5.25-5.32 (m, 1H), 4.76 (dd, J=13.0, 3.5 Hz, 1H), 4.49 (dd, J=13.0, 6.5 Hz, 1H), 2.59-2.54 (m, 2H), 1.83-1.73 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]3[O:12][CH:13]=[N:14][N:15]=3)[NH:10][C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]3[O:12][CH:13]=[N:14][N:15]=3)[N:10]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2[nH]c(-c3nnco3)cc2n1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccc(Cn2c(-c3nnco3)cc3nc(Cl)ccc32)c1
Reaction time: 1 h

Procedure:
5-Chloro-2-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[3,2-b]pyridine (0.060 g, 0.27 mmol, from Example 139, Step 1) in DMF (5 mL) was treated with Cs2CO3 (0.222 g, 0.681 mmol) and 1-(bromomethyl)-3-chloro-benzene (0.046 mL, 0.35 mmol). After 1 hour, additional 1-(bromomethyl)-3-chloro-benzene (0.040 mL, 0.30 mmol, Aldrich) was added and stirring continued for 1 hour. Water was added, and the solution was extracted with three portions of EtOAc. The combined organic extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes afforded purified product. Yield: (67 mg, 71%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:10])[CH2:5][CH:6]([OH:9])[CH2:7][OH:8].CS(O[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>C1C=CC=CC=1>[CH2:16]([O:8][CH2:7][CH:6]([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:5][N:4]([CH3:10])[CH3:3])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: CN(C)CC(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(CN(C)C)OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 123.6 %

Procedure:
To a suspension of NaH (95%, 5.2 g, 0.206 mol) in 120 mL of anhydrous benzene was added dropwise N,N-dimethyl-3-aminopropane-1,2-diol (2.8 g, 0.0235 mol) in 40 mL of anhydrous benzene under argon. Upon addition, the resulting mixture was stirred at room temperature for 15 min. Linoleyl methane sulfonate (99%, 20 g, 0.058 mol) in 75 mL of anhydrous benzene was added dropwise at room temperature under argon to the above mixture. After stirred at room temperature for 30 min., the mixture was refluxed overnight under argon. Upon cooling, the resulting suspension was treated dropwise with 250 mL of 1:1 (V:V) ethanol-benzene solution. The organic phase was washed with water (150 mL), brine (2×200 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo to afford 17.9 g of light oil as a crude product. 10.4 g of pure DLinDMA were obtained upon purification of the crude product by column chromatography twice on silica gel using 0-5% methanol gradient in methylene chloride. 1H NMR (400 MHz, CDCl3) δ: 5.35 (8H, m, CH═CH), 3.5 (7H, m, OCH), 2.75 (4H, t, 2×CH2), 2.42 (2H, m, NCH2), 2.28 (6H, s, 2×NCH3), 2.05 (8H, q, vinyl CH2), 1.56 (4H, m, 2×CH2), 1.28 (32H, m, 16×CH2), 0.88 (6H, t, 2×CH3) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([N+:20]([O-])=O)=[CH:14][C:13]=2[F:23])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[C:3]([C:12]2[C:13]([F:23])=[CH:14][C:15]([NH2:20])=[C:16]([O:18][CH3:19])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: COc1cc(-c2nn(C)c(C(F)(F)F)c2Br)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(-c2nn(C)c(C(F)(F)F)c2Br)c(F)cc1N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A solution of 3.16 g (7.9 mmole) 4-bromo-3-(2-fluoro-5-methoxy-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 59 mL acetic acid was heated to 80° C. under a nitrogen atmosphere. The heat and nitrogen were removed and 1.76 g (31.6 mmole) iron powder was added in 3 portions over 5 min. The solution was stirred at 80° C. for an additional 30 min. The solution was cooled and filtered through Celite®. The filtrate was diluted with 100 mL water and extracted three times with diethyl ether. The ether extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chromatographically using 40% ethyl acetate in hexane as the eluent to give 2.4 g (83%) of 4-(4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-methoxy-benzeneamine as a white solid, mp 85°-86° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[CH:26][S:27][CH:28]=3)=[C:18]([Cl:29])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:30][C@@H:31]1[CH2:36][CH2:35][O:34][C:32]1=[O:33]>>[Cl:29][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[C@H:31]([OH:30])[CH2:36][CH2:35][OH:34])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1
Reactant: O=C1OCC[C@H]1O
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Product: O=C(NCCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12)[C@H](O)CCO
Yield: 69 %

Procedure:
The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine and (R)-(+)-α-hydroxy-γ-butyrolactone to give the title compound in 69% yield; NMR spectrum (DMSO-d6 400 MHz) 1.44-1.55 (m, 1H), 1.73-1.85 (m, 1H), 3.41-3.52 (m, 2H), 3.65-3.77 (m, 2H), 3.93-4.02 (m, 1H), 4.31-4.48 (m, 3H), 5.38 (s, 2H), 5.50 (d, 1H), 7.17 (d, 1H), 7.33 (t, 2H), (7.60 (dd, 1H), 7.74 (t, 1H), 7.83 (s, 1H), 8.02 (s, 1H), 8.20 (t, 1H), 8.48 (s, 1H), 9.17 (s, 1H), 9.85 (s, 1H); Mass spectrum MH+ 529.9.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:40](=[O:41])[CH2:39][C:36]1[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccncc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 98 mg (0.561 mmol) of 4-pyridylacetic acid hydrochloride, 143 mg (0.562 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 209 μl (1.50 mmol) of triethylamine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.56, FD-MS: M+ =546.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:31][CH:20]3[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:31][CH:20]3[CH2:21][NH:22][CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)nn1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((1,5-dimethyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (256.3 mg, 0.57 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt for 1 h and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (a solution of NH3 in MeOH (7 M)/MeOH/DCM (v/v/v)=3/60/600) to give the title compound as a beige solid (199.0 mg, 100%).