Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([OH:23])=O)[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:23])[N:15]=2)[CH:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)O)nc3c2CCC3)n[nH]1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)N3CCOCC3)nc3c2CCC3)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.3 %

Procedure:
A mixture of 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (1 g, 2.8 mmol), morpholine (0.366 g, 4.2 mmol), HATU (1.28 g, 3 mmol) and DIPEA (0.58 g, 4 mmol) in DMF (5 mL) was allowed to stir at RT overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (8×25 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc gave an oily residue which was purified by reverse phase HPLC followed by chiral HPLC to afford 15 mg of (R)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(morpholino)methanone, and its enantiomer. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.29 (d, 6H), 1.92-2.15 (m, 5H), 2.30-2.42 (m, 1H), 2.67-2.81 (m, 4H), 2.90-3.04 (m, 1H), 3.41-3.90 (m, 10H), 4.98-5.08 (m, 1H), 5.85 (brs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:24]>C(Cl)Cl>[Cl:24][C:9]1[C:10]2[C:5](=[C:4]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]ncc2c1C#Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(Cl)nncc2c1C#Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6-methoxy-5-phenylethynyl-2H-phthalazin-1-one (0.67 g, 2.42 mmoles), prepared as described in example 60, in POCl3 (20 ml) was heated at 80° C. under stirring up to dissolution. After 30 minutes the solution was brought to dryness and the residue taken up in CH2Cl2 (100 ml), washed to alkalinity with a solution of K2CO3, then with water, then anhydrified over Na2SO4 and evaporated to give 715 mg of the title compound (quantitative yield). The compound was used as such in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C@@H:16]3[C@@H:12]([CH2:13][O:14][CH2:15]3)[O:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][C:21]([F:36])([CH:33]([F:35])[F:34])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:17][C:10]1[O:11][C@H:12]2[C@@H:16]([C@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:30]([C:27]4[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:21]([F:36])([F:20])[CH:33]([F:35])[F:34])=[CH:29][N:28]=4)=[O:31])[CH:3]=[CH:4][C:5]=3[F:19])([CH3:18])[N:9]=1)[CH2:15][O:14][CH2:13]2
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)C(F)F)cn3)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21

Procedure:
The coupling of (3aS,7S,7aS)-7-(5-amino-2-fluoro-phenyl)-7-methyl-3,3a,7,7a-tetrahydro-1H-2,4-dioxa-6-aza-inden-5-ylamine and 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid (prepared as described in Banner, D. et al., WO 2011/069934) following procedure G yielded the title compound as a white solid. MS: m/z=501.1 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][N:57]5[CH2:62][CH2:61][NH:60][CH2:59][C@H:58]5[CH3:63])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1>>[ClH:3].[ClH:53].[ClH:1].[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][N:57]5[CH2:62][CH2:61][N:60]([CH3:4])[CH2:59][C@H:58]5[CH3:63])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:33][CH2:34]1
Reactant: C[C@@H]1CNCCN1CCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: C[C@@H]1CN(C)CCN1CCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from (R)-2-{5-chloro-2-[2-(2-methyl-piperazin-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 485 (35Cl) and 487 (37Cl) [M(free base)+H].
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:19]1([Si:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCOCC.C1C=CC=CC=1>[C:32]1([Si:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CCOCC
Product: c1ccc([Si](c2ccccc2)(c2ccccc2)C2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a solution of 17 g of fluorene (102.4 mmol) in 300 mL of dry ether was added 46 mL of 2.3M n-butyllithium dropwise over a period of 20 minutes. The mixture was refluxed for 3 hours, cooled in an ice bath, and treated in one portion with a solution of 24 g (81.46 mmol) of triphenylsilyl chloride in 100 mL of dry benzene. The mixture was refluxed for 24 hours, cooled to room temperature, and washed with sat'd NH4Cl (100 mL), brine (150 mL), and water (150 mL). The organic layer was dried over MgSO4 and the solvent was evaporated in vacuo to give a yellow residue which was triturated with methanol to afford 34.18 g (98.9%) of the crude silane as an off-white solid. Recrystallization from EtOAc--EtOH (4:1) gave 27.46 g (79.5%) of the pure triphenylsilane as white needles, m.p. 182°-193° C.; 1H NMR (CDCl3): δ 4.72 (s, 1H, CH), 6.82-7.90 (m, 23H, aryl).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])#[N:14]>CCCCCC.C1COCC1.C(OCC)C>[C:13]([C:15]1[CH:16]=[C:17]([CH:18]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[OH:19])[CH:20]=[CH:21][CH:22]=1)#[N:14]
Reactant: Brc1cccnc1
Reactant: N#Cc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1cccc(C(O)c2cccnc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
52.8 ml of 2.5 molar butyllithium solution (0.132 mol) in n-hexane are cooled to -78° C. under argon in a mixture of 66 ml of abs. THF and 66 ml of abs. diethyl ether. 17.38 g (0.11 mol) of 3-bromopyridine in 132 ml of abs. diethyl ether are added dropwise to this in the course of 90 min. and the mixture is subsequently stirred for 10 min. 14.5 g (0.11 mol) of 3-cyanobenzaldehyde in 275 ml of abs. diethyl ether and 44 ml of abs. THF are added dropwise to this solution. It is slowly allowed to come to room temperature and stirred overnight at room temperature. It is then stirred into 1100 ml of ice water, extracted twice using 550 ether each time and the combined organic phases are washed by shaking with satd. NaCl solution. After drying over Na2SO4, the organic phase is evaporated and the residue is dried in a high vacuum.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:2][N:3]=[C:4]=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNC(Cl)=Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN=C=Nc1ccccc1
Reaction time: 0.17 h

Procedure:
A suspension of 2.05 g of N-methyl-N'-phenylchloroformamidine hydrochloride in 8 ml of chloroform is added, at 10°-12° C., to 6 g of 20% strength sodium hydroxide solution. The mixture is stirred for 10 minutes, the organic phase is separated off, the aqueous phase is extracted twice more with chloroform and the combined organic phases are dried over K2CO3. After filtering off the desiccant, the solution is subjected to further reaction without isolating the carbodiimide.
Reaction SMILES: [CH:1]1([C:6]2([CH2:26][CH2:27][C:28]3[CH:44]=[CH:43][C:31]([O:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)=[C:30]([CH2:45][CH3:46])[CH:29]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)[C:8](=[O:25])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O1CCOCC1>[NH2:35][CH2:34][CH2:33][O:32][C:31]1[CH:43]=[CH:44][C:28]([CH2:27][CH2:26][C:6]2([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[O:7][C:8](=[O:25])[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)=[C:10]([OH:12])[CH2:11]2)=[CH:29][C:30]=1[CH2:45][CH3:46]
Reactant: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1OCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1OCCN
Temperature: 25 °C
Reaction time: 12 h
Yield: 111.6 %

Procedure:
tert-Butyl 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethylcarbamate (Example A(70)) (250 mg) was dissolved in 4N HCl in dioxane (10 ml) and stirred at room temperature for 12 hrs. Upon completion the mixture was concentrated and azeotroped several times with dichloromethane to afford the title compound as a white solid (235 mg). 1H NMR (300 MHz, MeOD): δ 1.18 (t, J=7.56 Hz, 3 H) 1.32-2.35 (m, 11 H), 2.59-2.85 (m, 15 H), 2.92 (dd, J=116.54 Hz, 1 H), 4.05 (t, J=7.54 Hz, 2 H), 6.55 (d, J=1.56 Hz, 1 H), 6.65 (d, J=1.56 Hz, 1 H), 6.95 (s, 1 H), 6.99 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22](I)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C[NH:56]CCO.[CH:60]([OH:63])([CH3:62])[CH3:61]>[Cu](I)I>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:20]=[C:21]([NH2:56])[C:22]([CH2:61][CH:60]([CH3:62])[OH:63])=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[N:24]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(I)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: CC(C)O
Reactant: CNCCO
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nc(N)c(CC(C)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 80 °C
Reaction time: 20 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-iodopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in isopropanol (1 ml), then thereto are added copper iodide (2.7 mg), ethylene glycol (31 μl), potassium phosphate (119 mg) and 2-methylaminoethanol (20 μl), and the mixture is heated to 80° C. under nitrogen flow, and stirred for 20 hours. After adding distilled water, the mixture is extracted with ether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→3:7) to give (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[methyl-(2-hydroxyethyl)]-aminopyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (58.2 mg). MS (m/z): 657 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.[Na].[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].[I-].[Na+]>>[NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:17]2[C:18](=[O:20])[CH2:19][S:15][C:16]2=[O:21])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: Nc1ncccc1OCCCCCl
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Product: Nc1ncccc1OCCCCN1C(=O)CSC1=O

Procedure:
Using 10.06 g (50 mmol) of 2-amino-3-(4-chlorobutyloxy)pyridine, 6.97 g (50 mmol) of thiazolidine-2,4-dione sodium salt and 7.49 g (50 mmol) of sodium iodide, the same procedure as in Reference Example 11 was followed, to yield 9.53 g (67.8%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]2[CH2:9][C:4]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)([CH2:5]2)[C:3]1=[O:19].C(OCC)(=O)C>COCCO.[Pd]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:4]23[CH2:5][CH:6]([CH2:9]2)[C:7](=[O:8])[N:2]([CH3:1])[C:3]3=[O:19])=[CH:15][CH:14]=1
Reactant: CN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: COCCO
Product: CN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1a, 6.0 g of 3-methyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]-heptane-2,4-dione are dissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 197°-198° (from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCCCl
Yield: 46.4 %

Procedure:
A suspension of 4-chloro-6-methoxyquinazolin-7-ol (0.6 g, 2.86 mmol), 1 bromo 4 chlorobutane (0.63 g, 3.7 mmol), potassium carbonate (1.19 g, 8.6 mmol) and dimethylformamide (10 ml) were heated to 95 C for 1.5 hours. The excess potassium carbonate was filtered off and the reaction evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 60-100% dichloromethane in hexane and 30-50% ethyl acetate in hexane to give 4-chloro-7-(4-chlorobutoxy)-6-methoxyquinazoline as a solid (0.4 g, 47%)
Reaction SMILES: C(OC([N:11]([CH2:21][C@H:22]([NH:28][C:29](=[O:34])[CH2:30][C:31]([OH:33])=O)[C@@H:23]([OH:27])[CH2:24][CH2:25][CH3:26])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH3:20])=O)C1C=CC=CC=1.[Br:35][C:36]1[CH:37]=[C:38]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[NH2:39].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[Br:35][C:36]1[CH:37]=[C:38]([NH:39][C:31](=[O:33])[CH2:30][C:29]([NH:28][C@@H:22]([CH2:21][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[C@@H:23]([OH:27])[CH2:24][CH2:25][CH3:26])=[O:34])[CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=1
Reactant: CCC[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)NC(=O)CC(=O)O
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound N-[(1S,2S)-1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl]-malonamic acid (53 mg, 0.22 mmol, see procedure 17b) was dissolved in 4 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with 3-bromo-5-trifluoromethylaniline (105 mg, 0.22 mmol), N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) and HATU (102 mg, 0.27 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. A portion (25 mg) of this product was dissolved in 30% HBr/Acetic acid (2 mL). The solution was stirred for 4 h at RT and concentrated in vacuo. The residue was dissolved in benzene and the resultant solution was concentrated residue; this procedure was repeated. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=560.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([Cl:19])=[C:13]2[C:12]([CH:20]([CH3:22])[CH3:21])=[N:11]1)[C:5]#[N:6].C(O[BH-](O[C:33](=O)[CH3:34])OC(=O)C)(=O)C.[Na+].F[C:38](F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl.CC(C)=O>[Cl:19][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[N:10]([C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[NH:1][CH:33]([CH3:34])[CH3:38])[N:11]=[C:12]([CH:20]([CH3:22])[CH3:21])[C:13]=12
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2N)c2nccc(Cl)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)Nc1cc(C#N)ccc1-n1nc(C(C)C)c2c(Cl)ccnc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
Compound (107a) (0.100 g) and sodium triacetoxyborohydride (0.130 g) were suspended in dichloromethane (1.6 mL), and trifluoroacetic acid (0.3 mL) and acetone (0.050 mL) were added to the resulting suspension at 0° C., followed by stirring at 0° C. for 20 min. Saturated sodium bicarbonate water was added to the reaction solution, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and the solvent was distilled away. Methanol and water were added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to obtain compound (120a) (0.100 g, 93%) as a brown solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([CH:18]([CH2:29][CH2:30][CH2:31][OH:32])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH2:11]([CH:18]([CH2:29][CH2:30][CH:31]=[O:32])[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OCc1ccccc1)C(CCCO)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCCC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.2 %

Procedure:
A solution of oxalyl chloride (0.9 ml, 10 mmol in 25 ml of CH2Cl2) was slowly added to a flask containing DMSO (1.5 ml, 21 mmol in 3 ml CH2Cl2 at -60° C. under N2. After 5 min, the alcohol from Example 52 (3 g, 10 mmol, 5 ml CH2Cl2) was added dropwise over 5 min period. After stirring the contents for 30 min, Et3N (6.3 ml, 45 mmol) was added and the mixture was warmed to room temperature. The suspension was stirred for 1 h and then poured to a slurry of CH2Cl2 -H2O-ice. The organic layer was washed with dilute HCl, brine, dried over MgSO4, and finally concentrated in vacuo. The crude product was purified by column chromatography (silica gel, Hexane-AcOEt, 4:1) which gave 2.85 g (95%) of the title compound: 1H NMR (CDCl3, 300 MHz) δ: 9.70 (t,J=1Hz,1H,--CHO), 7.40-7.10 (m,10H), 5.05 (s,2H), 3.95 (t,J=6Hz,1H), 2.75 (m,2H), 2.41 (m,2H), and 1.90 (m,2H); DCI-NH3 -MS, m/z 314 (MNH4+, 100%), and 297 (MH+, 20%).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][NH2:8])[C:4]([OH:6])=[O:5].[OH-].[Na+].[C:11]([C:14]([CH3:16])=O)([CH3:13])=O>CO>[CH3:13][C:11]1[N:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[N:2][C:14]=1[CH3:16]
Reactant: CC(=O)C(C)=O
Reactant: NCC(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc(C(=O)O)nc1C
Reaction time: 0.5 h

Procedure:
To a solution of 2,3-diaminopropanoic acid hydrochloride (1 g, 7.11 mmol) in methanol (63 mL) was added sodium hydroxide (1.42 g, 28.4 mmol) at 10° C., and then the mixture was degassed with N2. After 30 min, biacetyl (612 mg, 7.11 mmol) was added and the reaction mixture was stirred at the same temperature for 3 h. Dry air was passed through the reaction mixture for 16 h. The solvent was then removed under reduced pressure, the residue was dissolved in water (7 mL), and the solution was adjusted to pH 2 with concentrated HCl slowly at 0° C., and the mixture was filtered. The yellow solid (580 mg) was used in the next step without further purification. MS (ESI): m/z 153.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:21][C:22]1[CH:30]=[C:26]([C:27]([OH:29])=[O:28])[C:25]([OH:31])=[CH:24][CH:23]=1>C(O)(=O)C>[C:27]([C:26]1[CH:30]=[C:22]([N:21]2[C:11]3[CH2:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[CH:1]=[C:2]2[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:23]=[CH:24][C:25]=1[OH:31])([OH:29])=[O:28]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1C(=O)CCc2ccccc21)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O

Procedure:
A mixture of 16.6 g. (0.063 mole) of 1-phenacyl-2-tetralone, 9.65 g. (0.063 mole) of 5-aminosalicylic acid, and 60 ml. of glacial acetic acid was heated under reflux under nitrogen for 2 hours, cooled and filtered. The collected solid was washed with acetic acid and water, dried and recrystallized from acetic acid to provide 16.3 g. (68%) of crystals, m.p. 223°-225°.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11].C(Cl)[CH:13]=[C:14]([CH3:16])[CH3:15].[CH3:18]O>C1(C)C=CC=CC=1.[Pd]>[CH3:3][C:4]1[C:5](=[O:11])[C:6]([CH3:18])([CH2:10][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:7][CH2:8][CH:9]=1
Reactant: Cc1cccc(C)c1O
Reactant: CC(C)=CCCl
Reactant: CO
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)=CCC1(C)CCC=C(C)C1=O
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (60%, 85 g, 2.13 mol) was added portionwise to a solution of 2,6-dimethylphenol (250 g, 2.05 mol) in 2 L of toluene at 10-15° C. The resulting suspension was stirred for 45 min. The mixture was cooled to 5° C., and prenyl chloride (262 g, 2.13 mol, 85%) was added during 1.5 h keeping the temperature at 5° C. The mixture was then stirred for further 2 h at 10-15° C. Methanol (1 L) and palladium (2.5 g, 10% on charcoal) was added and the gray suspension was hydrogenated at 0.3 bar overpressure, keeping the temperature at 20-22° C. (ice bath). The suspension was then filtered through a pad of celite. The yellow filtrate was washed with water (0.5 L), aqueous sodium hydroxide (0.5 L) and brine (0.5 L), dried (MgSO4) and concentrated in vacuo. The residue was distilled over a 5 cm Vigreux column to yield 318 g (81%, bp 78-82° C./0.05 Torr) of a colorless oil.