Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C@@H:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24]([C:7]2[CH:8]=[N:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: CON(C)C(=O)C[C@@H](c1ccc(Br)cc1)c1ccccc1C
Reactant: COc1ncc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ncc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)cn1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 3.31 mL, 5.3 mmol) in tetrahydrofuran (12 mL) was cooled to −95° C. and added dropwise, under nitrogen, to a stirred, cooled (−95° C.) solution of 5-bromo-2-methoxypyrimidine (1.00 g, 5.3 mmol) in dry tetrahydrofuran (40 mL). To the resulting yellow solution was immediately added a solution of (S)-3-(4-bromophenyl)-N-methoxy-N-methyl-3-o-tolylpropanamide (example 142, step 1; 1.6 g, 4.42 mmol) in dry THF (12 mL), with the temperature of the reaction mixture being kept between −90° C. and −100° C. The solution was stirred and allowed to warm to room temperature over 2 h. The reaction mixture was poured onto sat. aq. ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (700 mg, 35%), Colourless gum, MS (ESI+): m/z=: 411.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1B1OC(C)(C)C(C)(C)O1.CCN(C(C)C)C(C)C>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC1(C)OB(c2c(F)cccc2F)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(F)c(-c2c(F)cccc2F)n1
Temperature: 100 °C
Yield: 92 %

Procedure:
To a screw-cap vial equipped with a magnetic stir bar, methyl 6-bromo-5-fluoropyridine-2-carboxylate (Frontier Scientific, 200.2 mg, 0.8555 mmol) was added followed by 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Combi-Blocks, 310.2 mg, 1.292 mmol), and bis(tri-tert-butylphosphine)palladium (87.5 mg, 0.171 mmol). The vial was sealed with a PTFE-lined septum, evacuated and backfilled with nitrogen three times. 1,4-Dioxane (3.0 mL) was added via a syringe, followed by DIPEA (0.30 mL, 1.7 mmol) and deoxygenated water (0.1 mL). The mixture was heated at 100° C. for 2 h and was then allowed to cool to room temperature. The mixture was diluted with EtOAc (40 mL), washed with water (40 mL) and brine (40 mL), then dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound as a white solid (210.2 mg, 92%). LCMS calc. for C13H9F3NO2 (M+H)+: m/z=268.1. found 268.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][NH:26][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][C:14]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:25][CH:24]=1
Reactant: NCc1ccccn1
Reactant: O=C(O)c1ccc(CCc2cccnc2OCc2ccccc2)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccccn1)c1ccc(CCc2cccnc2OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
4-[2-(2-benzyloxy-3-pyridyl)ethyl]benzoic acid (0.48 g, 1.44 mmol) and 2-aminomethylpyridine (0.189 g, 1.748 mmol) were dissolved in DMF (20 ml) and cooled to 0° C. Triethylamine (0.15 g, 1.5 mmol) was added followed by diphenylphosphorylazide (0.41 g, 1.48 mmol). The reaction mixture was stirred under argon and allowed to warm to ambient temperature overnight. The reaction was partitioned between EtOAc/water, the organic phase was washed with aqueous sodium bicarbonate, water, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (MeOH/CH2Cl2) followed by recrystallisation from EtOAc/hexane and then from EtOH/water to give the title product.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:31](=[N:34]O)([NH2:33])[CH3:32]>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]1[O:5][N:34]=[C:31]([CH3:32])[N:33]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc([C@@H]2CCCN2C(=O)OCc2ccccc2)n1
Temperature: 115 °C
Reaction time: 5 h

Procedure:
To a solution of 122 mg Z-Pro-OH in 4 ml DMF was added a solution of 325 mg 1,1′-carbonyldiimidazole in 5 ml DMF and the solution was stirred for 30 minutes at RT before a solution of 148 mg acetamide oxime in 3 ml DMF was added. The reaction mixture was stirred for 12 h before 325 mg 1,1′-carbonyldiimidazole were added and the mixture stirred at 115° C. for 5 h. Then, the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4% w/w), saturated aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was used in the next reaction step without further purification. Yield: 337 mg.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].CS([O:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][O:15][CH3:16])(=O)=O.[Br:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23](O)=[CH:22][C:21]=1[CH3:28]>CN(C)C=O>[Br:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([O:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][O:15][CH3:16])=[CH:22][C:21]=1[CH3:28]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: COCC(C)(C)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCC(C)(C)COc1cc(C)c(Br)c(C)c1
Temperature: 120 °C

Procedure:
In a microwave vial Cs2CO3 (3.3 g) and KI (50 mg) are added to a solution of 3-methoxy-2,2-dimethylpropyl methanesulfonate (407 mg) and 4-bromo-3,5-dimethylphenol (415 mg) in N,N-dimethylformamide (5 mL). The vial is sealed and the mixture is heated to 120° C. for 12 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with water and brine and is dried (MgSO4). The solvents are evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→80:20). The product thus obtained is purified by HPLC on reversed phase to give the title compound. Yield: 171 mg; LC (method 8): tR=1.02 min; Mass spectrum (ESI+): m/z=301 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.Cl.[CH2:15]([NH2:18])[CH2:16][CH3:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([NH:18][CH2:15][CH2:16][CH3:17])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: CCCN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-methoxyphenyl)propionic acid (8.0 g, 44.4 mmol), propylamine hydrochloride (4.24 g, 44.4 mmol), 4-dimethylaminopyridine (0.65 g, 5.33 mmol) and triethylamine (6.9 mL, 48.96 mmol) in methylene chloride (70 mL) was added 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (10.21 g, 53.28 mmol). The reaction mixture was stirred overnight at ambient temperature followed by dilution with methylene chloride. The mixture was washed with 1N hydrochloric acid, 2N sodium hydroxide, water, brine and dried. Evaporation of the solvent yielded the pure product (10.36 g; 95.4%): 1HNMR (400 MHz, CDCl3) δ 7.76 (brs, 1H), 7.10 (d, 2H, J=8.8 Hz), 6.79 (d, 2H, J=8.0 Hz), 3.68 (s, 3H), 2.95 (q, 2H, J=5.6 Hz). 2.71 (t, 2H, J=7.6 Hz), 2.28 (t, 2H, J=7.2 Hz), 1.34 (m, 2H), 0.77 (t, 3H, J=7.2 Hz); ESMS m/z (relative intensity) 222.2 (M+H+, 100).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([N:7]=[O:8])[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10].N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl>[Si:22]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([N:7]=[O:8])[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1N=O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1N=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S,3S)-methyl 3-hydroxy-1-nitrosopyrrolidine-2-carboxylate (13 g, 0.0742 moles) in DCM (150 mL) at room temperature were added imidazole (15.2 g, 0.224 moles) and TBDMS-Cl (22.5 g, 0.149 moles) and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM and washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography over silica gel using 10% EtOAc in hexane as a solvent provided the title compound.
Reaction SMILES: [CH3:1][S:2][CH:3]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[C:5](=[O:18])[CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>>[CH3:1][S:2]([CH:3]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[C:5](=[O:18])[CH2:4]1)=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1CC(=O)N1CCCC(=O)c1ccccc1
Product: CS(=O)C1CC(=O)N1CCCC(=O)c1ccccc1
Yield: 89 %

Procedure:
Treatment of 4-methylthio-1-(4-phenyl-4-oxobutyl)azetidin-2-one (0.29 g, 1.09 mmol)with mCPBA as described in Example 2 gave the title compound as a yellow oil (0.27 g, 89%),
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:16]=3[C:15]=2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:27]([O:37][CH3:38])[CH:26]=2)=[CH:10][CH:9]=1)[NH2:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(Cl)Cl>[NH2:5][C@H:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:16]=3[C:15]=2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[C:27]([O:37][CH3:38])[CH:26]=2)=[CH:10][CH:9]=1)[CH2:3][OH:2]
Reactant: COC(=O)[C@@H](N)COc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(Cc2c(-c3ccc(OC[C@@H](N)CO)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Yield: 34.3 %

Procedure:
O-[4-[6-Hydroxy-3-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]benzo[b]thiophen-2-yl]phenyl]-L-serine methyl ester (25 mg, 0.045 mmol) in THF:CH2Cl2 (3:1, 4 mL) was treated with lithium aluminum hydride (12 mg) at ambient temperature under argon for 3 h. The reaction was quenched with water (0.5 mL) and sodium hydroxide solution (1.0 M, 1 mL) and stirred for 30 more min before dilution with water (50 mL) and extracting with ethyl acetate (50 mL×3). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography with Et3N:MeOH:EtOAc (10:20:70) afforded the product as a white solid (8 mg, 34%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[OH-:12].[Na+]>>[Cl:11][C:5]1[N:4]=[N:3][C:2]([OH:12])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1
Reactant: [OH-]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Agent: [Na+]
Product: O=C(O)c1cc(Cl)nnc1O

Procedure:
2 mmol of 3,6-Dichloropyridazine-4-carboxylic acid are treated with 8 ml of aqueous 2N NaOH and refluxed for 1 h. The reaction mixture was acidified to pH=1. The resulting white solid was filtered off and dried under vacuum. MS(ISO): 173.2 (M−H+)
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:2]=[N-:3].O[N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18])=[O:9])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a suspension of 5-azidovaleric acid (715 mg; 5 mmol; Example 2.2) and N-hydroxysuccinimide (632 mg; 5.5 mmol; Aldrich) in 30 ml dichloromethane, was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g; 5.5 mmol; Aldrich), and the reaction was stirred 12 h at room temperature. To the reaction mixture, was added water (50 ml), and the separated organic phase was washed with water (100 ml) and brine (100 ml), dried over sodium sulfate, dried in vacuo. The product was purified via flash chromatography on silica gel (240-400 mesh) in 3:1 (v/v) hexane:ethyl acetate. Yield: 843 mg (3.5 mmol, 70% yield). M+H+: expected, 241.09.7; found, 241.03.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)C.C(OC(=O)C)C>CCCCCC>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][NH:5][C:4]2=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)NCCc1ccc(OC)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 145 °C
Reaction time: 0.75 h
Yield: 22.7 %

Procedure:
[2-(4-methoxy-phenyl)-ethyl]-carbamic acid ethyl ester (I-35a: 10 g, 44.84 mmol) was added to PPA (100 mg) at 145° C. The resulting mixture was stirred at 145° C. for 45 minutes. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was quenched with chilled water and extracted with ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 1.8 g of the product (22.69% yield).
Reaction SMILES: [Li].[F:2][C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:9]=[CH:10][C:11]=2[C:12]([O-:14])=O)[CH:8]=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.[CH3:48][C@@H:49]1[NH:54][CH2:53][CH2:52][N:51]([S:55]([C:58]2[CH:63]=[CH:62][C:61]([C:64]([F:67])([F:66])[F:65])=[CH:60][CH:59]=2)(=[O:57])=[O:56])[CH2:50]1>CN(C=O)C>[F:2][C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:9]=[CH:10][C:11]=2[C:12]([N:54]2[CH2:53][CH2:52][N:51]([S:55]([C:58]3[CH:59]=[CH:60][C:61]([C:64]([F:67])([F:65])[F:66])=[CH:62][CH:63]=3)(=[O:56])=[O:57])[CH2:50][C@@H:49]2[CH3:48])=[O:14])[CH:8]=1
Reactant: O=C([O-])c1cnn2cc(F)cnc12
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cc(F)cnc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
The lithium salt of 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate (117 mg, 0.63 mmol) (may be prepared as described in Description 16) was weighed into a vial with HATU (247 mg, 0.65 mmol), suspended in DMF (2 ml) and treated with DIPEA (0.170 ml, 0.97 mmol). This mixture was stirred about 15 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (100 mg, 0.32 mmol) was added and stirring was continued for 3 h at ambient temperature. The reaction mixture was partitioned between DCM and sat. aq. NaHCO3 solution (10 ml each). The layers were separated (hydrophobic frit) and the aqueous layer was washed with further DCM (2×5 ml). The combined organic layers were concentrated to leave an orange gum. Purification by MDAP gave the title compound (112 mg, 0.24 mmol, 73% yield) as an orange solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH3:12])[CH2:5][CH2:4]1.[O:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]2)[CH2:31][CH2:30]1>>[F:28][C:2]([F:1])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:41]([CH:38]3[CH2:39][CH2:40][N:35]([CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH2:36][CH2:37]3)=[O:42])[CH2:14]2)[CH3:12])[CH2:5][CH2:4]1
Reactant: O=C(O)C1CCN(C2CCOCC2)CC1
Reactant: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CN(C(=O)C2CCN(C3CCOCC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(tetrahydro-pyran-4-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester was prepared from [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 634.2 [M]+.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[S:13]([NH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2)(=[O:15])=[O:14].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:11][C:9]([F:12])([F:10])[O:8][C:6]1[CH:7]=[C:2]2[C:3]([S:13](=[O:14])(=[O:15])[NH:16][C:17]3[C:18]2=[CH:19][CH:20]=[C:21]2[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]2)=[CH:4][CH:5]=1
Reactant: Nc1cc(OC(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2cc(OC(F)(F)F)ccc21
Yield: 8.1 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-quinolin-8-yl-4-trifluoromethoxy-benzenesulfonamide (Intermediate 301) (350 mg, 0.91 mmol), t-butyl nitrite (0.16 ml, 1.37 mmol), AcOH (3.5 ml) and THF (3.5 ml) gave the title compound (27 mg, 8%) after purification by column chromatography with DCM/MeOH (99.8:0.2) as the eluent.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][NH:10]2)=[C:6]([O:13][CH2:14][CH2:15][CH3:16])[N:5]=1.[F:17][C@@H:18]1[C@@H:22]([CH2:23][OH:24])[O:21][C@@H:20](N2C=C(C)C(=O)NC2=O)[CH2:19]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>CN(C)C=O.CS(C)=O.C(O)CC>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][NH:10]2)=[C:6]([O:13][CH2:14][CH2:15][CH3:16])[N:5]=1.[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:20]2[O:21][C@H:22]([CH2:23][OH:24])[C@@H:18]([F:17])[CH2:19]2)=[C:6]([O:13][CH2:14][CH2:15][CH3:16])[N:5]=1
Reactant: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CCCOc1nc(N)nc2[nH]cnc12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCCO
Solvent: CS(C)=O
Product: CCCOc1nc(N)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 37 °C
Reaction time: 576 h
Yield: 113.7 %

Procedure:
2-Amino-6-n-propoxy-9H-purine was prepared by displacement of the chlorine group on 2-amino-6-chloropurine (Aldrich Chemical Company) by propanol (Aldrich Chemical Company) in the presence of sodium hydride. 2-Amino-6-n-propoxy-9H-purine (0.50 g, 2.6 mmoles) was dissolved in dimethylformamide (5 ml, DMF) and dimethylsulphoxide (5 ml, DMSO). 3'-Deoxy-3'-fluorothymidine (0.76 g, 3.1 mmoles) and 30 ml 10 mM potassium phosphate buffer, pH 6.8, containing 0.04% potassium azide were added. Purified purine nucleoside phosphorylase (7,500 I.U.) and thymidine phosphorylase (3750 I.U.) adsorbed onto 5 ml DEAE-cellulose resin were added to the reaction mixture and the suspension stirred at 37° C. After 24 days, the reaction was filtered and the filtrate applied to a series of coupled columns. The initial column contained AG1-X2 (OH-form, 2.5×10 cm) while the second column contained Amberlite XAD-2 resin (2.5×20 cm). After sample application, the columns were washed with water (500 ml) and the product eluted with methanol. Product-containing fractions were then flash chromatographed down a silica gel column (4.8×20 cm) using dichloromethane:methanol (95:5) as eluant. Solvent was evaporated in vacuo and lyophilisation yielded 0.46 g of 2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-propoxy-9H-purine (56%): mp 128° C.;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:4][N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:24][CH2:23]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)[CH2:26][CH2:27]3)=[N:3][N:4]=2)=[CH:15][CH:16]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COc1ccc2c(-c3ccc(F)cc3)nnc(Cl)c2c1
Product: COc1ccc2c(-c3ccc(F)cc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-(4-fluorophenyl)-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH3:18])[C:3]=1[O:20][CH3:21].[CH3:22][CH2:23][O:24][C:25]([CH:27](P(OCC)(OCC)=O)[F:28])=[O:26].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:18])=[C:27](/[F:28])\[C:25]([O:24][CH2:23][CH3:22])=[O:26])[C:3]=1[O:20][CH3:21]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: COc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OC)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-8-isopropyl-3-methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-103, 358 mg, 1.02 mmol) and triethyl 2-fluoro-2-phosphonoacetate (0.83 μL, 4.08 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 2.55 mL, 4.08 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).