Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]([CH3:47])([CH2:45][OH:46])[C:41]([O:43][CH3:44])=[O:42].[C:48](=O)(OC(Cl)(Cl)Cl)[O:49]C(Cl)(Cl)Cl.C(OC(C)(C)C)=O>O.CC#N.CC#N.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:48]([O:46][CH2:45][C:40]([C:41]([O:43][CH3:44])=[O:42])([CH3:47])[CH3:39])=[O:49])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)CO
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Agent: CC(C)(C)OC=O
Solvent: O
Solvent: CC#N
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)OCC(C)(C)C(=O)OC)C2CC2)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described above for NVP-BGW706 from ((3R*,4R*)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and methyl 2,2-dimethyl-3-hydroxypropionate using bis(trichloromethyl) carbonate. MS (LC-MS): 592.1 [M+H-Boc]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.92 min.
Reaction SMILES: [O:1]=[C:2](C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]([O-])=O.C1(C2C(C=O)=C(C3C=CC(F)=CC=3)C3C(=CC=CC=3)N=2)CC1.CCCCCC.[CH2:55]([O:57][C:58](=[O:60])[CH3:59])[CH3:56]>C(#N)C>[CH2:55]([O:57][C:58](=[O:60])[CH2:59][C:2](=[O:1])[CH:3]=[CH2:4])[CH3:56]
Reactant: O=C([O-])CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CC#N
Product: C=CC(=O)CC(=O)OCC
Temperature: 25 °C

Procedure:
The ylide 3-oxo-4-(triphenylphosphoranylidene)butanoate (4.82 g, 12.36 mmol) is solved under argon atmosphere in 100 ml acetonitrile. Under vigorous stirring 2-cyclopropyl-4-(4-fluoro-phenyl)-quinoline-3-carbaldehyde (3 g, 10.3 mmol) is added in 5 portions and then heated to reflux. After 50 h the reaction is cooled to room temperature. The slight brown solvent is evaporated and the residue is dried under vacuum to obtain a brown waxy oil. Chromatography over silica gel with hexane:ethylacetate (4:1/v:v) give a yellow oil of 5-(2-cyclopropyl-4-fluoro-phenyl)-quinolin-3-yl)-3-oxo-pent-4-enoic acid ethyl ester. MS: 403.45
Reaction SMILES: [C:1]1([C:7]2[S:14][C:13]3[CH:12]=[N:11][N:10](C(=O)C)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C:7]2[S:14][C:13]3[CH:12]=[N:11][NH:10][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)n1ncc2sc(-c3ccccc3)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cc3[nH]ncc3s2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
To a mixture of 1-(5-phenyl-thieno[3,2-c]pyrazol-1-yl)-ethanone [3.82 g, 15.8 mmol, Intermediate (44)] and ethanol (50 mL) was added 6 N hydrochloric acid (50.0 mL, 300 mmol) in one portion and the resulting mixture heated at 70° C. After 18 hours, the reaction was cooled to ambient temperature and neutralized with 25% aqueous potassium carbonate. The mixture was diluted with water (200 mL) and aged at 0° C. for 1 hour. The resulting solid was collected, washed three times with water (50 mL), and then dried under vacuum to give 5-phenyl-1H-thieno[3,2-c]pyrazole [2.93 g, 92%, Intermediate (45)] as a beige powder. LC/MS: 201.0 (M+H), RT=3.15 minutes).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:44][CH2:45][C@@H:46]([OH:48])[CH3:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CO.O>[CH2:37]([O:44][CH2:45][C@@H:46]([CH3:47])[O:48][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([NH2:1])=[CH:3][C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:5]2)[CH:12]=[CH:11][CH:10]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2O)n1
Reactant: C[C@H](O)COCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](COCc1ccccc1)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 44.3 %

Procedure:
A mixture of Intermediate 95a (0.50 g, 2.2 mmol) in dry THF (17 mL) was treated with triphenylphosphine (1.13 g, 4.32 mmol) and (S)-(+)-1-Benzyloxy-2-propanol (0.52 mL, 3.24 mmol). The mixture was cooled to 0° C. then diisopropylazodicarboxylate (0.85 mL, 4.32 mmol) was added dropwise. After stirring at ambient temperature for 1.75 h the mixture was treated with water (0.2 mL) then applied to a pre-conditioned (with MeOH) SCX-2 cartridge. The cartridge was eluted with MeOH then 2N NH3 in MeOH. The product containing fractions were combined and concentrated in vacuo to a viscous brown oil. The oil was purified by FCC, using 0-30% EtOAc in cyclohexane, to give the title compound as a golden oil (0.37 g, 45%). LCMS (Method 3): Rt 3.71 min, m/z 380.3 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:36])=[C:23]([C:26]4[O:27][C:28]([CH:31]5OCC[O:32]5)=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37]>C1COCC1>[ClH:37].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:36])=[C:23]([C:26]4[O:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(C2OCCO2)o1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cc2F)o1
Reaction time: 1.5 h
Yield: 61 %

Procedure:
Prepared according to Procedure C from a stirred solution of (4-benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine (0.51 grams, 1.1 mmol) in 20 ml of THF was added 5 ml of 1 N HCl. After stirring for 90 minutes, the resultant suspension was filtered and washed with diethyl ether (200 ml) to yield, after drying under vacuum, a yellow solid (0.32 grams, 61% yield). δ1H NMR (400 MHz, DMSO-d6) 11.52(s, 1H), 9.70(s, 1H), 9.25(d, 1H), 8.76(s, 1H), 7.76(m, 2H), 7.55(d, 2H), 7.45(d, 2H), 7.33(m, 4H), 7.11(d, 2H), 5.14(s, 2H). ESI-MS m/z 440(M+1).
Reaction SMILES: [CH:1]1[C@H:6]([NH2:7])[C@H:5]([OH:8])[C@@H:4]([OH:9])[C@H:3]([OH:10])[C:2]=1[CH2:11][OH:12].C1[C@H](N)[C@H]([OH:20])[C@@H](O)[C@H](O)C=1CO.O=[CH:26][C@@H:27]([C@H:29]([C@@H:31]([C@@H:33]([CH2:35][OH:36])[OH:34])[OH:32])[OH:30])[OH:28]>C(O)CC>[CH2:1]1[C@:2]([OH:20])([CH2:11][OH:12])[C@@H:3]([OH:10])[C@H:4]([OH:9])[C@@H:5]([OH:8])[C@H:6]1[NH2:7].[CH2:35]1[O:36][C@@H:26]2[O:34][C@H:33]1[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:27]2[OH:28]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N[C@H]1C=C(CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CCCO
Product: N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Product: O[C@@H]1[C@@H](O)[C@@H]2OC[C@@H](O2)[C@H]1O
Yield: 59.2 %

Procedure:
A solution of protected valienamine, (1R)-(1,2,4/3)-2,3,4-tribenzyl-5-benzyloxy-methylcyclohex-5-enylamine, (compound 1) made according to the method of Ogawa et al. J. Chem Soc. Perkin Trans (1988)3 (1.41 g, 2.63 mmol). This was combined with the protected epoxide, 1,6-anhydro-4-O-benzyl-2,3-epoxy-glucose, made according to the method set forth in Cerny et al., J. Czechoslav. Chem. Commun 39 (1974)4 (compound 2) (3.28 g, 14.0 mmol), in n-propanol (28 ml) and was heated at 90° C. for 4 days. Solvent was evaporated, then co-evaporated with toluene and the residue was chromatographed on a silica gel column using hexane:ethylacetate (2:1) as eluent to provide 1,6-anhydro4-O-benzyl-2-deoxy-2-[1D-(1N,2,4/3)-(2,3,4-tri-O-benzyl-5-C-benzyloxymethyl-2,3,4-trihydroxy-5-cyclohexen-1-yl)amino]-β-D-glucopyranose (compound 3) (1.2 g, 59.2%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)=[C:4]([CH3:17])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].O=P(Cl)(Cl)[Cl:26]>>[Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([Cl:26])[CH:8]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1Oc1cc[n+]([O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Br)cc(C)c1Oc1ccnc(Cl)c1
Temperature: 105 °C
Yield: 73 %

Procedure:
A suspension of 4-(4-Bromo-2,6-dimethyl-phenoxy)-pyridine 1-oxide (14, 10 g, 34 mmol, 1 equiv) and Na2CO3 (3.6 g, 34 mmol, 1 equiv) in POCl3 (100 mL) was heated to 105° C. for 30 h. The reaction was cooled to RT and the POCl3 was removed by rotary evaporation. The residue was dissolved in EtOAc and partioned into a chilled biphasic solution of EtOAc and 1 N NaOH. The aqueous layer was treated with NaOH (s) until the pH >1. The aqueous layer was extracted with EtOAc (3×), and the combined organics were washed with brine, dried (MgSO4) and concentrated. Recrystallization (EtOH) provided the desired material as off-white crystals (73%). 1H NMR (300 MHz, CDCl3) δ8.21 (d, J=6.2 Hz, 1H), 7.28 (s, 2H), 6.66 (m, 2H), 2.10 (s, 6H). 13C NMR (100 MHz, CDCl3) δ165.6, 153.5, 151.3, 149.0, 133.3, 132.5, 119.6, 110.7, 110.2, 16.4.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:20][CH2:17][CH2:18][CH3:19])[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCCNc1cc(Nc2ccc(OC)cc2)ncn1
Temperature: 200 °C
Yield: 82 %

Procedure:
100 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 66 mg of propylamine and 120 mg of DIPEA were dissolved in 1 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated off and the evaporation residue was subjected to crystallization from n-BuOH-EtOH solvent mixture. N4-(4-Methoxyphenyl)-N6-propylpyrimidine-4,6-diamine was obtained in the form of a colorless solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:16][C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl.CO>CC(C)=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:16][C:17]#[N:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCl
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)=O
Product: N#CCOc1cccc(CN2CCCCC2)c1
Yield: 66.4 %

Procedure:
A mixture of 3-(piperidinomethyl)phenol (7 g), chloroacetonitrile (2.77 g) and potassium carbonate (5.06 g) in dry acetone (100 ml) was stirred under reflux overnight. The reaction mixture was filtered and the filtrate was evaporated to give a residue which was subjected to column chromatography on silica using chloroform:methanol (20:1) as eluant to afford 3-(piperidinomethyl)phenoxyacetonitrile (5.6 g).
Reaction SMILES: C([N:8]1[C:17]2=[CH:18][CH:19]=[CH:20][C:15]3=[C:16]2[N:10]([CH2:11][CH2:12][CH2:13][C:14]3=[O:21])[C:9]1=[O:22])C1C=CC=CC=1.OP(O)(O)=O.C1(O)C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl.O>[NH:8]1[C:17]2=[CH:18][CH:19]=[CH:20][C:15]3=[C:16]2[N:10]([CH2:11][CH2:12][CH2:13][C:14]3=[O:21])[C:9]1=[O:22]
Reactant: O=C1CCCn2c(=O)n(Cc3ccccc3)c3cccc1c32
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Oc1ccccc1
Solvent: O
Product: O=C1CCCn2c(=O)[nH]c3cccc1c32
Temperature: 150 °C
Yield: 48 %

Procedure:
A mixture of 29.2 g of the product of Step C, 292 g of o-phosphoric acid and 14.1 g of phenol were heated at 150° C. under an inert atmosphere for 2 hours, was cooled to about 35° C. and was poured into 1200 ml of iced water with stirring. 2 liters of methylene chloride were added to the mixture which was then made alkaline with sodium hydroxide. The mixture was filtered and the solids were washed with methylene chloride. The combined organic phases were washed, dried and evaporated to dryness under reduced pressure. The residue was crystallized and was chromatographed over silica gel. Elution with a 90-2-2 ethyl acetate-methanol-triethylamine mixture yielded 9.7 g of 5,6-dihydro-imidazo[4,5,l-j-k][1]benzazepin-2,7-[1H,4H]-dione melting at 235° C.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][C:8](=[O:43])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:32]=[CH:31][C:25]3[C:26](=[O:30])[CH2:27][CH2:28][O:29][C:24]=3[C:23]=2[CH2:33][CH2:34][CH3:35])=[C:11]([CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])[CH:10]=1)C.O.O.[OH-].[Li+].S(=O)(=O)(O)O>O1CCCC1.C(OCC)(=O)C>[C:38]([CH2:37][CH2:36][C:11]1[CH:10]=[C:9]([C:8](=[O:43])[CH2:7][CH2:6][CH2:5][C:4]([OH:44])=[O:3])[CH:14]=[CH:13][C:12]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:32]=[CH:31][C:25]2[C:26](=[O:30])[CH2:27][CH2:28][O:29][C:24]=2[C:23]=1[CH2:33][CH2:34][CH3:35])([OH:40])=[O:39]
Reactant: CCCc1c(OCCCCCCc2ccc(C(=O)CCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCCc2ccc(C(=O)CCCC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 19.3 h
Yield: 76.6 %

Procedure:
To a mixture of 0.442 g (0.73 mmol) of 4-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]-3-(3-ethoxy-3-oxopropyl)-δ-oxobenzenepentanoic acid ethyl ester from the preceding example, in 7 mL of tetrahydrofuran and 7 mL of water was added 91.7 mg (2.19 mmol) of lithium hydroxide monohydrate and the reaction was stirred at room temperature for 19.3 hr. After being acidified with 16 mL of 3N aqueous sulfuric acid, the mixture was worked-up with ethyl acetate in the usual manner. The crude product thus obtained was recrystallized from hexane-ethyl acetate to give 0.309 g (77%) of the title compound as a white solid, mp 136°-139° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>C(O)C.O>[CH2:17]([N:1]([CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:4]=1)[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1c(-c2ccccc2)sc2ccccc12
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(CN(Cc2ccccc2)c2c(-c3ccccc3)sc3ccccc23)cc1

Procedure:
Preparation of the starting material a solution of 15.0 g (67 mmol) of 3-amino-2-phenyl-benzo(b)thiophene and 7.8 g (74 mmol) of benzaldehyde freshly distilled in 50 milliliters of benzene is refluxed for 10 hours with a water trap. After cooling, it is diluted with benzene, the excess benzaldehyde is eliminated by stirring with a solution of sodium bisulphite, the organic phase is dried over Na2SO4 and evaporated: 3-benzylidenamino-2-phenyl-benzo(b)thiophene in the form of a crude oily product which crystallises when it is triturated with methanol: 19.0 g (91% of theory) of yellow crystals, mp 92°-93° C. (ethanol). 9.6 g (31 mmol) of this Schiff base and 12 g (0.32 mol) of NaBH4 in 300 milliliters of absolute ethanol are refluxed with stirring for 25 hours. The cooled reaction mixture is diluted in water and extracted with ether. By evaporating the organic phase dried over K2CO3, the 3-benzylamino-2-phenyl-benzo(b)thiophene is obtained in the form of a crude oily product which crystallises when it is triturated with methanol. 9.0 g (92% of theory), colourless crystals, mp 52°-53° C. (methanol).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)S(OC[C:33]([F:41])([F:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)(=O)=O>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:33]([F:41])([F:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=S(=O)(OCC(F)(F)c1ccccn1)C(F)(F)F
Product: Cl
Product: FC(F)(CSc1c(Cl)ccc2c1CCNCC2)c1ccccn1
Yield: 66 %

Procedure:
Example 647 may be prepared essentially as described in Example 646 using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2,2-difluoro-2-pyridin-2-yl-ethyl trifluoromethanesulfonate (prepared by following the procedure described in J. Med. Chem. 2003, 46, 461-473) (66% yield, MS (ES+) m/z 355 (M+H)+).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=1.CCN(C(C)C)C(C)C.O=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]1([CH3:24])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=1
Reactant: Cc1ccc(-c2nc3c(nc2-c2cccc(C)c2)CCCN3)cc1
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3cccc(C)c3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-m-Tolyl-3-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate FB)(61 mg, 0.193 mmol) in dry DCE (1 ml) at RT was treated with DIPEA (0.037 ml, 0.213 mmol) followed by ethyl 7-oxoheptanoate (66.6 mg, 0.387 mmol). The reaction mixture was stirred at RT for 10 minutes and sodium triacetoxyborohydride (205 mg, 0.967 mmol) was added. The resulting mixture was stirred at 60° C. overnight. After cooling to RT, the mixture was slowly added to water (50 ml) and extracted with DCM (3×). The combined organic extracts were passed through a phase separating column and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-5% EtOAc/iso-hexane to afford the title compound; LCMS Rt 1.61 mins MS m/z 473.4 [M+H]+; Method 2minLC_v003
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[CH2:13]([O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)C>CN(C=O)C>[CH3:13][O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:3][C:4]1=[O:12]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CCOC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)oc2ccccc21

Procedure:
The product is produced as described in example 1 from 3.0 g. of NaH (80% suspension in mineral oil), 13.5 g. of benzoxazolin-2-one, 200 cc. of DMF, 23.7 g. of 8-bromocaprylic acid ethyl ester and 3.0 g. of NaJ. Eluant in chromatographic purification: hexane/ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19]C)=[O:18])[C@@H:14]([NH:21][C:22](=[O:40])[CH:23]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[NH:24]C(OC(C)(C)C)=O)[C@H:12]1[OH:13].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(OCC)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([OH:19])=[O:18])[C@@H:14]([NH:21][C:22](=[O:40])[CH:23]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[NH2:24])[C@H:12]1[OH:13]
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: COc1ccccc1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)C(N)Cc2ccc(Cl)cc2)[C@H]1O
Yield: 68.2 %

Procedure:
A mixture of methyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-β-(4-chlorophenyl)-D,L-alanylamino]-β-D-ribofuranuronate (150 mg) prepared in Example 64 and anisol (0.3 ml) was stirred in an ice-bath, and trifluoroacetic acid (3 ml) was added. After stirring for 1 hour in an ice-bath, diethyl ether was added to the mixture. The resulting precipitates were collected by filtration, added to 1N sodium hydroxide (3 ml), and stirred for 30 minutes in an ice-bath. The reaction mixture was neutralized with 1N hydrochloric acid, subjected to column chromatography on a non-ionic adsorption resin "HP-20" (trade mark, Mitsubishi Chemical Industries Ltd.) (30 ml). After the column was washed with water, the elution was carried out with 50% aqueous methanol. The eluate was evaporated to remove methanol under reduced pressure and lyophilized to give 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[β-(4-chlorophenyl)-D,L-alanylamino]-β-D-ribofuranuronic acid (82 mg), mp. 170°-178° C. (dec.).
Reaction SMILES: Cl.[C:2]1([C:8]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:18][C:19](=O)/[C:20](/[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:21](\O)/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(OC(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C)(C)C>>[C:25]([O:24][C:22]([C:21]1[C:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:19]([OH:18])[N:16]=[C:14]([CH2:13][C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Reactant: N=C(N)CC1(c2ccccc2)CCCC1
Agent: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 51.8 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (27-01) (4.5 g, 51.8%) was synthesized from 2-(1-phenyl-cyclopentyl)-acetamidine HCl salt (26-01) (4.5 g, 18.86 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (10.2 g, 33.41 mmol) as a yellow solid following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-01).