Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH3:20])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]1.S(=O)(=O)(O)O.[N+:26]([O-])([O-:28])=[O:27].[Na+]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[C@:9]1([CH3:20])[CH2:14][C@@H:13]([C:15]([F:18])([F:16])[F:17])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: O=[N+]([O-])[O-]
Reactant: C[C@@]1(c2cccc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: C[C@@]1(c2cc([N+](=O)[O-])cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
To a cooled (ice bath) solution of (4S,6S)-4-(2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (4.94 g, 16.79 mmol) in sulfuric acid (20 ml, 375 mmol) was added sodium nitrate (1.855 g, 21.83 mmol) in one portion. After stirring for 15 min, ice bath was removed, and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water containing potassium carbonate (18g). The resulting suspension was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (10-60% EtOAc/hexane) to afford (4S,6S)-4-(2,3-difluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (5.6 g, 16.51 mmol, 98% yield) as light yellow solid in 91% pure. MS m/z=340.1 [M+H]+. Calculated for C12H10F5N3O3: 339.2
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH2:23].CO>ClCCl>[CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[N:23]([CH3:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(C(O)C(F)(F)F)occ1OCc1ccccc1
Reactant: CN
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(OCc2ccccc2)c(=O)cc1C(O)C(F)(F)F
Reaction time: 1 h
Yield: 77 %

Procedure:
In each of four parallel synthesis tubes equipped with a magnetic stir bar was placed 5-benzyloxy-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyran-4-one (0.90 g, 3.0 mmol), and a 2M methylamine solution in MeOH (5.5 mL, 11 mmol). The resulting solution was heated to reflux. The reaction was completed in 60 min. The solutions from the four reaction tubes were combined, and evaporated to dryness to give a semi solid mixture. The mixture was taken up in dichloromethane (15 mL) to give a thick solution. On standing, a solid product precipitated out to give the first crop of the title compound (2.90 g, 77% yield, HPLC Method 1 (Example 24); RT=13.0 min, HPLC purity (peak percent area): 99.5% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 7.64 (s, 1H), 7.37 (m, 5H), 6.49 (s, 1H), 5.38 (q, J=6.5 Hz, 1H), 4.97 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:33]1[C:45]2[NH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]=2[C:36]([O:46][CH2:47][CH:48]([OH:57])[CH2:49][NH:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:35][CH:34]=1>CN(C=O)C.C(Cl)Cl>[CH:33]1[C:45]2[NH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]=2[C:36]([O:46][CH2:47][CH:48]([OH:57])[CH2:49][NH:50][CH:51]2[CH2:52][CH2:53][N:54]([C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[CH2:55][CH2:56]2)=[CH:35][CH:34]=1
Reactant: OC(CNC1CCNCC1)COc1cccc2[nH]c3ccccc3c12
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])o1)N1CCC(NCC(O)COc2cccc3[nH]c4ccccc4c23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32 %

Procedure:
To a solution of 5-Nitrofuroic acid (0.14 g, 0.88 mmol) in DMF (6 mL) was added TEA (0.17 mL, 1.2 mmol), EDCI (0.2 g, 1.0 mmol), HOBt (0.031 g, 0.23 mmol), followed by 1-(9H-carbazol-4-yloxy)-3-(piperidin-4-ylamino)propan-2-ol (0.2 g, 0.6 mmol, prepared by following the procedure described in step 11, example 64). The reaction was stirred at room temperature for 12 hours and was diluted with DCM (25 mL), washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4, concentrated and purified by silica gel column chromatography using DCM/MeOH (9.5:0.5) to afford the title compound as red colored paste (45 mg, 32% yield). 1H NMR (400 MHz, DMSO): δ 1.20-1.80 (m, 3H), 1.90-2.30 (m, 2H), 2.50-3.60 (m, 6H), 4.00-4.60 (m, 3H), 6.72 (d, 1H, J=8.0 Hz), 6.90-7.60 (m, 6H), 7.77 (d, 1H, J=3.6 Hz), 8.22 (d, 1H, J=8.0 Hz), and 11.30 (s, 1H). MS m/z: 478.1 (M+).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH:28]3[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]3)=[CH:24][NH:25]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH:28]3[CH2:33][CH2:32][CH:31]([N:4]4[CH2:5][CH2:6][CH2:7][N:1]([C:8]5[CH:9]=[CH:10][CH:11]=[C:12]6[C:17]=5[N:16]=[CH:15][CH:14]=[CH:13]6)[CH2:2][CH2:3]4)[CH2:30][CH2:29]3)=[CH:24][NH:25]2)=[CH:21][CH:20]=1
Reactant: c1cnc2c(N3CCCNCC3)cccc2c1
Reactant: O=C1CCC(c2c[nH]c3cc(F)ccc23)CC1
Product: Fc1ccc2c(C3CCC(N4CCCN(c5cccc6cccnc56)CC4)CC3)c[nH]c2c1
Yield: 89 %

Procedure:
The title compound was prepared according to Example 3, Step 4 except that 8-[1,4]diazepan-1-yl-quinoline was used instead of 1-(2-methoxy-phenyl)-[1,4]diazepane and 4-(6-fluoro-1H-indol-3-yl)-cyclohexanone was used in place of 4-(5-fluoro-1H-3-indolyl)-cyclohexanone. Yield: 89%; MS (ES) m/z (relative intensity): 443 (M++H, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a clean, dry 100 mL round bottom flask is added methyl 3-hydroxy-5-nitrobenzoate (240a, 0.4 g, 2 mmole, 1 eq), orthofluorobenzyl bromide (0.57 g, 3 mmole, 1.5 eq), potassium carbonate (0.56 g, 4 mmole, 2 eq), and DMF (3 mL). The reaction mixture was stirred at room temperature for 18 h and quenched with water and ethyl acetate. The product was extracted into the organic layer, dried over magnesium sulfate, filtered and evaporated. A white solid was obtained (0.49 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.59 (dt, 1H, J=1.8, 8.0 Hz), 7.42 (m, 1H), 7.24 (dt, 1H, J=1.0, 8.0 Hz), 7.22 (dt, 1H, J=1.3, 8.0 Hz), 5.33 (s, 2H), 3.98 (s, 3H). Calc'd for C15H12FNO5; m/z (M+H+)=306; found 306.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=3)[S:4][C:3]=1[C:19]([NH2:21])=[O:20].[N:22]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:18][O:17][C:9]1[C:10]([O:15][CH3:16])=[CH:11][C:12]2[CH:13]=[C:14]3[C:2]4[N:1]=[N:22][NH:21][C:19](=[O:20])[C:3]=4[S:4][C:5]3=[N:6][C:7]=2[CH:8]=1
Reactant: O=N[O-]
Reactant: COc1cc2cc3c(N)c(C(N)=O)sc3nc2cc1OC
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2cc3c(nc2cc1OC)sc1c(=O)[nH]nnc13
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.0 g of 3-amino-6,7-dimethoxythieno[2,3-b]quinoline-2-carboxamide in 1.5 liters of glacial acetic acid was added dropwise a solution of 4.0 g of sodium nitrite in 20 ml of water. The resulting mixture was stirred at room temperature for 16 hours. The solvent was then evaporated from the reaction mixture under reduced pressure to concentrate it to a volume of 300 ml. The solid which formed was separated by filtration to give 8,9-dimethoxy-1,2,3-triazino[4',5':4,5]thieno[2,3-b]quinolin-4(3H)-one. A small portion of this product was washed with hot tetrahydrofuran to give an off-white solid melting at greater than 230° C. with decomposition. The product obtained has the following structural formula ##STR3##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>O.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[Cl:8][C:6]1[CH:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=[C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:12])[CH:18]=2)[CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Clc1cc(Cl)nc(C2CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: Clc1cccc(-c2cc(Cl)cc(C3CC3)n2)c1
Temperature: 90 °C
Reaction time: 23 h
Yield: 19.8 %

Procedure:
A 250-mL round bottomed flask was charged with 2,4-dichloro-6-cyclopropylpyridine (1.08 g, 5.74 mmol), (3-chlorophenyl)boronic acid (0.99 g, 6.32 mmol), tetrakis(triphenylphosphine)palladium(0) (0.332 g, 0.28 mmol), and Cs2CO3 (5.61 g, 17.2 mmol). Toluene (40 ml), EtOH (10 ml) and water (20 ml) were added. The resulting mixture was stirred under Ar at 90° C. for 23 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and dichloromethane (50 mL). The mixture was filtered through celite washing solids with dichloromethane. The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organic extract was washed with saturated sodium chloride (25 mL) then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/dichloromethane (100:0 to 0:100) as eluent to afford the title compound (0.30 g, 20%) as a colorless oil. MW=264.15. 1H NMR (CDCl3, 500 MHz) δ 7.98-7.96 (m, 1H), 7.85-7.80 (m, 1H), 7.45 (d, J=1.5 Hz, 1H), 7.39-7.35 (m, 2H), 7.12 (d, J=1.5 Hz, 1H), 2.18-2.01 (m, 1H), 1.18-1.12 (m, 2H), 1.06-1.00 (m, 2H).
Reaction SMILES: C(B(CC)CC)C.C(B(CC)OC)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([CH:46]([CH3:48])[CH3:47])[N:25](/[CH:34]=[CH:35]/[C@@H:36]([OH:45])[CH2:37][C:38](=[O:44])[CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:18][CH:17]=1.[BH4-].[Na+]>C(OCC)(=O)C.CO.C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([CH:46]([CH3:48])[CH3:47])[N:25](/[CH:34]=[CH:35]/[C@@H:36]([OH:45])[CH2:37][C@@H:38]([OH:44])[CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:26]=2[C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)CC(=O)C[C@H](O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Agent: CCB(CC)CC
Agent: CCB(CC)OC
Agent: [BH4-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C[C@H](O)C[C@H](O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A mixture of dry THF (4 ml) and dry methanol (1 ml) under nitrogen at room temperature was treated with a solution of triethylborane (1.0M in THF, 0.6 ml). After 1 h, the mixture was cooled to -78°, and a portion of this diethyl methoxyborane solution (1.93 ml) was added to methyl (5S,E)-7-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-5-hydroxy-3-oxo-6-heptenoate (73.8 mg) under magnetic stirring. The homogeneous solution was stirred for 1 h, then treated with powdered sodium borohydride (98%, 6.4 mg) at -78°. After 4.5 h, the reaction mixture was diluted with ethyl acetate, quenched with saturated aqueous ammonium chloride solution and allowed to warm to room temperature overnight. The organic solution was separated and the aqueous solution washed with ether (3×). The combined organic solutions were dried and evaporated. The residue was azeotroped with methanol (3×) to give a brown gum. This gum was subjected to preparative t.l.c. eluting with System A (3:2), to give the title compound (36.1 mg) as a brown gum, [α]D20 +5.38° (c 1.86, ethyl acetate), δ(CDCl3) 1.40 (d, J 7 Hz, 6H, --CH(CH3)2), 1.4-1.8 (m, 2H, CH(OH)CH2CH(OH)), 2.44 (d, J 5 Hz, 2H, CH2CO2CH3), 3.13 (septet, J 7 Hz, 1H, --CH(CH3)2), 3.73 (s, 3H, OCH3), 3.85 (broad s, 2H, CH(OH)CH2CH(OH)), 4.15 (m, 1H, CH(OH)CH2CO2CH3), 4.42 (m, 1H, =CHCH(OH)CH2), 5.31 (dd, J 15 and 5 Hz, 1H, NCH=CH--), 6.66 (dd, J 15 and 2 Hz, 1H, NCH=CH--), 6.90 (t, J 9 Hz, 2H, C-3 and C-5 protons of 4-(4-fluorophenyl)), 7.09 (t, J 9 Hz, 2H, C-3 and C-5 protons of 5-(4-fluorophenyl)), 7.23 and 7.39 (2 dd, J 9 and 6 Hz, 4H, C-2 and C-6 protons of 4-fluorophenyls).
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[Br:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH:10]=[CH:11][C:12]([OH:14])=[O:13]>CO>[Br:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH:10]=[CH:11][C:12]([O:14][CH3:1])=[O:13]
Reactant: O=C(O)C=Cc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)C=Cc1cccc(Br)c1
Reaction time: 4 h

Procedure:
Trimethylsilyl chloride (5.6 ml) was added dropwise to a stirred solution of m-bromocinnamic acid (5.0 g, 22 mmol) in methanol (110 ml). After 4 h, the mixture was evaporated to give product as a white solid, M+ 242; 360 MHz 1H n.m.r (CDCl3) 7.67 (1H, s), 7.60 (1H, d, J 16 Hz), 7.50 (1H, d, J 7.9 Hz), 7.43 (1H, d, J 7.9 Hz), 7.26 (1H, d, J 15.6 Hz), 6.43 (1H, d, J 16.1 Hz), 3.81 (3H, s).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:45]=[CH:44][C:39]([C:40]([NH:42][CH3:43])=[O:41])=[CH:38][C:37]=1[O:46][CH3:47].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:30]1([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]([C:15](=[O:16])[NH:17][CH3:18])=[CH:13][CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:45]=[CH:44][C:39]([C:40]([NH:42][CH3:43])=[O:41])=[CH:38][C:37]=3[O:46][CH3:47])[N:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCCC4)c23)cc1
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Nc4ccc(C(=O)NC)cc4OC)nc(OC4CCCC4)c23)cc1
Temperature: 110 °C
Yield: 67.1 %

Procedure:
4-(2-Chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide 1 equiv), 4-amino-3-methoxy-N-methylbenzamide (1.2 equiv), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (binap) (0.2 equiv), cesium carbonate (5 equiv) and palladium(II) acetate (0.1 equiv) were combined in a sealed tube along with 1,4-dioxane (0.14 M). Nitrogen gas was bubbled through the reaction mixture for 2 min, the reaction vessel was sealed and heated in an oil bath at 110° C. for 4 h. The solvent was removed under reduced pressure and the crude material was stirred in DCM. The solids were filtered off and the filtrate was loaded directly onto a silica gel column. The product was purified by silica gel chromatography (Biotage, 20-100% ethyl acetate in hexane over 400 mL, 100% ethyl acetate for 200 mL, 0-10% MeOH in ethyl acetate over 600 mL then held at 10% MeOH in ethyl acetate for 500 mL). The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (67.1% yield) as a tan solid. MS (ESI) m/z 645.6 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH3:10])[N:5]=[C:4]([NH2:11])[CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: C/C=C/c1cc(C)cc(N)n1
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(C)cc(N)n1
Reaction time: 16 h
Yield: 56.5 %

Procedure:
To a solution of (E)-4-methyl-6-(prop-1-enyl)pyridin-2-amine (235 mg, 1.59 mmol) in ethanol (5.29 mL) was added 10% palladium on carbon (169 mg, 159 μmol). The reaction mixture was evacuated and back filled with H2 three times. The mixture was stirred under an atmosphere of hydrogen (balloon at 1 atm) for 16 h, then filtered through a pad of celite. The filtrate was collected, concentrated in vacuo and purified by chromatography (silica, 30 to 60% ethyl acetate in hexanes gradient) to give 4-methyl-6-propylpyridin-2-amine (135 mg, 899 μmol, 57%) as a colorless oil. MS (EI/CI) m/z: 150.8 [M+H].
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[C:5]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6].[OH-].[K+].C([BH3-])#N.[Na+]>CO>[C:5]([N:10]1[CH2:15][CH2:14][CH:13]([NH:4][CH2:2][CH3:3])[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Reactant: CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Product: CCNC1CCN(C(=O)OCC)CC1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ethylamine hydrochloride (5 g, 61.34 mmol) was added to the stirred solution of 1-carbethoxy-3-methyl-4-piperidone (3.5 g, 18.9 mmol) obtained as described in Preparation 1, in methanol (30 ml) followed by 3.43 g (61.34 mmol) KOH. Stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (1.4 g, 22.22 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 16 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and, concentrated to dryness to give 1-carbethoxy-4-ethylamino-3-methylpiperidine. Yield 2.3 g (54%), C11H22N2O2, m/z 215 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH3:11][NH:12][C:13](=[O:30])[C@H:14]1[O:22][CH:17](OC(=O)C)[C@H:16]([O:23][C:24](=[O:26])[CH3:25])[C@@H:15]1[N:27]=[N+:28]=[N-:29].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C[Si](C)(C)N[Si](C)(C)C.ClC(Cl)C>[CH3:11][NH:12][C:13]([C@@H:14]1[C@@H:15]([N:27]=[N+:28]=[N-:29])[C@@H:16]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:22]1)=[O:30]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CNC(=O)[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Temperature: 110 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
6-Chloropurine (20.4 g, 0.132 mol) was suspended in hexamethyl disilazane (165 mL) and heated at 110° C. After 2 h, the now homogeneous mixture was concentrated and the solid residue reconcentrated from toluene 2× and placed under high vac for 1 hour. The resulting solid was combined with 1,2-bis-O-acetyl-3-azido-3-deoxy-D-ribofuranuronic acid methyl amide (12.7 g, 0.044 mol) and dissolved in anhydrous dichloroethane (350 mL). Powdered 4A molecular sieves (15 g) were added and the mixture stirred for 15 minutes. TMSOTf (16.0 mL, 0.088 mol) was added and the reaction was then heated to 60° C. for two hours, cooled and quenched by the careful addition of saturated sodium bicarbonate solution (200 mL). Ethyl acetate (350 mL) was added and the mixture was filtered through sintered glass. The filtrate was extracted with ethyl acetate (3×) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (15% then 20% acetone/dichloromethane) to afford the title compound (10.6 g) as an off-white foam. MS 381 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.8 (s, 1H); 8.2 (s, 1H); 7.6 (bs, 1H); 6.13 (d, 1H, J=7.0 Hz); 5.87 (dd, 1H, J=7.0, 5.6 Hz); 4.85 (dd, 1H, J=5.6, 3.0 Hz); 4.58 (d, 1H, J=3.0 Hz); 2.9 (d, 1H, J=4.9 Hz); 2.11 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[CH:18]([C:17]1[CH:20]=[CH:21][C:14]([O:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[CH:15][CH:16]=1)=[O:19]
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CN(CCOc1ccc(C=O)cc1)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 52 %

Procedure:
A solution of N-(2-hydroxyethyl)-N-methylcarbamic acid, 1,1-dimethylethyl ester (7.05 g, 40.2 mmol; W. S. Saari and all, J. Med. Chem. 33, 97 (1990)), 4-hydroxybenzaldehyde (3.75 g, 30.7 mmol) and triphenylphosphine (10.57 g, 40.3 mmol) in dry benzene (120 ml) was cooled to 15° C. and treated with diisopropyl azodicarboxylate (8.15 g, 40.3 mmol) in dry benzene (20 ml) added dropwise over 20 min. After 16 h at 22° C., and chromatography on silica gel (elution toluene-ethyl acetate 9:1-8:2) gave 4.40 g (52%) of the title material as white cubes: mp 62-65° C. (ether-hexane).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].CN.[CH2:17]([N:19](CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:19][CH3:17])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1NC

Procedure:
4-Methylamino-2-methylsulfanylpyrimidine-5-carboxylic acid ethyl ester was prepared from 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester and methylamine in tetrahydrofuran (THF) under basic conditions with triethylamine at temperatures between 5° C. and room temperature (RT).
Reaction SMILES: C1C2C(COC([N:18]3[C@@H:23]([CH:24]([OH:26])[CH3:25])[CH2:22][O:21][CH2:20][C@H:19]3[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>C(#N)C.C1(C)C=CC=CC=1>[F:34][C:29]1[CH:28]=[C:27]([C@H:19]2[NH:18][C@@H:23]([CH:24]([OH:26])[CH3:25])[CH2:22][O:21][CH2:20]2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CC(O)[C@H]1COC[C@@H](c2ccc(F)c(F)c2)N1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(O)[C@H]1COC[C@@H](c2ccc(F)c(F)c2)N1
Yield: 85.4 %

Procedure:
To a solution of (3R,5R)-3-(3,4-difluorophenyl)-5-(1-hydroxyethyl)morpholine-4-carboxylic acid 9H-fluorene-9-ylmethyl ester (950 mg) in acetonitrile (16 mL) was added diethylamine (4 mL), and the resultant solution was stirred for 1 hour at room temperature. The reaction solution was then diluted with toluene (20 mL), and solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate 4/1→1/1), to thereby obtain the titled compound (424 mg). The physical properties of this crude product were as follows.