Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C>[Pd].C1(C)C=CC=CC=1.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:13])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: COc1ccc(I)cc1
Agent: [Pd]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 4.68 g (20 mmol) of p-iodoanisole, 4.05 g (22 mmol) of 2-ethylhexyl acrylate, 2.22 g (22 mmol) of triethylamine, 1.32 g (22 mmol) of acetic add and 15 mg of palladium of charcoal (5%) is stirred at 150° C. After one hour it is established by gas chromatography that the reaction has been completed. The mixture is then treated at about 80° C. with water and toluene and the catalyst is filtered off. The organic phase is washed in sequence with 2N hydrochloric acid and water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. After distillation there is obtained pure 2-ethylhexyl p-methoxycinnamate, b.p. about 185° C./0.3 Torr. The yield is 92% of theory. 1H-NMR (CDCl3, 200 MHz): 0.86-0.98 ppm (m, 6H), 1.25-1.72 ppm (m, 9H), 3.84 ppm (s, 3H), 4.11 ppm (d, 6 Hz, 2H), 6.32 ppm (d, 15.5 Hz, 1H), 6.85-6.95 ppm (duplettoid m, 1H), 7.44-7.54 ppm (duplettoid m, 1H), 7.64 ppm (d, 15.5 HZ, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[Br:16]Br.O>O1CCOCC1>[Br:16][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc(Cl)cc(NS(C)(=O)=O)c1
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)Nc1cc(Cl)cc(C(=O)CBr)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
N-(3-acetyl-5-chlorophenyl)methanesulfonamide (500 mg) was dissolved in dioxane (10 mL). The temperature was maintained at 50° C. and bromine (0.11 mL) was added. After stirring for 30 minutes, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with water (50 mL) twice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (1:2 ethyl acetate/hexane) to yield N-(3-bromoacetyl-5-chlorophenyl)methanesulfonamide (600 mg) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[S:11][CH:12]=2)=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[S:11][C:12]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: O=C1CCCCN1c1nc(-c2ccc(Cl)cc2)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ccc(-c2sc(N3CCCCC3=O)nc2-c2ccc(Cl)cc2)cc1
Temperature: 150 °C
Yield: 32.6 %

Procedure:
To a solution of 1-(4-(4-chlorophenyl)thiazol-2-yl)piperidin-2-one (Step 2 of compound 10, 0.5 g. 1.71 mmol) in dimethyl acetamide (5 ml) were added 4-bromobenzenesulfonamide (0.48 g, 2.05 mmol) and potassium acetate (0.42 g, 4.27 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To this was added palladium(II) acetate (0.02 g, 0.08 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 150° C. for 15 hr under stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml), reaction mixture was washed with water (2×10 ml), dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product; which was purified by preparative HPLC to obtain the title compound (0.25 g, 32.7%). MS: m/z 450 (M+1).
Reaction SMILES: C(OC([N:6]1[CH2:12][CH:11]([NH2:13])[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=O)C.[BrH:25]>C(O)(=O)C>[BrH:25].[BrH:25].[NH2:13][CH:11]1[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7][NH:6][CH2:12]1
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(N)C1
Agent: Br
Solvent: CC(=O)O
Product: NC1CNCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 125.1 %

Procedure:
To a solution of 9.70 g (23.59 mmol) of (+/−)-9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester (step 1.4) dissolved in 118 mL of glacial acetic acid was added 41.38 mL (235.86 mmol) of hydrobromic acid (33 wt % solution in glacial acetic acid). The resulting mixture was stirred at 90° C. for 16 hours, cooled and evaporated to dryness. Toluene was added to the residue and evaporated. Ethanol was added to the residue and evaporated. The crude was triturated with diethyl ether and filtered to afford 12.40 g of the product as a brown powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15].C(N(CC)CC)C.C(Cl)(Cl)Cl>O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccccc1C(=O)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccccc1C(=O)c1ccncc1)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
4-Fluorobenzoyl chloride (78.0 mg, 0.55 mmol) was added to 4-(2-aminobenzoyl)pyridine (12) (100 mg, 0.50 mmol), triethylamine (0.35 mL, 2.52 mL), and chloroform (5.0 mL) at 23° C. under argon. After 24 h at 23° C., the reaction was poured into water (50 mL), extracted with ethyl acetate (3×50 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate: methylene chloride 1:1) to afford 4-(2-(4-fluoro-N-benzoylamino)benzoyl) pyridine (14): Mass Spectrum (CI) 321 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: NCCCN1CCCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NCCCN2CCCC2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 24 h

Procedure:
1 g (5.884 mmol) 4-fluoro-2-methoxy-1-nitro-benzene, 975 mg (7.369 mmol) 1-(3-aminopropyl)pyrrolidine and 1.5 ml (8.765 mmol) diisopropyethylamine are dissolved in 5 ml dioxane and stirred for 24 h at 95° C. The solvents are eliminated in vacuo and the crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 15% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution has been added.
Reaction SMILES: [C:1]([O:5]C)(=[O:4])C=C.[CH3:7][CH:8](O)CCCCCC.ON1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=O.O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(#N)C>[CH2:26]([C:19]1([CH3:18])[O:5][C:1](=[O:4])[CH:21]([OH:22])[CH2:20]1)[CH2:25][CH2:24][CH2:23][CH2:7][CH3:8]
Reactant: C=CC(=O)OC
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCCCCC(C)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CC#N
Product: CCCCCCC1(C)CC(O)C(=O)O1
Yield: 74 %

Procedure:
A mixture of 3 mmol of methyl acrylate, 15 mmol of 2-octanol, 0.6 mmol of N-hydroxyphthalimide, 0.003 mmol of cobalt(II) acetate, and 0.03 mmol of acetylacetonatocobalt(III), and 1 ml of acetonitrile was stirred at 50° C. in an oxygen atmosphere (1 atm) for 8 hours. A reaction mixture was subjected to column chromatography on a silica gel to yield γ-hexyl-α-hydroxy-γ-methyl-γ-butyrolactone in a yield of 74%.
Reaction SMILES: C([C:3]1[C:11]([NH2:12])=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])C.[C:13](Cl)(=[O:15])[CH3:14].N1C=CC=[CH:19][CH:18]=1>>[C:13]([NH:12][C:11]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH2:18][CH3:19])=[O:6])(=[O:15])[CH3:14]
Reactant: c1ccncc1
Reactant: CC(=O)Cl
Reactant: CCc1c(C(=O)O)ccnc1N
Product: CCOC(=O)c1ccnc(NC(C)=O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-(2-acetamido)-pyridyl))-propionate: A solution of 2-chloroisonicotinic acid (25.0 g, 0.16 mol) in 65 mL of concentrated ammonium hydroxide was warmed to 205 Celsius in a steel bomb for 72 h. After cooling to 23 C, the solution was acidified to a pH of 1 using 6N HCl and subsequently filtered to remove unreacted starting material. The solution was concentrated to one fourth the original volume (approx 200 mL) in vacuo, and carefully adjusted to a pH of 6 using 1 N NaOH. After storing the cloudy solution at 0 C for 20 h, the desired 2-aminoisonicotinic acid was filtered off. To a suspension of 2-aminoisonicotinic acid in ethanol (600 mL) was added 47.1 mL of 4 N anhydrous HCl in dioxane. After warming to achieve reflux for 20 h, an additional 47.1 mL of 4 N anhydrous HCl in dioxane was added and the reaction was warmed to -reflux for an additional 20 h. Concentration with a stream of nitrogen in the hood was followed by further concentration in vacuo, the remaining solid was diluted with saturated bicarbonate (200 mL), extracted with ethyl acetate (2×200 mL), dried (Na2SO4). After concentration in vacuo, the desired ethyl 2-aminoisonicotinate was obtained. To a solution of ethyl 2-aminoisonicotinic acid in pyridine (45 mL) at 0 C under an argon atmosphere was added acetyl chloride dropwise over 5 min. After 2 h at 0 C, the reaction was pored into over ice 300 g, extracted with ethyl acetate (2×300 mL), washed with water (2×100 ml) followed by brine (2×100 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by application of flash chromatography (step gradient ethyl acetate: hexane 1:4 then ethyl acetate: hexane 1:1) to afford ethyl 2-acetamidoisonicotinate.
Reaction SMILES: ClC1C(OCC2(C#N)CCCCC2)=C[C:5](F)=[C:6]([CH:14]=1)C(OC(C)(C)C)=O.Cl[C:27]1[C:28]([O:38][CH:39]2[CH2:46][CH2:45][C:42]3([CH2:44][CH2:43]3)[CH2:41][CH2:40]2)=[CH:29][C:30]([F:37])=[C:31]([CH:36]=1)[C:32]([O:34][CH3:35])=[O:33]>>[CH:14]1([C:27]2[C:28]([O:38][CH:39]3[CH2:46][CH2:45][C:42]4([CH2:44][CH2:43]4)[CH2:41][CH2:40]3)=[CH:29][C:30]([F:37])=[C:31]([CH:36]=2)[C:32]([O:34][CH3:35])=[O:33])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C#N)CCCCC2)cc1F
Reactant: COC(=O)c1cc(Cl)c(OC2CCC3(CC2)CC3)cc1F
Product: COC(=O)c1cc(C2CC2)c(OC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 374 Step 3 and making non-critical variations to replace tert-butyl 5-chloro-4-((1-cyanocyclohexyl)methoxy)-2-fluorobenzoate with methyl 5-chloro-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoate, the title compound was obtained as a colorless syrup (0.389 g, 72% yield): 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=8.5 Hz, 1H), 6.56 (d, J=13.0 Hz, 1H), 4.46-4.39 (m, 1H), 3.86 (s, 3H), 2.10-2.01 (m, 1H), 1.99-1.90 (m, 2H), 1.86-1.76 (m, 2H), 1.54-1.24 (m, 4H), 0.96-0.84 (m, 3H), 0.66-0.60 (m, 2H), 0.32-0.26 (m, 4H); MS (ES+) m/z 287.05 (M−31).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:31])[CH2:10][N:11]1[CH2:16][C@H:15]([CH3:17])[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)(=[O:20])=[O:19])[C@H:13]([CH3:30])[CH2:12]1.O.NN>C(O)C.[Pd]>[NH2:27][C:23]1[CH:22]=[C:21]([S:18]([N:14]2[C@@H:15]([CH3:17])[CH2:16][N:11]([CH2:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])=[O:31])[CH2:12][C@H:13]2[CH3:30])(=[O:19])=[O:20])[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc([N+](=O)[O-])c2)[C@@H](C)C1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(N)c2)[C@@H](C)C1
Reaction time: 1 h

Procedure:
To a stirred solution of the product of Example 56 (3.0 g) in ethanol (1500 ml) was added 5% palladium on charcoal (1.5 g) followed by dropwise addition of hydrazine hydrate (20 ml). The mixture was stirred for 1 hour, filtered through ‘hyflo’ and the filtrate was evaporated to dryness. The solid residue was crystallised from ethanol to give the title compound as a white solid. Yield 1.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)=[O:5].[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][CH:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH:8]=1)=[O:5]
Reactant: Nc1cccc(NC(=O)c2ccc(F)cc2Cl)c1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 218.1 %

Procedure:
Combine 2-chloro-4-fluoro-N-(3-aminophenyl)benzamide (Preparation 1, 200 mg, 0.756 mmol), 1-methylpiperidin-4-one (0.093 mL, 0.756 mmol), sodium triacetoxyborohydride (208 mg, 0.982 mmol), acetic acid (0.043 mL, 0.756 mmol) and dichloromethane (8 mL). Stir at room temperature overnight. Dilute with dichloromethane (5 mL) and wash twice with sodium hydroxide (10 mL 1N aq.). Combine the organic layers and wash with saturated aqueous NaCl (10 mL). Dry over magnesium sulfate, filter under reduced pressure and concentrate to dryness. Purify by flash chromatography on a Biotage® silica cartridge eluting with a 20/1 mixture of dichloromethane and 2N ammonia in methanol to give the free base of the title compound (239 mg, 87%). Dissolve the residue in diethyl ether and treat with ethereal hydrogen chloride. Triturate the resulting gum with ether to give the title compound as a white solid (31 mg): mp 180° C.; mass spectrum (free base, ion spray): m/z=362.1(M+1), 1H NMR (free base, CDCl3): 7.80–7.75 (m, 2H), 7.23 (bs, 1H), 7.19 (dd, J=2.4 Hz, 8.3 Hz, 1H), 7.13 (t, J=8.2 Hz, 1H), 7.08 (dd, J=2.4 Hz, 8.3 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.41 (dd, J=2.0 Hz, 8.3 Hz, 1H), 3.68 (bd, J=7.9 Hz, 1H), 3.36 (bs, 1H), 2.92–2.81 (bm, 2H), 2.35 (s, 3H), 2.82–2.17 (bm, 2H), 2.10 (bd, J=13.0 Hz, 2H), 1.64–1.51 (bm, 2H). Analysis calc'd for C19H23Cl3FN3O: C, 51.95; H, 5.39; N, 9.57. Found: C, 52.03; H, 5.46; N, 9.17.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH2:19])[N:13]=2)=[CH:6][C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:4][N:3]=1>ClCCl.CO>[NH2:19][C:14]1[CH:15]=[C:16]([CH3:18])[CH:17]=[C:12]([CH2:11][CH2:10][C:9]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH:6]=[C:7]3[N:8]=2)[N:13]=1
Reactant: Cc1cc(N)nc(CCC(=O)Nc2cc(-c3ccc(Cl)cc3)cnc2N)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N)nc(CCc2nc3cc(-c4ccc(Cl)cc4)cnc3[nH]2)c1
Yield: 17.5 %

Procedure:
36 mg of N-[2-amino-5-(4-chloro-phenyl)-pyridin-3-yl]-3-(6-amino-4-methyl-pyridin-2-yl)-propionamide (compound A9) are treated with 2 g polyphosphoric acid at 125° C. for 24 h. Subsequent workup according to the procedure described herein for example A6 yields 6 mg of the title compound as a viscous oil after chromatography (dichloromethane/methanol 8:1). ESI-MS: 364.4/366.4 (MH+, 100%/36%). TLC: Rf=0.30 (dichloromethane/methanol 8:1).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@@H:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]3[C@@H:18]([C:26](O)=[O:27])[O:17]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC1C=C[C:39]2[C:34](=CC=CC=2)[N:33]1C(OCC)=O)C.C(=[N:49]O)C>C(COC)OC>[CH3:24][C:22]1([CH3:25])[O:23][C@H:19]2[C@@H:18]([C:26]3[O:27][N:33]=[C:34]([CH3:39])[N:49]=3)[O:17][C@@H:16]([N:11]3[CH:10]=[N:9][C:8]4[C:12]3=[N:13][CH:14]=[N:15][C:7]=4[NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C@@H:20]2[O:21]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21
Reactant: CC=NO
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: COCCOC
Product: Cc1noc([C@H]2O[C@@H](n3cnc4c(NC5CCCC5)ncnc43)[C@@H]3OC(C)(C)O[C@H]32)n1
Temperature: 22 °C
Yield: 28.7 %

Procedure:
A mixture of (3aS,4S,6R,6aR)-6-(6-cyclopentylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (0.2 g), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (146 mg), acetaldoxime (76 mg) and dimethoxyethane (DME, 25 ml) was heated under reflux for 4 days and then cooled to 22° C. The mixture was concentrated in vacuo and ethyl acetate (40 ml) added to the residue. The resulting suspension was washed with 0.5M citric acid solution (3×20 ml) and the aqueous washings were extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water (20 ml) and brine (30 ml) and dried (MgSO4). After concentration in vacuo the residue was purified by chromatography on silica gel, eluting with ethyl acetate:cyclohexane (1:1), to give the title compound (63 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:23][CH2:24][CH2:25][OH:26])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:23][CH2:24][CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCO)c2cccc(F)c2F)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCOS(C)(=O)=O)c2cccc(F)c2F)C1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of (3R)-tert-butyl 3-((2,3-difluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate in dry CH2Cl2 (50 mL) was added Et3N (5.2 mL, 37.6 mmol) at −5-0° C. Then a solution of MsCl (1.3 g, 11.3 mmol) in dry CH2Cl2 (20 mL) was added dropwise at the same temperature. After addition, the reaction was allowed to gradually warm to rt. Upon completion of the reaction, 50 mL of water was added, the aqueous layer was extracted with CH2Cl2, the combined organic layers were washed with 10% citric acid, sat. NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give (3R)-tert-butyl 3-((2,3-difluorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (4.2 g, 99%), which was used in the next step without purification. 1H NMR (CDCl3, 400 MHz) δ 7.12 (m, 3H), 4.52 (q, 1H), 4.31 (m, 3H), 4.09 (t, 1H), 3.57 (m, 2H), 3.06 (d, 3H), 2.70 (m, 2H), 1.93 (m, 2H), 1.44 (d, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH:7]=O.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[NH:10][NH2:11]>>[CH2:14]([O:13][C:9](=[O:12])[NH:10][N:11]=[CH:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])[CH3:15]
Reactant: CCOC(=O)NN
Reactant: Cc1[nH]cnc1C=O
Product: CCOC(=O)NN=Cc1nc[nH]c1C

Procedure:
A mixture of 7.0 gm. of 5-methyl-4-imidazolecarboxaldehyde and 7.3 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 195°-203° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=C(C=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)N.[O:15]1C[C@@H:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[O-]S(C(F)(F)F)(=O)=O.[Li+].[C:32]([N:39]1[CH:43]=[CH:42]N=[CH:40]1)(N1C=CN=C1)=[O:33]>C(#N)C>[F:1][C:2]1[CH:3]=[C:43]([N:39]2[CH2:40][C@H:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:15][C:32]2=[O:33])[CH:42]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)[C@H]1CO1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CCOC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-fluoro-4-morpholinoaniline (J. Med. Chem. 1996, 39(3), 673-679, 0.796 g, 4.0 mmol), ethyl 2(R)-epoxypropanoate (0.696 g, 6.0 mmol) and lithium triflate (0.97 g, 6.2 mmol) in acetonitrile (12 mL) is stirred at 50-60° C. overnight. Solvent and excess epoxide is removed under reduced pressure, and the crude amino alcohol is redissolved in dry acetonitrile (40 mL) and 1,1′-carbonyldiimidazole (1.46 g, 9.0 mmol) is added. The mixture is stirred at ambient temperature overnight, and then the solvent is removed under reduced pressure. The residue is partitioned between ethyl acetate (70 mL) and 3% aqueous citric acid (100 mL), the layers are separated, and the organic phase is washed with 3% aqueous citric acid (3×100 mL), water and saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product mixture is then purified by silica gel chromatography, eluting with ethanol/methylene chloride (2/98), and the appropriate fractions are pooled and concentrated to give the title compound, MS (ESI+) for C16H19N2O5F m/z 339 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][OH:14])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[Br:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[N:20][CH:21]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:15][C:16]1[CH:17]=[N:18][C:19]([O:14][CH2:13][C:2]2([CH3:1])[O:6][C:5]3=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]3[CH2:3]2)=[N:20][CH:21]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(COc2ncc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
(2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)-methanol (0.10 g, 0.50 mmol), 5-bromo-2-chloropyrimidine (0.16 g, 0.82 mmol) and NaH (˜30 mg, 60% in mineral oil) were suspended in 2 mL DMF and stirred at r.t. for 2 hours. The resulting mixture was diluted with 150 mL EtOAc, washed with 100 mL NaHCO3 and 100 mL water. The aqueous layer was re-extracted with 100 mL EtOAc. The organic layer was washed with brine and dried over Na2SO4. The concentrated residue was purified by column chromatography (DCM/MeOH, 0 to 3%) to give the title compound (152 mg, 83%) as a white solid. APCI MS m/z 356.6, 358.6 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.77 (s, 2H), 8.14 (s, 1H), 4.61 (s, 2H), 4.41 (d, J=11.1 Hz, 1H), 4.20 (d, J=11.1 Hz, 1H), 1.70 (s, 3H).