Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[CH:22]=1)=[O:5]
Reactant: COc1cc(N)ccn1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (25 g, 110.3 mmol) in dichloromethane (125.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8 mL, 330.9 mmol) and dichloromethane (500.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)benzamide (33.6 g, 97.00%) as an off-white solid. ESI-MS m/z calc. 314.07. found 315.2 (M+1)+; Retention time: 1.44 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.12-8.07 (m, 2H), 8.07-7.98 (m, 1H), 7.65 (t, J=9.2 Hz, 1H), 7.24-7.19 (m, 2H), 3.85 (s, 3H) ppm.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:8][C:9]([CH3:13])=[N+:10]([O-:12])[CH:11]=1)([OH:3])=[O:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:17][O:2][C:1]([CH2:4][O:5][C:6]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:8][C:9]([CH3:13])=[N+:10]([O-:12])[CH:11]=1)=[O:3]
Reactant: Cc1cc([N+](=O)[O-])c(OCC(=O)O)c[n+]1[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 59.7 %

Procedure:
The carboxylic acid (c) (8.4 g) in DMF (100 ml) was treated with potassium carbonate (7.6 g) and iodomethane (2.8 ml) and stirred for 3 days. After evaporation of solvent, water (200 ml) was added and the solid filtered off and dried under vacuum to give the product (5.32 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19]CC=C)=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1.Cl[C:26]1[CH:31]=CC=C[C:27]=1Cl>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:31][CH:26]=[CH2:27])[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1
Reactant: C=CCOc1ccc2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1
Reactant: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc2oc(C(=O)c3ccc(OC)cc3)c(C)c12
Yield: 87 %

Procedure:
A mixture of 2-(p-methoxybenzoyl)-3-methyl-5-allyloxybenzofuran (1 gm, 3.10 mmole) in ortho dichlorobenzene (5 mL) was refluxed under nitrogen for a period of 5 hours. On cooling, the product crystallized. It was diluted with hexane, filtered, washed with hexane, and air-dried to yield 870 mg (87%) of 2-(p-methoxybenzoyl)-3-methyl-4-allyl-5-hydroxy-benzofuran, mp. 155°-158° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][CH3:9])/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: CSc1ccccc1I
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccccc3SC)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo-2-methylsulfanyl-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 2.31 (s, 3H), 3.90 (s, 3H), 5.00 (dd, 2H), 6.03 (d, 1H), 6.60-6.64 (m, 2H), 7.04 (t, 1H), 7.26-7.30 (m, 2H), 7.33-7.56 (m, 9H), 7.95 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C:19]2[NH:18][C:17](=[O:20])[CH:16]=[CH:15][C:14]3=[CH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][Cl:31])=[CH:26][CH:25]=4)[N:12]([C:13]=23)[CH2:11]1)C1C=CC=CC=1>C(Cl)Cl>[Cl:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[N:12]3[CH2:11][C@@H:10]([CH2:9][OH:8])[C:19]4[NH:18][C:17](=[O:20])[CH:16]=[CH:15][C:14]([C:13]=43)=[CH:21][N:22]=2)=[CH:25][CH:26]=1
Reactant: O=C1C=CC2=CN=C(c3ccc(CCl)cc3)N3C[C@@H](COCc4ccccc4)C(=C23)N1
Solvent: ClCCl
Product: O=C1C=CC2=CN=C(c3ccc(CCl)cc3)N3C[C@@H](CO)C(=C23)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of intermediate 238b (1.35 g, 3.12 mmol) in 75 mL of CH2Cl2 at 0° C., was added solid boron trichloride dimethylsulfide complex (2.75 g, 15.3 mmol) all at once. The reaction was stirred overnight, allowing to warm to room temperature. The reaction was quenched by addition to 400 mL of pH 7 phosphate buffer and 200 mL Et2O. After stirring overnight, the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated. The product was used without further purification. Obtained 680 mg (64%) of an off white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH:22]=[CH:23][CH3:24].[OH2:31]>O1CCOCC1>[OH2:4].[OH2:31].[ClH:1].[ClH:1].[CH2:21]([N:25]1[CH2:30][CH2:29][N:28]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:27][CH2:26]1)[CH:22]=[CH:23][CH3:24]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CC=CCN1CCNCC1
Solvent: C1COCCO1
Solvent: O
Product: CC=CCN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Product: Cl

Procedure:
8.62 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 8.7 gm of 1-(n-but-2-enyl)-piperazine (R1 =--CH2 --CH=CH--CH3) were refluxed in 100 ml of dioxane for 3 hours, and the reaction mixture was then evaporated in vacuo. The residue was purified on a silica gel column, and the obtained oily base was dissolved in 70 ml of hot isopropanol. The solution was acidified with hydrochloric acid, whereby the dihydrochloride crystallized out which was recrystallized from 94% ethanol. The obtained crystals included 2 mols of water of crystallization and melted at
Reaction SMILES: ClCCl.CO[C:6]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:9]2=[N:10][C:11](C)=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=1.B(Br)(Br)Br.[CH3:39][OH:40]>>[OH:40][CH2:39][C:6]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:9]2=[N:10][CH:11]=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=1
Reactant: CO
Reactant: COc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccnc2c1nc(CO)n2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
30 ml of a dichloromethane solution of 410 mg (1 mmol) of 2-methoxy-methyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl)-3H-imidazo[4.5-b]pyridine was stirred, cooled with ice. During this step, 10 ml (10 mmol) of dichloromethane solution of 1M boron tribromide was added little by little thereto dropwise. The mixture was further agitated at a room temperature for 12 hours. The reaction product mixture was cooled, while stirred. During this step, methanol was added little by little. The solvent was distilled out at a reduced pressure. The residue was mixed with water, neutralized with sodium bicarbonate, adjusted to a weak acidity with acetic acid and decanted to remove the water. The residue was mixed with methanol. The solvent was distilled out at a reduced pressure. The residue was treated with isopropylether for re-crystallization to obtain 330 mg of the intended compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C@@H:16]([C:22]([N:24]([CH:42]1[CH2:44][CH2:43]1)[CH2:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[N:37]1[CH:41]=[N:40][N:39]=[N:38]1)=[O:27])=[O:23])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O)(C)(C)C>C(Cl)Cl>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][C@H:16]([C:22]([N:24]([CH:42]1[CH2:44][CH2:43]1)[CH2:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[N:37]1[CH:41]=[N:40][N:39]=[N:38]1)=[O:27])=[O:23])[NH2:15]
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)NCc1cc(Cl)ccc1-n1cnnn1)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H](N)C(=O)N(CC(=O)NCc1cc(Cl)ccc1-n1cnnn1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (3 mL) was added to a solution of N-(tert-butoxycarbonyl)-4-methyl-D-leucyl-N1-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-N2-cyclopropylglycinamide (80 mg, 0.15 mmol) in CH2Cl2 (6 mL). The solution was stirred at room temperature for 30 min and the solvent was then removed in vacuo. The residue was taken up in DMF and purified by reverse phase HPLC. The product fractions were combined and reduced in vacuo and the residual oil was concentrated repeatedly from Et2O to give the title compound as a white foam. 1H NMR (500 MHz, CD3O): δ 9.52 (s, 1 H), 8.50 (m, 1 H), 7.68 (d, J=2.5 Hz, 1 H), 7.57 (dd, J=2.5, 8.5 Hz, 1 H), 7.50 (d, J=8.0 Hz, 1 H), 4.72 (dd, J=3.5, 8.5 Hz, 1 H), 4.28 (d, J=16.0 Hz, 1 H), 4.24 (d, J=15.5 Hz, 1 H), 4.10 (d, J=16.0 Hz, 1 H), 3.99 (d, J=16.0 Hz, 1 H), 2.91–2.86 (m, 1 H), 2.02 (dd, J=3.5, 15.5 Hz, 1 H), 1.70 (dd, J=8.5, 15.0 Hz, 1 H), 1.06 (s, 9 H), 1.03–0.86 (m, 4 H). HRMS (APCI, M+H): 434.2055 (found); 434.2066 (calculated).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN1C(=O)CCC1>[CH2:18]([O:25][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:11])[CH:5]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Clc1cc(OCc2ccccc2)cc(Cl)n1
Temperature: 90 °C

Procedure:
A mixture of 2,6-dichloro-4-nitropyridine (1.0 equiv.), potassium carbonate (2 equiv.) and benzyl alcohol (2.4 equiv.) in NMP (4 M) were heated to 90° C. for 2 h in the microwave. The mixture was partitioned between water and EtOAc. The organic phase was washed with brine and dried over sodium sulfate. The solution was concentrated and dried under vacuo to give crude 4-(benzyloxy)-2,6-dichloropyridine and was used in the next step without further purification. LCMS (m/z) (M+H)=254.0/256.0, Rt=1.05 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:15])=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][CH3:13])[CH2:8][C:7]2=[O:14].[CH2:16]([O:18][C:19](=[O:25])[C:20](OCC)=[O:21])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:25])[C:20]([NH:15][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:10]2[C:6]=1[C:7](=[O:14])[CH2:8][CH:9]2[CH2:11][CH2:12][CH3:13])=[O:21])[CH3:17]
Reactant: CCCC1CC(=O)c2c(N)ccc(C)c21
Reactant: CCOC(=O)C(=O)OCC
Product: CCCC1CC(=O)c2c(NC(=O)C(=O)OCC)ccc(C)c21
Temperature: 25 °C

Procedure:
A solution of 7.2 g of 7-methyl-3-oxo-1-propyl-4-indanylamine in 34 ml oxalic acid diethyl ester is boiled under reflux for 2 hours and then cooled to room temperature. The reaction mixture is then heated at 90°-100° at 11 mm Hg to remove the excess oxalic acid diethyl ester. The residue is chromatographed on 200 g silica gel to afford the pure title compound which is recrystallised from ether. M.pt. 84°-86°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C:10]23[C:16]([CH3:18])([CH3:17])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH4+]>CCO>[Cl:21][C:5]1[C:6]([NH:9][C:10]23[C:16]([CH3:17])([CH3:18])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)=[C:7]2[N:8]=[C:32]([C:31]3[CH:30]=[CH:29][C:28]([N:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)=[CH:35][CH:34]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: CC12CCC(Nc3c(Cl)cnc(N)c3N)(CC1=O)C2(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC12CCC(Nc3c(Cl)cnc4[nH]c(-c5ccc(N6CCOCC6)cc5)nc34)(CC1=O)C2(C)C
Temperature: 70 °C

Procedure:
4-(2,3-diamino-5-chloropyridin-4-ylamino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (10) (300 mg, 0.971 mmol), 4-morpholinobenzaldehyde (167 mg, 0.873 mmol) were taken in EtOH (15 ml) to which ammonium acetate (112 mg) was added and the reaction mixture was heated at 70° C. for 48 h. Crude LCMS showed the desired product along with trace of starting material. The reaction mixture was allowed to come to rt and the precipitated was filtered and washed well with ethanol to afford the desired product (466 mg, 23%) as a yellow solid. NMR: δ (1H, 400M Hz, DMSO-d6): 0.91 (3H, s), 0.92 (3H, s), 1.09 (3H, s), 1.40-1.50 (1H, m), 1.70-1.80 (2H, m), 2.40-2.60 (1H, m), 3.00-3.10 (1H, m), 3.20-3.30 (4H, m), 3.72-3.80 (5H, m), 5.37 (1H, s), 7.09 (2H, d, J=8.8 Hz), 7.99 (2H, d, J=8.8 Hz), 8.02 (1H, s), 13.15 (1H, s). LCMS (254 nm): [M+H]+ 480.20 (95.88%) HPLC: 95.55% (220 nm)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.[CH3:25][N:26](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:24]=[C:2]([C:25]#[N:26])[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([CH3:23])=[N:18]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2cc(C#N)ccc2OCC3)n(C(C)C)n1
Temperature: 150 °C

Procedure:
A microwave vial was charged with a solution of 10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.200 mg, 0.466 mmol) in 1.4 ml DMF. To this solution was added zinc cyanide (160 mg, 1.4 mmol). The reaction mixture was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and Bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (66 mg, 0.093 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 150° C. for 30 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water ×1, saline ×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 455. MS: (ESI+)=335.1
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:25]=[CH:24][C:14]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:13][C:11]1=[O:12].C(NC1C=CN([C@@H]2O[C@H](CO[C:46]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)([C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=3)[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[C@@H](O)C2)C(=O)N=1)(=O)C1C=CC=CC=1>>[CH3:62][O:61][C:58]1[CH:57]=[CH:56][C:55]([C:46]([O:9][CH2:8][C@H:5]2[O:4][C@@H:3]([N:10]3[CH:25]=[CH:24][C:14]([NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][C:11]3=[O:12])[C@@H:2]([F:1])[C@@H:6]2[OH:7])([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)=[CH:60][CH:59]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)n1)c1ccccc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
This compound is prepared from 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-N4 -benzoylcytosine by the same procedure used for the preparation of N4 -benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxycytidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC1C=C(C=CC=1)CNC(C1C2NC(C3C(=O)NC=CC=3NC[C@@H](O)C3C=CC=CC=3)=NC=2C=CC=1)=O>CN(C=O)C>[CH2:30]([NH:37][C:27]([C:26]1[C:20]2[NH:19][C:18]([C:12]3[C:13](=[O:17])[NH:14][CH:15]=[CH:16][C:11]=3[NH:10][CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:22][C:21]=2[CH:23]=[CH:24][CH:25]=1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(NCc1cccc(F)c1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12

Procedure:
2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid benzylamide was synthesized from 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid, benzylamine, DIEA, HATU and DMF using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid 3-fluoro-benzylamide yielding 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid benzylamide. LC/MS calcd for C28H24ClN5O2 (m/e) 497.0, obsd 498 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: C1COCCN1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(Br)cc(N2CCOCC2)c1F
Temperature: 90 °C
Yield: 76 %

Procedure:
A mixture of 5-bromo-1,2,3-trifluorobenzene (2.5 g, 11.8 mmol), morpholine (1.0 mL, 11.8 mmol), K2CO3 (1.6 g, 11.8 mmol) and DMSO (2 mL) in a sealed tube was heated up to 90° C. for 2.5 h. The reaction mixture was cooled to room temperature and diluted with water. The resulting colorless precipitate was filtered, washed with water, and dried in vacuo to afford 4-(5-bromo-2,3-difluorophenyl)morpholine in 76% yield. 1H NMR (CDCl3, 400 MHz) δ 6.91-6.87 (m, 1H), 6.75-6.72 (m, 1H), 3.80-3.78 (m, 4H), 3.04-3.02 (m, 4H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[C:13](Cl)(=[O:15])[CH3:14]>>[CH3:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([F:12])=[C:6]([Cl:5])[CH:11]=1)=[O:15]
Reactant: Fc1ccccc1Cl
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc(F)c(Cl)c1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
53.2 gm. (400 mmol) of aluminum chloride was carefully added in portions to a mixture of 26.2 gm (200 mmol) of 1-chloro-2-fluorobenzene and 31.2 gm of acetyl chloride at 50° C. After all the Lewis acid had been added, the reaction temperature was raised to 100° C. and maintained at that temperature for 3 hours. The hot reaction mixture was carefully poured onto ice and the resulting light-red oil twice extracted with ether. The combined ether extraacts were washed with saturated sodium chloride solution, dried and evaporated in vacuo to yield a crude brown oil. The oil was distilled to yield 26.47 gm of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C@H:4]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]([OH:14])[C@H:5]2[N:6]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C([O-])(O)=O.[Na+]>[OH:13][C@@H:8]1[C@@H:9]([CH2:11][OH:12])[O:10][C@H:4]2[C@H:5]([N:6]=[C:2]([NH:1][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:3]2)[C@H:7]1[OH:14]
Reactant: NC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1)c1ccccc1
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
A solution of (3aR,5R,6S,7R,7aR)-2-amino-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (110 mg, 0.50 mmol) in THF (20 mL) and saturated aqueous NaHCO3 (5 mL) was treated with benzoyl chloride (77 mg, 0.55 mmol) for 1 hour at 0° C. After filtration, the solution was concentrated under vacuum to give a residue, which was purified by Prep-HPLC with the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18,19*50 mm Sum; mobile phase, WATER with 0.03% NH4OH and CH3CN(10% CH3CN up to 45% in 10 min); Detector, UV 220 nm;] to give the title compound as a white solid (39.3 mg, 24%). (ES, m/z)[M+H]+324.9; 1H NMR (300 MHz, D2O) δ 7.83-7.85 (d, J=7.5 Hz, 2H), 7.49-7.54 (m, 1H), 7.36-7.42 (m, 2H), 6.13-6.15 (d, J=6.3 Hz, 1H), 3.97-4.02 (dd, J=6.3 Hz, 6.9 Hz, 1H), 3.89-3.93 (t, J=5.7 Hz, 1H), 3.45-3.73 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH3:12])[C:10]=1[Cl:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:20][C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])[N:8]=[C:9]([CH3:12])[C:10]=1[Cl:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]nc(C)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)c1c(Cl)c(C)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 6.94-7.1 (m, 2H), 6.84-6.88 (dd, 2H), 5.04 (s, 2H), 4.38-4.44 (q, 2H), 3.62-3.80 (m, 4H), 3.02-3.14 (m, 4H), 2.3 (s, 3H), 1.36-1.42 (t, 3H). 13C NMR (400 MHz, CDCl3): 182, 165, 119, 116.2, 116, 61.4, 52.3, 51, 50.8, 45.8, 42.6, 14.4, 10.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:28])[CH:26]=[O:27])[CH3:23]>C1(C)C=CC=CC=1.C(N(CC)CC)C.C(Cl)Cl>[CH2:22]([O:24][C:25](=[O:28])[CH:26]([OH:27])[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:23]
Reactant: CCCCC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(=O)C(c1ccc(OCc2ccccc2)cc1)C(O)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(4-benzyloxy-phenyl)-hexan-2-one (40.36 mmol, 11.4 g), oxo-acetic acid ethyl ester solution in toluene (30 mL, 50% solution in toluene) and triethylamine (15 mL) was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DCM (300 mL), washed with water (3×100 mL), and the organic layer was dried and concentrated under reduced pressure. The resultant residue was purified by flash silica gel chromatography eluting with 30% ethyl acetate in hexanes to provide 3-(4-benzyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester.