Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[N:20]=[C:19]([CH2:21]O)[CH:18]=[CH:17][CH:16]=3)=[CH:14][C:9]=2[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([CH2:21][N:46]4[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:44][CH2:45]4)[N:20]=3)=[CH:14][C:9]=2[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CN1c2cc(-c3cccc(CO)n3)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN1c2cc(-c3cccc(CN4CCN(S(C)(=O)=O)CC4)n3)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To (6-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}pyridin-2-yl)methanol (25-1) (30 mg, 0.079 mmol, 1.0 eq) was dissolved in NMP (1 mL) and triethylamine (0.04 mL, 0.24 mmol, 3.0 eq) was added followed by mesyl chloride (0.008 mL, 0.1 mmol, 1.2 eq). After 10 minutes, 1-(methylsulfonyl)piperazine (28.6 mg, 0.17 mmol, 2.1 eq) and DIPEA (0.061 mL, 0.35 mmol, 4.4 eq) were added. The resulting mixture stirred at 80° C. for 10 minutes. The mixture was cooled and purified by reverse phase chromatography (Waters Sunfire MSC18, 10-100% acetonitrile in water with 0.1% TFA modifier) to afford 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-(6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (25-2) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.99 (s, 1 H); 7.98 (d, J=8.0 Hz, 1 H); 7.84 (dd, J=1.6, 8.4 Hz, 1 H); 7.77 (d, J=1.6 Hz, 1 H); 7.44 (dd, J=1.6, 6.0 Hz, 1 H); 7.13 (d, J=8.4 Hz, 1 H); 4.66 (s, 2 H); 3.97 (d, J=7.2 Hz, 2 H); 3.62 (brs, 8 H); 3.39 (s, 3 H); 2.99 (s, 3 H); 2.21 (m, 1 H); 1.65 (m, 1 H); 1.44 (m, 1 H). HRMS m/z (M+H) 528.1538 found, 528.1545 required.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:16]2[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(CC)CC)c(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCC(CC)COc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 70 °C
Yield: 26 %

Procedure:
To a solution (10 ml) of ethyl 1-(3-cyano-4-(2-ethylbutoxy)phenyl)pyrazole-4-carboxylate (0.88 g) in ethanol was added 2 N aqueous sodium hydroxide solution (1.5 ml) with siring and the mixture was heated at 70° C. for 1 hour. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from ethyl acetate to give 0.21 g of 1-(3-cyano-4-(2-ethylbutoxy)phenyl)pyrazole-4-carboxylic acid, melting point 180-182° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:9]1)C1C=CC=CC=1.O.NN>C(O)C.[C].[Pd]>[CH3:16][N:15]([CH2:14][C@@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:17]
Reactant: CN(C)C[C@H]1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)C[C@H]1CNCCO1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
(S)-4-Benzyl-2-(N,N-dimethylaminomethyl)morpholine (78.9 g) was dissolved in ethanol (800 ml) and 10% palladium carbon (31.1 g) and hydrazine monohydrate (22.1 g) were added with stirring at room temperature. The mixture was refluxed with stirring for 1 hour. After cooling, the reaction mixture was filtered through celite and the solvent was distilled off to give 42.8 g of (R)-2-(N,N-dimethylaminomethyl)morpholine as a pale-yellow oil.
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][CH2:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl.C(N(CC)CC)C.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>O>[CH2:3]([O:10][CH2:11][C@@H:12]1[NH:13][CH2:14][CH2:15][N:16]([S:33]([C:29]2[S:28][CH:32]=[CH:31][CH:30]=2)(=[O:35])=[O:34])[CH2:17]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: c1ccc(COC[C@H]2CNCCN2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccs1)N1CCN[C@@H](COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A 1-L round-bottomed flask was charged with (R)-2-(benzyloxymethyl)piperazine dihydrochloride (55.5 g, 199 mmol) and 300 mL of CH2Cl2. After cooling to 0° C., triethylamine (111 mL, 795 mmol) and 2-thiophenesulfonyl chloride (36.3 g, 199 mmol, Sigma-Aldrich, St. Louis, Mo.) were added. This mixture was stirred at 0° C. for 30 min and then diluted with water. The organics were separated, dried (MgSO4), filtered and concentrated to give a brown oil. Purification via column chromatography on silica gel (25 to 100% EtOAc in hexanes) gave (3R)-3-((benzyloxy)methyl)-1-(2-thiophenylsulfonyl)piperazine (47.8 g) as a light-brown solid.
Reaction SMILES: CN(C)C=[CH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]=[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=1.I([O-])(=O)(=O)=[O:23].[Na+].CCOC(C)=O>C1COCC1.O>[N+:11]([C:10]1[C:5]([CH:4]=[O:23])=[CH:6][C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH:9]=1)([O-:13])=[O:12]
Reactant: CN(C)C=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl-[2-(5-nitro-2-phenoxy-pyridin-4-yl)-vinyl]-amine (0.2 g, 0.7 mmol) in THF (2 mL) and water (2 mL) was added sodium periodate (0.46 g, 2.1 mmol). The reaction mixture was stirred for 30 min, treated with EtOAc and the solids filtered. The filtrate was washed with sat NaHCO3, dried (Na2SO4), and concentrated to yield 5-nitro-2-phenoxy-pyridine-4-carbaldehyde, the title compound, as a bright yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1CCCCN1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH2:18][N:19]([CH:23]([CH3:25])C)[CH:20]([CH3:22])C.F[C:27]1[CH:32]=[CH:31]C=C[N:28]=1>CC#N>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:17][CH2:18][N:19]([C:20]2[CH:22]=[CH:31][CH:32]=[CH:27][N:28]=2)[CH2:23][CH2:25]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CCCCN1
Reactant: CCN(C(C)C)C(C)C
Reactant: Fc1ccccn1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCC1CCN(c2ccccn2)CC1
Temperature: 100 °C

Procedure:
To a solution of N-t-butoxycarbonyl 2-(piperidin-2-yl) ethylamine (8.1 g) and DIEA (14.1 mL) in CH3CN (29 mL) was added 2-fluoropyridine (3.5 mL) and the resulting mixture was heated in a sealed-tube at 100° C. for three days. Solvent was removed and the crude product was purified via column chromatography (20% EtOAc/hexane) to afford 3.9 g of N-t-butoxycarbonyl 2-[1-(pyrid-2-yl)piperidin-4-yl]ethylamine. 1H NMR (CDCl3) δ=8.16 (dd, J=1.8, 5.0 Hz, 1H), 7.44–7.38 (m, 1H), 6.61 (d, J=8.7 Hz, 1H), 6.53 (dd, J=5.0, 7.2, 1H), 4.58 (bs, 1H), 4.23 (d, J=12.6 Hz, 2H), 3.15 (q, J=6.6 Hz, 2H), 2.76 (dt, J=2.7, 12.6 Hz, 2H), 1.75 (d, J=12.6 Hz, 2H), 1.55–1.35 (m, 11H), 1.28–1.15 (m, 3H);
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].ClC1C=CC(C(NN)=O)=CC=1.[CH3:21][N:22]=[C:23]=[O:24].C(N=C=O)C>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH:9][C:23]([NH:22][CH3:21])=[O:24])=[O:7]
Reactant: CN=C=O
Reactant: NNC(=O)c1cccs1
Agent: CCN=C=O
Agent: NNC(=O)c1ccc(Cl)cc1
Product: CNC(=O)NNC(=O)c1cccs1

Procedure:
When in the procedure of Example 1, 2-thiophenecarboxylic acid hydrazide is substituted for 4-chlorobenzoic acid hydrazide and methyl isocyanate is substituted for ethyl isocyanate, the title compound is obtained.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26](C(OCC)=O)[C:27]([O:29]CC)=[O:28].CC(C)=O>CN(C)C=O>[Br:18][C:16]1[CH:17]=[C:9]2[C:10](=[CH:14][CH:15]=1)[CH2:11][O:13][C:26]([C:27]([OH:29])=[O:28])=[C:1]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)C1=C(c2ccccc2)c2cc(Br)ccc2CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.6 %

Procedure:
A mixture of 2-benzoyl-4-bromobenzoic acid (25 g, 82 mmol), potassium carbonate (12 g, 87 mmol), diethyl bromomalonate (22 g, 92 mmol), acetone (450 mL) and N,N-dimethylformamide (8 mL) was stirred at room temperature for 15 h. The solvent was evaporated under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The residue was crystallized from hexane and the crystals were collected by filtration. The obtained crystals were added to a mixture of acetic acid (235 mL) and concentrated hydrochloric acid (360 mL) and the mixture was stirred at 120° C. for 8 h. The reaction mixture was cooled and concentrated. The residue was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with diisopropyl ether and dried to give 6-bromo-4-phenyl-1H-isochromene-3-carboxylic acid (17 g, 60%) as crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[S:5][C:6]=1[O:7][CH3:8].[CH3:13][N:14]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[N:15]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:8][O:7][C:6]1[S:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][C:2]=1[C:18]1[N:14]([CH3:13])[N:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(Br)c(OC)s1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(OC)s1
Temperature: 85 °C
Yield: 143 %

Procedure:
To a 350 mL sealed flask reactor was added methyl 4-bromo-5-(methyloxy)-2-thiophenecarboxylate (772 mg, 3.07 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (773 mg, 3.72 mmol) [prepared according to the procedure of Preparation 7], K2CO3 (1.419 g, 10.27 mmol) and Pd(Pt—Bu3)2 (103 mg, 0.20 mmol) in 1,4-Dioxane (12 mL) and Water (3 mL). The reaction was heated at 85° C. for 2 hours. The mixture was partitioned between CHCl3/H2O and the aqueous layer made acidic with 6N HCl. The separated organic layer was dried over Na2SO4 and evaporated. The resulting material was adsorbed onto silica and purified via column chromatography (0-50% EtOAc/Hexane) affording the title compound (967 mg, 4.39 mmol, 85%): LC-MS (ES) m/z=253 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7]Cl)[CH3:2].[CH2:16]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[O:21][CH2:22][CH2:23][NH2:24])[CH3:17].[C:29](=[O:32])([OH:31])[O-].[Na+].CN(C)C=O>O>[C:4]([OH:3])(=[O:18])[C:29]([OH:31])=[O:32].[CH2:1]([O:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7][NH:24][CH2:23][CH2:22][O:21][C:20]1[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=1[O:18][CH2:16][CH3:17])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCOC(CCCCl)c1ccc(F)cc1
Reactant: CCOc1ccccc1OCCN
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccccc1OCCNCCCC(OCC)c1ccc(F)cc1
Product: O=C(O)C(=O)O
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of 4.4 g of 4-ethoxy-4-(4-fluorophenyl)-butyl chloride, 3.6 g of 2-(2-ethoxyphenoxy)ethylamine, 2 g of sodium bicarbonate and 44 ml of N,N-dimethylformamide was stirred at about 110° C for 20 hours. After cooling, the reaction mixture was poured into cold water and extracted with benzene. The benzene layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue was treated with ethanolic oxalic acid and recrystallized from ethanol to give N-[4-ethoxy-4-(4-fluorophenyl)butyl]-2-(2-ethoxyphenoxy)-ethylamine oxalate, M.P. 157° - 160° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:50][N:51]1[CH:56]2[CH2:57][CH2:58][CH:52]1[C:53]([NH2:65])([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:54][CH2:55]2>CN(C)C=O>[CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([NH:65][C:53]2([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH2:54][CH2:55][CH:56]3[N:51]([CH3:50])[CH:52]2[CH2:58][CH2:57]3)=[O:8])[CH2:2][CH2:3]1
Reactant: CN1C2CCC1C(N)(c1ccccc1)CC2
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C2CCC1C(NC(=O)c1ccc(C(F)(F)F)cc1C1CC1)(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 23.4 mg (0.102 mmol) 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate B2), 53.1 mg (0.139 mmol) HATU and 64 ul (0.370 mmol) N-ethyldiisopropylamine in 0.8 ml N,N-dimethylformamide, was added a solution of 20 mg (0.0925 mmol) (1RS,2RS,5SR)-8-methyl-2-phenyl-8-aza-bicyclo[3.2.1]oct-2-ylamine (intermediate A1) in 0.2 ml N,N-dimethylformamide. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed once with water and twice with a saturated sodium bicarbonate solution. The aqueous layer was extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica (5 g) eluting with a gradient formed from n-heptane and ethyl acetate (0 to 50%) to provide 10 mg (y: 25.2%) of the title compound as a colorless viscous oil. MS (m/e): 429.2 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[N:33]=[CH:34][O:35][C:36]=1[C:37]1([NH2:40])[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:36]6[O:35][CH:34]=[N:33][C:32]=6[CH3:31])[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cc1ncoc1C1(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ocnc5C)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(4-methyloxazol-5-yl)cyclopropanamine (0.103 g, 0.74 mmol, 1.2 eq), EDCI.HCl (0.105 g, 0.54 mmol, 1.1 eq), HOBT (0.067 g, 0.5 mmol, 1.0 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The organic layer was separated, washed with water and concentrated to give the crude product which was purified by Prep. HPLC. Yield: 25 mg (25%) 1HNMR (400 MHz, DMSO-d6): δ1.21 (broad s, 4H), 2.17 (s, 3H), 2.28 (s, 3H), 2.83 (d, J=4.8 Hz, 3H), 7.37-7.43 (m, 4H), 7.56 (d, J=1.6 Hz, 1H), 7.74-7.79 (m, 3H), 7.98-8.02 (m, 2H), 8.0 (s, 1H), 8.44-8.45 (m, 1H), 9.20 (s, 1H). LCMS: (ES+) m/z=524.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH:13]([OH:29])[CH2:12]1.[H-].[Na+].[CH3:32]I.O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH:13]([O:29][CH3:32])[CH2:12]1
Reactant: CI
Reactant: COc1cccc(OC)c1C1CC(O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C1CC(OC)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A cooled (0° C.) solution of rac-(3S*,5S*)-5-(2,6-dimethoxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (53 mg; 0.12 mmol) in anh. THF (3 ml) was treated with NaH (60% dispersion in mineral oil; 6 mg; 0.14 mmol). Stirring was continued at 0° C., under nitrogen, for 5 min., and then at rt for 20 min. The mixture was again cooled to 0° C., and a solution of CH3I (20 mg; 0.14 mmol) in anh. THF (1 ml) was added. The obtained mixture was further stirred at 0° C. for 5 min., and then at rt for 17 h. Water and AcOEt were added, and the separated aq. layer was further extracted with AcOEt. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded rac-(3S*,5S*)-5-(2,6-dimethoxyphenyl)-3-methoxy-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one as a yellow oil. LC-MS (conditions A): tR=0.88 min.; [M+H]+: 426.19 g/mol.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([CH2:15][CH2:16][OH:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]([CH2:15][CH2:16][O:17][CH3:26])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1
Reactant: CI
Reactant: COCOc1cc(CCO)c(-c2ccccc2)c(OCOC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCc1cc(OCOC)cc(OCOC)c1-c1ccccc1
Temperature: 4 °C
Reaction time: 0.07 h
Yield: 89.4 %

Procedure:
2-[3,5-Bis(methoxymethoxy)-2-phenylphenyl]ethanol (1.2 g, 3.7 mmol) obtained in Example 3, Step 3 was dissolved in N,N-dimethylformamide (15 mL), and a 60% sodium hydride dispersion in mineral oil (0.30 g, 7.5 mmol) was added thereto in an atmosphere of nitrogen, followed by stirring at 4° C. for 4 minutes. After methyl iodide (0.70 mL, 11 mmol) was added dropwise to the reaction mixture, the mixture was stirred at 4° C. for 1 hour, followed by further stirring for 48 hours, while the temperature of the mixture was raised to room temperature. To the reaction mixture was added water (10 mL) and a saturated aqueous solution of ammonium chloride (20 mL), and the mixture was extracted with ethyl acetate (0.10 L). The organic layer was washed with water (0.10 L) and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain 3,5-bis(methoxymethoxy)-1-(2-methoxyethyl)-2-phenylbenzene (1.1 g, 91%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]2=3)[CH:5]=[CH:4]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:19]([O:1][CH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]2=3)[CH:5]=[CH:4]1)(=[O:21])[CH3:20]
Reactant: Nc1nc2c(ncn2[C@H]2C=C[C@@H](CO)C2)c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1C=C[C@H](n2cnc3c(=O)[nH]c(N)nc32)C1
Yield: 70 %

Procedure:
(1R,4S)-9-(4-Hydroxymethyl-2-cyclopentenyl)guanine (150 mg, 0.607 mmole), acetic anhydride (freshly distilled, 65 mg, 0.161 mmole), 4-dimethylaminopyridine (3 mg), and dry dimethylformamide (5 mL) were stirred under nitrogen for days. The solvent was evaporated and the residue applied to a silica gel column. Title compound was eluted with 10% methanol-chloroform as a waxy white solid. Crystallization from ethanol gave white powder (123 mg, 70%), m.p. 247°-249° C.; 1H-NMR (DMSO-d6) 10.55 (hr s, 1, NHCO), 7.55 (s, 1, purine H-8), 6.42 (br s, 2, NH2), 6.06 and 5.94 (both m, 2, CH=CH), 5.34 (m, 1, CH--N), 4.07 (d, J=6.0, 2, CH2O), 3.05 (m, 1, CH), 2.6 and 1.55 (both m, 2, CH2), 1.98 (s, 3, COCH3).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:18]Br)=[C:7]2[C:14]([O:16][CH3:17])=[O:15].[Na+].[C:21]1([S:27]([O-:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>CC(N(C)C)=O.O>[C:21]1([S:27]([CH2:18][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:2]=3[Br:1])[C:7]=2[C:14]([O:16][CH3:17])=[O:15])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S([O-])c1ccccc1
Reactant: COC(=O)c1c(CBr)ccc2c(Br)ccc(OC)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc2c(Br)ccc(OC)c12
Temperature: 50 °C
Yield: 28.5 %

Procedure:
A mixture of methyl 5-bromo-2-bromomethyl-8-methoxynapthalene-1-carboxylate (Intermediate 189, 0.716 g), benzenesulphinic acid sodium salt (0.68 g) and sodium hydrogen carbonate (0.35 g) in DMA (15 ml) and water (3 ml) was heated at 50° C. for 2 hours. After cooling, water was added and the mixture was extracted with diethyl ether. The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give methyl 2-(benzenesulphonylmethyl)-5-bromo-8-methoxynaphthalene-1-carboxylate (0.236 g) as an oil which crystallised on standing.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][N:15]([C:19](=[O:25])[CH2:20][O:21]C(=O)C)[CH2:16][CH2:17][CH:18]=3)=[C:9]([F:26])[CH:8]=2)[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O.C(Cl)Cl>[OH:21][CH2:20][C:19]([N:15]1[CH2:16][CH2:17][CH:18]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:26])[CH2:14]1)=[O:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCCN(C(=O)COC(C)=O)C3)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCCN(C(=O)CO)C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-5,6-dihydro-2H-pyridin-3-yl]phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 70, Step 3, 105 mg) and anhydrous potassium carbonate (67 mg) in methanol (4.8 mL) is stirred under N2 at ambient temperature for 2 hrs and is then neutralized with hydrochloric acid (1 M), diluted with water (10 mL) and methylene chloride (40 mL), and the layers are separated. The organic phase is washed with saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which is then chromatographed on silica gel (70-230 mesh, 15 g), eluting with methanol/methylene chloride (5/95). Pooling and concentration of those fractions with an Rf=0.30 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 188-190° C.