Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.O>CC(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)[C@H]1CC[C@H](N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)[C@H]1CC[C@H](N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Reaction time: 0.5 h

Procedure:
trans Ethyl 4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate (0.8 g) was dissolved in t-BuOH (180 ml) at 38° C. To this was added Candia rugosa lipase powder (3 g). This was stirred for 30 minutes then water (20 ml) was added over 4 h. The mixture was then stirred for 48 h and filtered. The enzyme was washed with 9:1 t-BuOH-water (2×20 ml) and the filtrate was evaporated. Ethyl acetate was added to the residue and then decanted. The resultant solid was dissolved in methanol/DMSO and was purified by HPLC (Waters XTerra® column with at-column dilution of sample) (gradient (5% MeCN/NH3(aq) (0.2%) to 40% MeCN//NH3(aq) (0.2%)] gave the title compound (0.44 g) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][NH2:40]>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:40][CH2:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: NCc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4ccccn4)cc3)oc2C)cc1
Yield: 79.8 %

Procedure:
Method E. Reaction of oxalyl chloride (75 λL, 0.9 mmol) and benzoic acid 4 (215 mg, 0 6 mmol) with subsequent coupling to 2-pyridinylmethylamine (68.2 λL, 0.6 mmol) gave benzamide 8 (221 mg, 83%) as a white powder: mp (EtOAc) 154-155° C.; 1H NMR δ 9.21 (t, J=6.0 Hz, 1 H, CONH), 8.52 (dd, J=4.8, 1.5 Hz, 1 H, H-6′), 8.04 (d, J=8.6 Hz, 2 H, H-2, H-6), 7.91 (d, J=8.6 Hz, 2 H, H-3, H-5), 7.77 (dt, J=7.8, 1.8 Hz, 1 H, H-4′), 7.67 (d, J =8.3Hz, 2 H, H-2″, H-6″), 7.42 (d, J=8.3Hz, 2 H, H-3″, H-5″), 7.35 (d, J=7.8 Hz, 1 H, H-3′), 7.27 (dd, J=7.7, 4.8 Hz, 1 H, H-5′), 4.63 (s, 2 H, CH2SO2), 4.59 (d, J=6.0 Hz, 2 H, CH2N), 2.41 (s, 3 H, CH3), 2.14 (s, 3 H, CH3); 13C NMR δ 165.6, 158.6, 158.0, 149.9, 148.8, 144.5, 136.7, 135.6, 135.5, 129.6 (2), 128.8, 128.3 (2), 128.1 (2), 126.0, 125.4 (2), 122.1, 121.0, 53.0, 44.8, 21.0, 9.7; MS m/z 462.6 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 65.03; H, 5.00; N, 9.11%.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[CH:22]([N:25]1[C:29](B(O)O)=[CH:28][CH:27]=[N:26]1)([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([C:29]3[N:25]([CH:22]([CH3:24])[CH3:23])[N:26]=[CH:27][CH:28]=3)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: CC(C)n1nccc1B(O)O
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccnn2C(C)C)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 100 °C
Yield: 44.4 %

Procedure:
To a solution of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.12 mmol), (1-isopropyl-1H-pyrazol-5-yl)boronic acid (23 mg, 0.12 mmol) and Na2CO3 (22 mg, 0.25 mmol) in 1,4-dioxane (0.5 mL) and water (0.05 mL) was added Pd (dppf)Cl2 (10 mg) under nitrogen. The mixture was heated at 100° C. for 4 hour and filtered through the Celite pad. The filtrate was extracted with EtOAc, and then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by the prep-TLC (PE:EA=1:1) to give 5-bromo-2-(1-isopropyl-1H-pyrazol-5-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (25 mg, yield: 50%). 1H-NMR (CDCl3, 400 MHz) δ 8.50 (s, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 6.58 (d, J=2.0 Hz, 1H), 5.74 (d, J=3.6 Hz, 1H), 4.45˜4.52 (m, 1H), 3.28 (s, 3H), 3.04 (s, 3H), 2.82 (d, J=4.8 Hz, 3H), 1.51 (s, 6H). MS (M+H)+: 469/471.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[O:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17].C([O-])(=O)C.[K+]>C1(C)C(C)=CC=CC=1.[Cu]>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([N:14]2[CH2:15][CH2:16][O:12][C:13]2=[O:17])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: O=C1NCCO1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=C1OCCN1c1cnc2ccccc2c1

Procedure:
26,0 g of 3-bromoquinoline and 4.35 g of 2-oxazolidinone in 200 ml of xylene are heated under reflux in the presence of 7.4 g of potassium acetate and 4.8 g of copper powder for 9 h, analogously to the process of B.Renger in Synthesis (1985) 856. After the mixture has been worked up, the crude product is purified over silica gel with a 500:10:1 mixture of methylene chloride, methanol and concentrated ammonia as the mobile phase, to give 3-(quinolin-3-yl)-2-oxazolidinone as a crystalline solid: Rf (500:10:1 mixture of methylene chloride, methanol and concentrated ammonia)=0.39; FAB-MS: (M+H)+ =215. Hydrogenation of 0.67 g of the resulting product in 10 ml of ethanol in the presence of 0.1 g of palladium-on-charcoal (10% of palladium) at 50° C. in the course of 20 h and FC over 80 g of silica get (mobile phase N) gives 3(R,S)-(2-oxo-oxazolidin-3-yl)-1,2,3,4-tetrahydroquinoline as a white solid: Rf (N)=0.61; MS: M+ =218.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15](Cl)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[S:18]([O:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([C:13]=2[C:15]([O:37][C:34]2[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][O:28][S:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=4)(=[O:19])=[O:20])=[CH:36][CH:35]=2)=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1c2ccccc2nc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(O)cc2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(OC(=O)c3c4ccccc4nc4ccccc34)cc2)cc1
Yield: 54.7 %

Procedure:
In 30 ml of pyridine, 2.4 g of the compound (2) obtained in Example 2 were dissolved. Under ice cooling and stirring, 2.9 g of the compound (1) obtained in Example 1 were added in small portions. Subsequent to stirring at room temperature for 2 hours, the pyridine was distilled off under reduced pressure. CHCl3 was added further, and distillation was repeated twice under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (eluent: CHCl3), whereby 2.7 g of the compound (3) were obtained (yield: 54%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[B:32](OC)([O:35]C)[O:33]C.Cl>O1CCCC1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([B:32]([OH:35])[OH:33])=[CH:8][CH:9]=2)=[CH:14][CH:15]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
Butyllithium (6 ml, 1.6 M in hexanes, 9.6 mmol) was added dropwise to a solution of 4-bromo-4′-(dodecyloxy)biphenyl (4 g, 9.6 mmol) in THF (tetrahydrofuran) (150 mL) under N2 at −78° C. with stirring. Stirring was continued for 1 h and trimethyl borate (3 g, 28.8 mmol) was added. The resulting mixture was warmed to room temperature overnight, acidified with HCl (2 M, 100 mL), extracted with EtOAc (3×200 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using EtOAc (0-100% gradient in DCM) as eluent. The solvent was removed under reduced pressure and the residue washed with hexane to give the title compound (0.84 g, 23%) as a colourless powder.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([NH:42][CH2:43][CH2:44][O:45][CH3:46])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][NH:42][CH2:43][CH2:44][O:45][CH3:46])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: COCCNC(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCNCCOC)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 13.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-methoxyethyl)acetamide (14 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (3.5 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]([CH3:12])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].Cl.CN(C)CCCN=C=NCC>ClCCl>[O:22]=[C:17]1[CH2:18][CH2:19][C:20](=[O:21])[N:16]1[O:10][C:9]([C:8]1[CH:7]=[C:6]([CH3:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[O:2][CH3:1])=[O:11]
Reactant: O=C1CCC(=O)N1O
Reactant: COc1c(C(=O)O)cc(C)n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C(=O)ON2C(=O)CCC2=O)cc(C)n(C)c1=O
Reaction time: 15 h
Yield: 97.8 %

Procedure:
To a solution of 5 (5.36 g, 27.2 mmol) in dichloromethane (500 mL) was added N-hydroxysuccinimide (4.23 g, 36.7 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.89 g, 35.9 mmol), and the resulting reaction mixture was stirred under dinitrogen for 15 h. The reaction mixture was washed twice with a 0.01 N HCl solution (150 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification was performed using silica gel chromatography (1:49 methanol/dichloromethane) to yield 7.83 g (98%) of 6 as a tan solid. 1H NMR (300 MHz, CDCl3): δ=2.31 (s, 3H, C—CH3), 4.08 (s, 4H, CH2), 3.50 (s, 3H, N—CH3), 3.98 (s, 3H, O—CH3), 6.29 (s, 1H, CH); 13C NMR (75 MHz, CDCl3): δ=20.6 (C—CH3), 25.8 (CH2), 32.0 (N—CH3), 60.8 (O—CH3), 103.0 (CH), 122.8, 140.7, 148.8, 159.9, 160.3, 169.0; TLC: Rf=0.33 (1:19 methanol/dichloromethane); ESI-MS calcd for C13H14N2O6 [M+H]+: 295.0930. found 295.0931.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:21][CH:20]=1>>[C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]4)=[CH:23][CH:24]=3)=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)c4ccccc4)cc3)cc2)CC1
Yield: 6.6 %

Procedure:
The title compound (3.0 mg, 7%) was prepared from [4-(phenylcarbonyl)phenyl]boronic acid (22.6 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to example 9, Step 3. LRMS (ESI), m/z 480 (M+Na).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1>CCN(C(C)C)C(C)C.O>[OH:16][CH:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)[CH2:11][CH2:12]1
Reactant: OC1CCNCC1
Reactant: Cn1nc(Cl)ccc1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(N2CCC(O)CC2)ccc1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a slurry of 6-chloro-2-methylpyridazin-3(2H)-one (1 g, 6.94 mmol) in DIPEA (20 mL) was added piperidin-4-ol (0.84 g, 8.33 mmol) and the reaction mixture was stirred at 120° C. overnight. The resulting mixture was diluted with water (30 mL) and extracted with DCM (3×30 mL) to remove impurities. The aqueous phase was concentrated to dryness to afford the title compound as a yellow solid (1.2 g, 83%). [LCMS: Rt=1.07 min, m/z 210.1 (M+H)]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH2:23][OH:24]>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:22][CH2:23][OH:24])[CH:10]=2)[O:3]1
Reactant: OCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.15 mmol) and cesium carbonate (5.04 g, 15.47 mmol) were suspended in 10 mL of dimethylformamide. 2-Bromoethanol (0.73 mL, 10.30 mmol) was added and the mixture was stirred at 70° C. for 3 hours. Additional amounts of cesium carbonate (5.04 g, 15.47 mmol) and 2-bromoethanol (0.73 mL, 10.30 mmol) were added and the mixture was left at 70° C. overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated to give 770 mg (63% yield) of a yellowish oil that was used in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])=[CH:14][CH:13]=1
Reactant: OCc1ccccc1I
Reactant: COc1ccc(S)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1ccc(Sc2ccccc2CO)cc1
Yield: 88.9 %

Procedure:
The general procedure in example 39 was followed. 2-Iodobenzylalcohol (234 mg, 1.0 mmol), 4-methoxythiophenol (123 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 2-(4-methoxyphenyl)sulfanylbenzylalcohol (219 mg, 89% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=5/1). Rf=0.3 (hexane/ethyl acetate=5/1). 1H NMR (CDCl3, 300 MHz) δ 7.40 (dd, 1 H, J=6.6 Hz, 1.5 Hz), 7.29 (dt, 2 H, J=8.7 Hz, 2.1 Hz), 7.13-7.21 (m, 2 H), 7.08 (dd, 1 H, J=8.1 Hz, 2.1 Hz), 6.86 (dt, 2 H, J=9.0 Hz, 2.1 Hz), 4.78 (d, 2 H, J=6.3 Hz), 3.80 (s, 3 H), 2.12 (t, 1 H, J=6.3 Hz). 13C NMR (CDCl3, 75 MHz) δ 159.7, 140.0, 135.9, 134.3, 130.8, 128.6, 128.5, 127.1, 124.5, 115.3, 63.9, 55.7. IR (neat, cm−1) 3365 (broad), 3015, 2962, 2904, 2867. MS (EI) m/z (relative intensity) 246 (100), 138 (40), 108 (70). HRMS (EI), Cald. for C14H14O2S 246.0709; Found 246.0707.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH:24]=[O:25])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CO.C(Cl)Cl>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]1[CH:14]=[CH:15][C:16]([S:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH2:24][OH:25])(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)cc1)c1ccccc1CO
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Sodium borohydride (89 mg, 1.8 mmol) was added to a solution of 2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzaldehyde (Step 1; 233 mg, 0.61 mmol) in MeOH (7 mL) and CH2Cl2 (3 mL). After 2 h, the mixture was partitioned between CH2Cl2 (10 mL) and water (10 mL), the phases were separated and the aqueous portion extracted with further CH2Cl2 (10 mL). The combined organics were then dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (eluant 40% EtOAc/isohexane) gave the title compound as a white solid (208 mg). δH (500 MHz, d6 DMSO): 8.08 (1H, d, J 7.7), 7.89-7.83 (5H, m), 7.77 (1H, d, J 7.6), 7.72 (1H, t, J 7.4), 7.55 (1H, t, J 7.5), 7.42-7.34 (2H, m), 7.33-7.27 (1H, m), 7.15 (1H, td, J 2.1, 8.4), 5.39 (1H, t, J 5.7), 4.69 (2H, d, J 5.7). m/z (ES+) 369 [(M-OH)+].
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH:11]3[CH2:14][C:9]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)([CH2:10]3)[C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC>COCCO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:9]23[CH2:10][CH:11]([CH2:14]2)[C:12](=[O:13])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]3=[O:24])=[CH:16][CH:17]=1
Reactant: O=C1C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C(=O)N1C1CCCCC1
Agent: [Pd]
Solvent: CCOCC
Solvent: COCCO
Product: Nc1ccc(C23CC(C2)C(=O)N(C2CCCCC2)C3=O)cc1

Procedure:
In a manner analogous to that described in Example 1a, 6.0 g of 3-cyclohexyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]-heptane-2,4-dione are dissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 139°-14020 (from ether).
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].CC[O:11][C:12]([CH:14]1[C:19](=O)[CH2:18][CH2:17][CH2:16][CH2:15]1)=O>CO>[N+:2]([NH:5][C:6]1[NH:8][C:12](=[O:11])[C:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:7]=1)([O-:4])=[O:3]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: [Na]
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])nc2c1CCCC2
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
To 14 ml of methanol, 256 mg of sodium was added at room temperature under stirring, then 1.04 g of nitroguanidine was added, followed by 45 minutes' heating under reflux. Successively, 1.70 g of ethyl 2-cyclohexanonecarboxylate was added, followed by 9 hours' heating under reflux. After cooling the reaction mixture, the solvent was distilled off under reduced pressure. Water was added to the residue, and the system was acidified with acetic acid. The precipitate was recovered by filtration and dried to provide 1.76 g (84%) of 2-nitroamino-5,6,7,8-tetrahydro-3H-quinazolin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:14]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH:13]=[CH2:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 7.4 g of 2-chloro-5-nitrophenol, 5.4 g of allyl bromide, 5.9 g of anhydrous potassium carbonate and 50 mL of dry N,N-dimethylformamide (DMF) was stirred at room temperature over a weekend. Then the mixture was poured into water, and the resulting mixture was extracted twice with ethyl acetate and twice with ether. The combined extracts were washed with water, then with brine, dried (Na2SO4), filtered and stripped of the solvents. The residue was recrystallized from hexane to give 1-(allyloxy)-2-chloro-5-nitrobenzene (3A), as orange needles, m.p.: 58°-59.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:21]([Br:22])=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>>[Br:22][C:21]1[C:2]([N:1]2[CH2:24][CH2:25][CH2:26][C:27]2=[O:28])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)=[C:6]([C:16]([NH:18][CH3:19])=[O:17])[C:5]=2[CH:20]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(Br)cc12
Reactant: O=C(Cl)CCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)c(Br)cc12

Procedure:
A solution of 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylic acid (280 mg, 0.67 mmol), HOBT (150 mg, 1.11 mmol) and EDCI (280 mg, 1.47 mmol) in dry DMF (2 mL) was allowed to stir at room temperature for 1 hour. Then Et3N (0.2 mL) and CH3NH2 (HCl salt, 100 mg, 1.48 mmol) was added to the mixture, and the reaction was allowed to stir for about 15 hours. After being concentrated in vacuo, water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried and concentrated in vacuo and the resulting resulting residue was purified using column chromatography (eluted with petroleum ether:EtOAc=1:1) to provide 5-bromo-2-(4-fluorophenyl-N-methyl-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxamide (220 mg, yield: 73%), which was also prepared from 6-amino-5-bromo-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide and 4-chlorobutanoyl chloride using the method described in step 1 above. 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.82˜7.86 (m, 2H), 7.32 (s, 1H), 7.09˜7.14 (m, 2H), 6.29 (s, 1H), 3.75˜3.78 (m, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.56˜2.60 (m, 2H), 2.24˜2.26 (m, 2H). MS (M+H)+: 431/433.
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[N:13]=2)[N:8]=[CH:7][C:6]=1[O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]([C:29]2[CH:30]=[CH:31][C:32]3[S:37][CH2:36][C:35](=[O:38])[NH:34][C:33]=3[CH:39]=2)=[O:28])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[N:13]=2)[N:8]=[CH:7][C:6]=1[O:17][CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:27]([C:29]2[CH:30]=[CH:31][C:32]3[S:37][CH2:36][C:35](=[O:38])[NH:34][C:33]=3[CH:39]=2)=[O:28])[CH2:24][CH2:25]1)[CH3:2]
Reactant: COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)c(O)c2n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(OCCN2CCC(NC(=O)c3ccc4c(c3)NC(=O)CS4)CC2)cnc2ccc(OC)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl iodide (13 μL, 0.16 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(4-hydroxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-amide (90 mg, 0.16 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by potassium carbonate (22 mg, 0.16 mmol, 1.0 eq). After 3 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(4-ethoxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-amide as a white lyophilizated powder (29 mg, 32% yield).