Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[OH2:17].[OH2:18].O.O.O.O.O.O.O.[S-2:26].[Na+].[Na+]>C(O)C.O>[CH3:15][C:6]([CH3:16])([CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[CH2:5][CH2:4][CH2:3][CH2:2][S:26][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][O:17][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:9][O:18]1
Reactant: [S-2]
Reactant: O
Reactant: CC(C)(CCCCBr)COC1CCCCO1
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CCCCSCCCCC(C)(C)COC1CCCCO1)COC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
A solution of 2-(6-bromo-2,2-dimethyl-hexyloxy)-tetrahydro-pyran (14.9 g, 50.8 mmol) in ethanol (100 ml) was added dropwise over 30 min to a solution of sodium sulfide nonahydrate (6.10 g, 25.41 mmol) in water (10 ml) at rt under N2 atmosphere. The reaction mixture was stirred at rt for 18 h and then heated to reflux for 3.5 h. The solution was concentrated in vacuo, 5% NaOH (100 ml) was added, and the reaction mixture was extracted with CH2Cl2 (200 ml). The organic layer was dried over MgSO4, concentrated in vacuo, and dried in high vacuo to give bis-(5,5-dimethyl-6-tetrahydropyranyloxy-hexyl)-sulfide (9.17 g, 78%) as a slightly yellowish oil. 1H NMR (300 MHz, CDCl3), d (ppm): 4.54 (t, 2H, J=2.9); 3.83 (m, 2H); 3.48 (m, 2H); 3.45 (d, 2H, J=9.2); 2.98 (d, 2H, J=9.2); 2.50 (t, 4H, J=7.3); 1.82 (m, 2H); 1.75-1.44 (m, 16H); 1.42-1.18 (m, 10H); 0.894 (s, 6H); 0.887 (s, 6H). 13C NMR (75 MHz, CDCl3), d (ppm): 98.90; 76.26; 61.68; 38.77; 34.04; 32.00; 30.51; 25.44; 24.42; 24.36; 23.20; 19.28. Calcd. for C26H51SO4: 459.3508, found 459.3504.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Mn]([O-])(=O)(=O)=[O:22].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([C:13]([OH:22])=[O:14])=[CH:11][C:10]=1[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(C=O)cc(F)c1OCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C(=O)O)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 7.5 g of 4-benzyloxy-3-fluoro-5-methoxybenzaldehyde in 200 ml of acetone was added dropwise at 15 to 20° C. to a mixture of 200 ml of water and 6.8 g of potassium permanganate. The mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated to about a half amount under reduced pressure. Aqueous sodium hydrogen sulfite solution and dilute hydrochloric acid were added to the concentrate and extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 4-benzyloxy-3-fluoro-5-methoxybenzoic acid.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][C:19]=2[CH3:30])[CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Cl:31][C:32]1[C:33]2[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:34]=2[S:35][C:36]=1[C:37](Cl)=[O:38]>>[Cl:31][C:32]1[C:33]2[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:34]=2[S:35][C:36]=1[C:37]([N:16]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:19]=1[CH3:30])[CH:13]1[CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:11][CH2:12]1)=[O:38]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: Cc1ccc(-c2ccncc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: Cc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 232 (36 mg) is treated with acid chloride 8 (29 mg, 0.11 mmol) using Method D to afford the title compound.
Reaction SMILES: ClCCl.[CH3:4][N:5]=[C:6]=[S:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[N:16]2[CH2:19][C:18](=[CH:20][S:21]([CH2:24][C:25]3[CH:26]=[C:27]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[CH:28]=[CH:29][CH:30]=3)(=[O:23])=[O:22])[CH2:17]2)=[CH:11][CH:10]=1>O>[CH3:4][NH:5][C:6]([N:34]1[CH2:35][CH2:36][N:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][S:21]([CH:20]=[C:18]3[CH2:17][N:16]([CH:15]([C:12]4[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)[C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[CH2:19]3)(=[O:22])=[O:23])[CH:26]=2)[CH2:32][CH2:33]1)=[S:7]
Reactant: CN=C=S
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Solvent: O
Solvent: ClCCl
Product: CNC(=S)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 6 h
Yield: 99.1 %

Procedure:
2 cm3 of dichloromethane and then 11 mg of methyl isothiocyanate are successively added, at a temperature close to 20°C., to 54.25 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 6 hours at a temperature close to 20° C., 0.05 cm3 of water is added to the reaction mixture. After stirring for 15 minutes at the same temperature, the reaction medium is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 61 mg of 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carbothioic acid N-methylamide are thus obtained in the form of a beige lacquer (1H NMR spectrum (400 MHz, CDCl3), δ in ppm): 2.77 (s, 3H), 3.20 (d, J=5 Hz, 3H), 3.32 (t, J=5.5 Hz, 4H), 3.81 (mt, 2H), 4.00 (t, J=5.5 Hz, 4H), 4.33 (mt, 2H), 4.49 (s, 1H), 5.63 (broad q, J=5 Hz, 1H), 6.80 (d, J=8 Hz, 1H), 6.85 (dd, J=8 and 2.5 Hz, 1H), 6.94 (broad s, 1H), from 7.20 to 7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH:22]=[CH2:23])([CH2:18][CH2:19]2)[O:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:24]O>C1COCC1.CCOCC.[OH-].[Na+].CCOC(C)=O>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][OH:24])([CH2:18][CH2:19]2)[O:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: C=CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a solution of 4-(3-phenoxyphenyl)-1-vinyl-2-oxabicyclo[2.2.2]octane (14 mg, 0.046 mmol) in THF (1 mL) at 0° C. was added BH3.SMe2 complex (0.046 mL of a 2.0 M solution in Et2O; 0.091 mmol). The reaction mixture was stirred at 0° C. for 10 min and then warmed to rt. After stirring for 1 h at rt, the reaction mixture was cooled to 0° C. and a few drops of 1 N aqueous NaOH and 30% aqueous H2O2 solution were added. The resulting mixture was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (0 to 70% gradient EtOAc:hexanes) to afford the title compound (9 mg, 57% yield) as a colorless oil. LCMS, [M+H]+=325.1. 1H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 3H), 7.14-7.08 (m, 2H), 7.04-6.95 (m, 4H), 6.84 (ddd, J=8.1, 2.3, 0.8 Hz, 1H), 4.01-3.94 (m, 2H), 3.85-3.78 (m, 2H), 2.17-1.89 (m, 6H), 1.74-1.69 (m, 2H), 1.68-1.62 (m, 2H).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([S:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])=[O:13])[CH2:9]2)C=CC=CC=1.[Cl:26]CCCl.ClC(OC(Cl)C)=O>CO>[ClH:26].[CH2:15]([S:12]([CH:10]1[CH2:11][NH:8][CH2:9]1)(=[O:14])=[O:13])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: ClCCCl
Reactant: CCCCCS(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: CCCCCS(=O)(=O)C1CNC1
Product: Cl
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
A 16 mL flask was charged with 1-(diphenylmethyl)-3-(pentylsulfonyl)azetidine (136 mg, 0.38 mmol; which may be prepared as described in Step 3) and 1,2-dichloroethane (1.7 mL). 1-Chloroethyl chloroformate (53 μL, 0.49 mmol) was added and the reaction mixture was stirred at 70° C. for 1.5 h. After cooling to room temperature, methanol (1.7 mL) was added and the reaction mixture stirred at 70° C. for 1.5 h. The reaction mixture was concentrated dryness. LCMS analysis showed a mixture of the final product and the starting material. The residue was dissolved again in 1,2-dichloroethane and 1-chloroethyl chloroformate (4 eq., 164 μL) was added. The reaction mixture was stirred at 70° C. for 5 h and overnight after addition of methanol. No starting material was detected by TLC monitoring, so the reaction mixture was concentrated to dryness and the resulting solid triturated in pentane to give the title product (39 mg, 45%) as a dark orange oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:13]([C:15]2[CH:16]=[C:17]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[CH:18]=O)=[O:14])=[N:5][C:6]([O:11][CH3:12])=[N:7][C:8]=1[O:9][CH3:10])[CH3:2].[C:24]([CH2:26]P(=O)(OCC)OCC)#[N:25].CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([C:3]1[C:4]([C:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:26][C:24]#[N:25])[CH:20]=[C:21]([CH3:23])[CH:22]=2)=[O:14])=[N:5][C:6]([O:11][CH3:12])=[N:7][C:8]=1[O:9][CH3:10])[CH3:2]
Reactant: CCc1c(OC)nc(OC)nc1C(=O)c1cc(C)cc(C=O)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1c(OC)nc(OC)nc1C(=O)c1cc(C)cc(C=CC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a stirred mixture of 3-(5-ethyl-2,6-dimethoxy-pyrimidine-4-carbonyl)-5-methyl-benzaldehyde (3.11 g, 9.9 mmol) and diethyl cyanomethyl-phosphonate (1.6 ml, 10 mmol) in anhydrous THF (20 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (1.26 g, 11.2 mmol). After 1 hr., the mixture was stirred at room temperature for 5 hr. The mixture was then partitioned between ether and water. The ether layer was taken, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow syrup. The crude product was purified by silica gel column chromatography (eluent, EA:hexanes (1:4)) to afford 2.39 g (72%) of a white solid. m.p. 165-166° C.; 1H NMR (200 MHz, CDCl3) δ 1.09 (3H, t, J=7.8 Hz), 2.42-2.53 (5H, m), 3.96 (3H, s), 4.09 (3H, s), 5.93 (1H, d, J=16.8 Hz), 7.40 (1H, s, J=16.8 Hz), 7.50 (1H, s), 7.73 (1H, s), 7.79 (1H, s).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[F:10][C:11]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:12]=1[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:10][C:11]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([NH:18][S:4]([CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:6])=[O:5])=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Nc1ccc(Oc2ccc(F)cc2F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(CC(F)(F)F)Nc1ccc(Oc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2,2,2-Trifluoroethanesulfonyl chloride (10.0 g, 54.8 mmol) was added dropwise to a solution of 4-(2,4-difluorophenoxy)aniline (11.0 g, 50.0 mmol) and 4-dimethylaminopyridine (9.1 g, 74.6 mmol) in methylene chloride (100 mL) at 0° C. under nitrogen. The mixture was slowly warmed to room temperature, stirring for a total of 72 h. The mixture was washed with saturated aqueous sodium bicarbonate solution (200 mL), dried over MgSO4, filtered and the solvent was removed under reduced pressure to afford the crude product as an orange oil. This residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/chloroform (1:4), to provide the title compound as a yellow solid: mp 105-108° C.; TLC Rf (1:9 ethyl acetate/chloroform)=0.75; 1H NMR (300 MHz, CDCl3) 7.23 (d, J=8.9 Hz, 2H), 7.14-6.87 (m, 3H), 6.93 (d, J=8.9 Hz, 2H), 3.76 (q, J=8.8 Hz, 2H) ppm; APCI MS m/z 366 [C14H10F5NO3S—H]−.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.BrC[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]=1.O>O1CCCC1>[C:26]1([C:18]2[N:17]=[C:16]([CH2:5][CH2:4][C:3]([OH:11])=[O:10])[C:25]3[C:20]([CH:19]=2)=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1nc(-c2ccccc2)cc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1nc(-c2ccccc2)cc2ccccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
Sodium hydride (6.5 g, 80% strength in oil) is placed with tetrahydrofuran (160 cc) under nitrogen, and a solution of diethyl malonate (34.9 g) in anhydrous tetrahydrofuran (200 cc) is added dropwise. After 1 hour's stirring at room temperature (approximately 20° C.), a solution of 1-bromomethyl-3-phenylisoquinoline (16.2 g) in anhydrous tetrahydrofuran (200 cc) is added. After 20 hours' stirring at 20° C., water (200 cc) is added and the aqueous phase extracted with ethyl acetate. The organic phase is dried and evaporated to dryness under reduced pressure. The residual product is chromatographed on silica gel with a cyclohexane/ethyl acetate (8:2 by volume) mixture as eluant. The product (11.5 g) is recovered, taken up in concentrated hydrochloric acid (115 cc) and brought to boiling for 20 hours. Water (200 cc) is added, and the precipitate is filtered off and washed with water and acetone. 3-Phenyl-1-isoquinolinepropanoic acid (6.7 g) m.p. 160° C., is obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].[CH3:28][C:29]([CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:30]CCO.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][CH:5]1[O:4][CH2:1][CH2:2][CH:28]=[C:29]([CH3:30])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:42])[CH3:43])(=[O:10])[CH3:9]
Reactant: CC(=CCCO)CCCC(C)CCCC(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1OC(OCCC=C(C)CCCC(C)CCCC(C)C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
2.11 g (5.41 mmol) of β-D-glucose pentaacetate and 1.0 g (4.2 mmol) of 4,8,12-trimethyltridec-3-en-1-ol were dissolved in dry acetonitrile (4 mL). 1.0 mL (8.3 mmol) of boron trifluoride diethyl etherate complex was added to the solution with cooling on ice. The reaction mixture was allowed to warm up slowly to room temperature while being stirred for 24 hours before addition of 1.7 mL (12 mmol) of triethylamine at 0° C. The resulting solution was diluted with ethyl acetate, and washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over sodium sulfate. After filtration, the filtrate was concentrated to obtain 1-O-(4,8,12-trimethyltridec-3-enyl)-D-glucopyranoside tetraacetate as a crude product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH2:10][C@@H:11]([NH2:26])[C:12]([NH:14][C@H:15]([C:20](=[O:25])[N:21]([O:23][CH3:24])[CH3:22])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH:37](OC)O[CH:35]2OC)=[CH:30][CH:29]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:8][C:9](=[O:27])[CH2:10][C@@H:11]([N:26]1[CH:37]=[CH:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:29][CH:30]=2)=[CH:35]1)[C:12]([NH:14][C@H:15]([C:20](=[O:25])[N:21]([O:23][CH3:24])[CH3:22])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 48 %

Procedure:
As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17 ]-octadeca-11(18),12,14,16-tetraen-9-yl)-3-(3-phenyl-1H-pyrrol-1-yl acid benzyl ester, 3(R)-amino-N-(1(S)-(N-methoxy-N-methylcarbamoyl)-3-methylbutyl)succinamic acid benzyl ester was deprotected. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to provide in 48% yield 3(R)-(3-biphenyl-4-yl-1H-pyrrol-1-yl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl]succinamic acid benzyl ester as an amorphous solid. 1H NMR (CDCl3): δ 7.62 (d, 2H, J=7.4 Hz), 7.58 (s, 3H), 7.44 (t, 2H, J=7.7 Hz), 7.35-7.21 (m, 7H), 7.10 (s, 1H), 6.80 (t, 1H, J=2.2 Hz), 6.60 (bs, 1H), 5.17-1.13 (m, 1H), 5.10 (s, 2H), 4.97-4.92 (m, 1H), 3.77 (s, 3H), 3.44 (dd, 1H, J=5.7, 17.1 Hz), 3.17 (s, 3H), 3.03 (dd, 1H, J=8.8, 16.5 Hz), 1.67-1.36 (m, 3H), 0.92 (d, 3H, J=6.25 Hz), 0.87 (d, 3H, J=6.3 Hz). Anal. Calculated for C35H39N3O5 : C, 72.27; H, 6.76; N, 7.22. Found: C, 72.19; H, 6.78; N, 7.16.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:4].C([Li])CCC.CON(C)[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CCCCCC>[C:29]([C:7]1[CH:8]=[C:9]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:20])([CH3:19])[CH3:1])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: CN1CCN(c2ccc(NC(=O)C(C)(C)C)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCN(c2ccc(NC(=O)C(C)(C)C)c(C(=O)c3ccccc3)c2)CC1
Temperature: -70 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
A solution of 1.375 g (5 mmol) of 2,2-dimethyl-N-[4-(4-methyl-piperazin-1-yl)-phenyl]-propionamide was dissolved in 25 ml tetrahydrofuran and cooled to −70° C. Under argon 7.8 ml (12.5 mmol) of a 1.6 M n-butyl lithium solution in hexane was added slowly at this temperature. The cooling bath was removed and the mixture was stirred for 3 h at room temperature. The reaction mixture was cooled down again to −70° C. and a solution of 1.234 g N-methoxy-N-methyl benzamide (7.2 mmol) in 5 ml tetrahydrofuran was added slowly at −70° C. After 10 min the cooling bath was removed and stirring was continued at room temperature for 1 hour. Water (50 ml) was added to quench the reaction and the mixture was extracted with diethylether (three times 50 ml). The organic layer was dried with magnesium sulfate and evaporated to give a brown oil, which was purified by flash chromatography with dichloromethane/methanol to yield 315 mg (17%) of the product as a light orange solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([Cl:24])=[CH:19][CH:20]=2)[N:15]=1.CN(C)C=O>O>[Cl:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=3)=[N:15]2)=[CH:20][CH:19]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc1
Temperature: 20 °C
Yield: 31.6 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 4-dimethylaminobenzoic acid (14.9 g), N,N'-carbonyldiimidazole (14.6 g) and 2-amino-7-chloro-1,8-naphthyridine (10.8 g). The crude product obtained by filtration of the reaction mixture (6.4 g; m.p. 248° C.) is dissolved in boiling dimethylformamide (95 cc). After cooling for 2 hours at 20° C., water (95 cc) is added. The crystallized solid is separated by filtration, washed with a dimethylformamide/water (50:50 by volume) mixture (2×10 cc), and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-4-dimethylaminobenzamide (6.2 g), m.p. 248° C., is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:11]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[CH3:11][O:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=C([O-])[O-]
Reactant: OCc1ccc(I)cc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(I)ccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydroxy-4-iodo-benzylalcohol from Step 3 (1.0 g, 4.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol) and iodomethane (0.25 mL, 4.0 mmol) were dissolved in DMF and heated to 800 for 1 hour and then stirred at room temperature for 2 hours. The DMF was removed in vacuo and the residue was partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc (2×). The organic layers were combined, washed with H2O and brine, dried (MgSO4), filtered and concentrated to yield an oil. This oil was purified by flash chromatography eluting product with 30% EtOAC/Hexane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:13]([CH2:15]C(O)=O)#[N:14].C([O-])(=O)C.[NH4+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:15][C:13]#[N:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OCC2=O
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1C
Product: COc1cccc2c(CC#N)coc12
Yield: 30 %

Procedure:
The solution of 7-methoxy-1-benzofuran-3(2H)-one (reference) (7.5 g, 0.046 mol), cyanoacetic acid (19.55 g, 0.23 mol) and ammonium acetate (7.08 g, 0.092 mol) in xylene was refluxed for 16-18 h. using dean stark apparatus. Xylene was removed under diminished pressure. Brown black residue was taken in ethyl acetate, washed with water and concentrated. On purification on silica gel it yielded (7-methoxy-1-benzofuran-3-yl)acetonitrile (30%).