Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:37][N:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1.O>CN(C)C=O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:26][C:27]5[CH:28]=[CH:29][C:30]([C:33](=[O:37])[CH2:34][C:35]#[N:36])=[CH:31][CH:32]=5)[C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: BrCc1ccc(-c2ccno2)cc1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(C(=O)CC#N)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.35 g, 1.20 mmol) in anhydrous N,N-dimethylformamide (20 mL) at 0° C. was added slowly sodium hydride (60% w/w dispersion in mineral oil, 0.072 g, 1.50 mmol). The solution was stirred at ambient temperature for 30 min, 5-(4-(bromomethyl)phenyl)isoxazole (Sasaki et al., Biorg. Med. Chem. Lett. (1998) 8:2241-2246) (0.24 g, 1.00 mmol) was added and the mixture was stirred for 16 h at ambient temperature. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (3×100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes to afford 3-{4-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]1′(2′H)-yl)methyl]phenyl}-3-oxopropanenitrile (0.33 g, 61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.96-7.92 (m, 2H), 7.63-7.60 (m, 2H), 7.50-7.46 (m, 1H), 7.23-7.13 (m, 2H), 7.04, 6.97 (m, 2H), 6.71-6.67 (m, 1H), 5.43-4.76 (m, 4H), 4.06 (s, 2H), 2.46 (s, 3H).
Reaction SMILES: I[C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[CH3:27][C:28]([CH3:35])([CH3:34])[CH:29]=[CH:30]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:27][C:28]([CH3:35])([CH3:34])[CH:29]=[CH:30][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)C=CB(O)O
Reactant: O=C(NOCc1ccccc1I)c1ccccc1NCc1ccncc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)C=Cc1ccccc1CONC(=O)c1ccccc1NCc1ccncc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
Argon was bobbled through a mixture of N-(2-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (example 360, 151 mg, 0.33 mmol) in toluene (20 ml) for 10 to 15 minutes. Tetrakis(triphenylphosphine) palladium (19 mg) was added and the mixture was stirred for 10 minutes before addition of 3,3-dimethyl-1-butenylboronic acid (Aldrich, 50 mg) and a degassed 2M solution of sodium carbonate (0.329 ml). The reaction flask (screw-cap) was sealed and the reaction mixture was heated to 120° C. for 3 hours. More tetrakis(triphenylphosphine) palladium (0.05 eq.), 2M sodium carbonate (0.329 ml), and 3,3-dimethyl-1-butenylboronic acid (50 mg) was added and stirring was continued at 120° C. over night. The mixture was cooled to room temperature and 25% ammonium acetate was added and stirring was continued for 10 min. The mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was subjected to chromatography on silica gel (elution with 1% methanol in dichloromethane v/v) and gave the title compound (130 mg). 13C-NMR (CDCl3) δ 168.9, 149.8, 149.1, 148.7, 145.1, 138.8, 133.4, 131.1, 129.2, 127.4, 126.8, 126.2, 122.0, 121.5, 115.7, 112.8, 112.0, 76.2, 46.1, 33.8, 29.6.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[N:20]=[C:21]([Cl:23])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:21]1[CH:22]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:18](=[O:25])[N:19]([CH3:24])[N:20]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 90 °C
Yield: 30.3 %

Procedure:
6-aminopyridin-3-yl-morpholino-methanone (800 mg, 3.86 mmol, Eq: 1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1 g, 4.48 mmol, Eq: 1.16), cesium carbonate (4.4 g, 13.5 mmol, Eq: 3.5) and xantphos (335 mg, 579 μmol, Eq: 0.15) were suspended in dioxane (40 ml). The suspension was degassed with argon. Finally Pd2(dba)3 (265 mg, 290 μmol, Eq: 0.075) was added and the reaction mixture was stirred at 90° C. over night under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and then filtered over celite. Filtrate was concentrated in vacuo to give a light brown solid. The crude material was purified by flash chromatography (silica gel, 110 g, 0% to 10% MeOH in (EtOAc 1:1 Hex) to afford a light yellow solid (408 mg, 1.17 mmol). MS (H+)=350.0 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.60-3.80 (m, 8H) 3.83 (s, 3H) 6.96 (d, J=8.69 Hz, 1H) 7.77 (dd, J=8.50, 2.45 Hz, 1H) 8.35-8.44 (m, 2H) 8.47 (d, J=2.27 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](Cl)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(CC(O)=O)C=CC=1OC.S(Cl)(Cl)=O.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[CH2:38][CH2:39][NH2:40].[OH-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[CH2:38][CH2:39][NH:40][C:12](=[O:13])[CH2:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][CH:6]=1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1ccc(CCN)cc1OC
Agent: COc1ccc(CC(=O)O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)Cc2ccc(OC)c(OC)c2)cc1OC

Procedure:
A dry dichloromethane solution (1000 ml) of 3,4-dimethoxyphenylacetyl chloride prepared from 325 g of 3,4-dimethoxyphenylacetic acid and 300 ml of thionyl chloride was slowly added to a two-phase solvent consisting of 300 g of 3,4-dimethoxyphenethylamine, 850 ml of 2N sodium hydroxide, and 2000 ml of dichloromethane while stirring under ice-cooling. Chloroform was added to the mixture to dissolve the precipitated solid. The aqueous layer was removed, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution, dried, and the solvent was evaporated. To the residue was added methanol, the mixture was heated and allowed to cool, and the thus precipitated crystal was collected by filtration to yield 570 g of the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[P:11]([O-:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].[CH2:19]([O:26][C:27]([NH:29][CH2:30][CH2:31][CH:32]=[O:33])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]([NH:29][CH2:30][CH2:31][CH:32]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[OH:33])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOP([O-])OCC
Reactant: O=CCCNC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(O)CCNC(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
To a solution of potassium bis(trimethylsilyl)amide (1.13 g, 5.66 mmol) in tetrahydrofuran (10 mL) at 0° C. was added diethyl phosphite (0.73 g, 5.66 mmol). After 10 min, 3-(benzyloxycarbonylamino)propanal (0.78 g, 3.77 mmol) was added as a solution in tetrahydrofuran (5 mL). After 30 min, the reaction was quenched by the addition of 2N hydrochloric acid (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with sat'd sodium chloride (50 mL), dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with hexane/acetone (1:1) gave a colorless oil (0.36 g): ESI-MS 346.1 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:34])=[C:12]([CH2:14][C:15]([NH:17][C:18]2([C:30]([O:32]C)=O)[CH2:23][CH2:22][C:21]([O:28][CH3:29])([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]2)=[O:16])[CH:13]=1.Cl>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:34])=[C:12]([C:14]2[C:15](=[O:16])[NH:17][C:18]3([CH2:19][CH2:20][C:21]([O:28][CH3:29])([C:24]([F:26])([F:25])[F:27])[CH2:22][CH2:23]3)[C:30]=2[OH:32])[CH:13]=1
Reactant: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCC(OC)(C(F)(F)F)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1(C(F)(F)F)CCC2(CC1)NC(=O)C(c1cc(Br)ccc1C)=C2O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2.26 g (20.16 mmol) of potassium tert-butoxide were added to 4.70 g (10.08 mmol) of methyl 1-{[(5-bromo-2-methylphenyl)acetyl]amino}-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Example 36A) in 50 ml of N,N-dimethylformamide. The reaction mixture was stirred at 80° C. for 60 minutes. For work-up, the cold reaction mixture was poured into 800 ml of ice-water and acidified with aqueous hydrochloric acid. The crude product was filtered off and dried. This gave 3.68 g (84% of theory) of the title compound as a beige powder.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=1)=[O:2]
Reactant: CCOC(=O)CCCOc1ccc(C=O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=Cc1ccc(OCCCC(=O)O)c([N+](=O)[O-])c1
Yield: 69.1 %

Procedure:
4-(4-Formyl-2-nitrophenoxy)butanoic acid, ethyl ester (135 mg, 0.48 mmol) is dissolved in 3 mL of methanol/water (3:2) and treated with 232 mg (1.68 mmol) of potassium carbonate according to the procedure described for Example 4 to give 84 mg (69%) of 4-(4-formyl-2-nitrophenoxy)butanoic acid as a yellow powder: m.p. 136°-139°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3400, 1730, 1700, 1650, 1600, 1570 cm-1 ; MS (CI) m/e 254, 236, 224, 208, 196, 168.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.Cl[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]>>[N+:25]([C:24]1[CH:23]=[CH:22][S:21][C:20]=1[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)([O-:27])=[O:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: O=[N+]([O-])c1ccsc1-c1ncco1

Procedure:
2-(3-nitrothiophen-2-yl)oxazole was prepared from 2-(tributylstannyl)oxazole (0.94 g, 2.62 mmol) and 2-chloro-3-nitrothiophene (0.429 g, 2.62 mmol) according to protocol E. Retention time (min)=1.794, method [1], MS (ESI) 197.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:22][C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=3)=[N:25][C:24]=2[CH3:38])=[CH:6][CH:5]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
To a mixture of 4-hydroxy-benzoic acid methyl ester (152 mg, 1 mmol) and potassium carbonate (152 mg, 1.1 mmol) add acetonitrile (4 mL). To this mixture add 5-bromomethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (Example 4, 314 mg, 1 mmol). Warm the resulting reaction mixture to 60° C., and stir at this temperature for 5 hrs. Cool the mixture to room temperature, dilute with ethyl acetate, wash with water, then brine, dry over MgSO4, filter and concentrate to give the title compound as a white solid (364 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N(CC)(CC)CC.Cl>C(Cl)Cl.CCOCC.O>[C:29]([NH:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture, under N2, of 12.6 g of 1-(2-amino-4-trifluoromethylphenyl)indoline hydrochloride in 150 ml of dry CH2Cl2 is treated with 8.09 g of triethylamine. The mixture is cooled to 0°-5° C., and kept at that temperature while a solution of 5.62 g of benzoyl chloride and 25 ml of CH2Cl2 is added dropwise over 1.0 hour. After stirring at room temperature overnight, water is added to dissolve (C2H5)3N.HCl and the layers are separated. The organic phase is extracted further with water, 3 N--HCl, 3 N--NaOH, water again and dried over N2SO4. The solvent is removed leaving an oil which, when digested with ether, becomes a crystalline mass. After cooling, 1-(2-benzamido-4-trifluoromethylphenyl)indoline is obtained having m.p. 114°-119° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15](OS(C(F)(F)F)(=O)=O)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](=[N:41][NH2:42])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:42][N:41]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NN=C(c3ccccc3)c3ccccc3)c2CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.39 g, 10.2 mmol) in dry, degassed toluene (100 mL) under nitrogen, then add benzophenone hydrazone (2.00 g, 10.2 mmol), sodium tert-butoxide (1.37 g, 14.3 mmol), BINAP (635 mg, 1.02 mmol) and bis(dibenzylideneacetone)palladium (0) (280 mg, 0.306 mmol). Stir at 100° C. for 8 hr, cool to RT, concentrate and purify (silica gel chromatography, eluting with 95:5 2-methylpentane:EtOAc) to give the title compound (4.2 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[N:22]=[CH:21][C:20]([CH:23]([OH:46])[CH2:24][CH2:25][O:26][C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[CH:10]=1.[H-].[Na+].[CH3:49][O:50][CH2:51]Cl.[Cl-].[NH4+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([O:46][CH2:49][O:50][CH3:51])[CH2:24][CH2:25][O:26][C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:21][N:22]=2)[CH:10]=1
Reactant: COCCl
Reactant: Cc1cccc(C)c1-c1cccc(COc2ccc(C(O)CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COCOC(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(OCc2cccc(-c3c(C)cccc3C)c2)nc1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 32 %

Procedure:
1-{6-[(2′,6′-Dimethylbiphenyl-3-yl)methoxy]pyridin-3-yl}-3-(trityloxy)propan-1-ol (250 mg, 0.413 mmol) produced in Example 31 (31C) was dissolved in dimethylformamide (2.5 mL), and sodium hydride (about 63%, oily, 32 mg, 0.83 mmol) was added thereto at 0° C., and then, the resulting mixture was stirred under a nitrogen atmosphere at 0° C. for 50 minutes. Thereafter, chloromethyl methyl ether (0.063 mL, 0.825 mmol) and tetra-n-butyl ammonium iodide (8.0 mg, 0.021 mmol) were sequentially added thereto at 0° C., and the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 5 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride was added at 0° C., and the organic matter was extracted with ethyl acetate. The organic layer was washed with water, a saturated sodium bicarbonate solution, and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 75:25 (v/v)), whereby the objective title compound was obtained (85 mg, yield: 32%).
Reaction SMILES: C(C1(C(NC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C(O)=O)NC(C(OCC2C=CC=CC=2)=[O:14])C2(CCNCC2)S1)C1C=CC=CC=1.[CH:52]([N:55]=[C:56]=[N:57][CH:58]([CH3:60])[CH3:59])([CH3:54])[CH3:53].ClCCl.[N+](C)([O-])=O>C(Cl)(Cl)Cl>[CH:52]([NH:55][C:56]([NH:57][CH:58]([CH3:60])[CH3:59])=[O:14])([CH3:54])[CH3:53]
Reactant: CC(C)N=C=NC(C)C
Reactant: O=C(OCc1ccccc1)C1NC(Cc2ccccc2)(C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)SC12CCNCC2
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=O)NC(C)C
Reaction time: 12 h

Procedure:
The reation between 8 benzyl-4-benzyloxycarbonyl-alpha- tritylamino-1-thia-3,8-diazaspiro[4.5 ]decane-2-acetic acid (obtained in 6.2.) and diisopropylcarbodiimide (80 g) can be performed in chloroform (400 ml), dichloromethane or a mixture of nitromethane and chloroform, either at ambient temperature, leaving the mixture to stand for 4 weeks, or at 50° C. for 12 hours. In all cases, the 1,3-diisopropylurea formed is removed by filtration, the solvent and excess reagent are evaporated and the residue is passed through a column of silica gel (60 Merck), using chloroform as eluent. In all cases, benzyl 1°-benzyl-6-tritylamino-spiro[penam-2,4'-piperidine ]-3-carboxylate is obtained, which is crystallized from diethy ether in a yield of 25 to 40%; M.P. 191°-192° C. (recrystallized from acetonitrile).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CC(C)([O-])C.[K+].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=1.[Cl-].[NH4+]>O1CCCC1.[Cl-].[Na+].O.O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=1)[CH3:2]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (benzhydrylidene-amino)-acetic acid ethyl ester (2.84 g, 10.4 mmol) in anhydrous tetrahydrofuran (15 mL) at −78° C. under an atmosphere of argon was added a 1 M solution of potassium tert-butoxide in tetrahydrofuran (11 mL, 11 mmol) to form a red/orange solution. After stirring at −78° C. for 15 minutes a solution of 1-bromomethyl-3-nitro-benzene (2.14 g, 9.7 mmol) in tetrahydrofuran (20 mL) was added and the reaction mixture left to warm slowly to ambient temperature and stir for 16 hours. To the reaction mixture was added saturated aqueous ammonium chloride (20 mL), the mixture was poured into water (100 mL), diluted with brine (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried over sodium sulfate and concentrated in vacuo to give crude 2-(benzhydrylidene-amino)-3-(3-nitro-phenyl)-propionic acid ethyl ester as a red/brown viscous oil which was used without further purification (4.1 g, ≈100%).
Reaction SMILES: C(O)=O.[N:4]1[O:5][N:6]=[C:7]2[CH:12]=[C:11]([C:13](Cl)=[O:14])[CH:10]=[CH:9][C:8]=12.O.OS(O)(=O)=O.[CH2:22]1[CH2:26]O[CH2:24][CH2:23]1>CO.C(Cl)(Cl)Cl>[CH:22]12[N:4]([C:13]([C:11]3[CH:10]=[CH:9][C:8]4=[N:4][O:5][N:6]=[C:7]4[CH:12]=3)=[O:14])[CH:8]([CH2:9][CH2:26]1)[CH2:7][CH2:24][CH2:23]2
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O=CO
Solvent: O
Product: O=C(c1ccc2nonc2c1)N1C2CCCC1CC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tropane (2.5 g, 20 mmol) in toluene (80 ml) was slowly added [2,2,2]-trichloroethyl chloroformate (20 ml, 94.4 mmol) and Na2CO3(1.5 g, 14 mmol). The mixture was heated to 110° C. overnight. The solution was cooled to room temperature, ethyl acetate (150 ml), water (100 ml) and H2SO4 (→pH 2) were added. The organic phase was dried over sodium sulfate, and concentrated under vacuum to yield 9.3 g colorless oil. The preceding product (3.3 g) was dissolved in THF (50 ml) and methanol (50 ml), and freshly prepared Zn/Cu (15 g) was added followed by formic acid (5 ml). The mixture was stirred at room temperature for 20 minutes before filtering the solids and evaporating the solvent until ˜10 ml remained. Concentrated sodium hydroxide solution was added until pH 10 was reached and the mixture extracted with chloroform (100 ml) and the organic phase dried over sodium sulfate. Triethylamine (2 ml) was added followed by a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (0.5 g, 2.73 mmol) in chloroform (20 ml), slowly. After stirring the mixture for 20 minutes, water (100 ml) and H2SO4 (→pH2) were added and the aqueous phase extracted with chloroform (100 ml), dried over magnesium sulfate, and concentrated under vacuum to give an oil. The material was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:2), to give after crystallization from dicloromethane/MTBE 133 mg of a white solid: mp=128-130° C., LC-MS, MH+=258; 1H NMR (300 MHz, CDCl3) δ 7.92 (s, 1H); 7.90 (d, 1H, J=6.3 Hz); 7.52 (d, 1H, J=6.3 Hz); 4.84 (s, 1H); 4.06 (s, 1H); 2.06-1.50 ppm (m, 10H).