Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:10])[CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1.F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>O1CCCC1.C(N(C(C)C)C(C)C)C.CN(C)C=O>[F:1][CH:2]([F:10])[CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=2[N+:22]([O-:24])=[O:23])[CH2:5]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N[C@@H]1CCN(CC(F)F)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(N[C@@H]2CCN(CC(F)F)C2)c([N+](=O)[O-])c1
Reaction time: 72 h

Procedure:
To a solution of EXAMPLE 407B (468 mg) in tetrahydrofuran (20 mL), N-ethyl-N-isopropylpropan-2-amine (2.193 mL) and N,N-dimethylformamide (2 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (473 mg) and the reaction mixture was stirred 72 hours. The crude product was isolated by concentration and was purified on silica gel, and was eluted with a 0.5, 2.5, and 5% methanol in methylene chloride step gradient to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:40])=[N:14][C:15]([CH3:39])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:40])=[N:14][C:15]([CH3:39])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(Oc3ccccc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(Oc2ccccc2)cc1
Yield: 89.7 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-phenoxyphenyl)pyridin-3-yl)acetate (0.016 g, 0.029 mmol) and LiOH (7.03 mg, 0.294 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 4 h. The, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-phenoxyphenyl)pyridin-3-yl)acetic acid (0.0132 g, 0.026 mmol, 87% yield) as solid. 1H NMR (500 MHz, CDCl3) δ 7.35-7.40 (m, 2H), 7.22-7.27 (m, 1H), 7.08-7.18 (m, 4H), 7.03-7.08 (m, 2H), 6.01 (br. s., 1H), 3.35-3.70 (m, 1H), 2.80-3.08 (m, 1H), 2.65 (s, 3H), 2.28-2.38 (m, 1H), 2.26 (s, 3H), 2.06-2.21 (m, 1H), 1.18-1.42 (m, 4H), 1.26 (s, 9H), 0.82 (br.s., 3H), 0.75 (br.s., 3H). LCMS (M+H)=517.4.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)(=[O:19])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>CN1C(=O)CCC1.C(N(CC)CC)C.COCCOC>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:41]2[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccccc3)cc2)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of N-(2-Benzoyl-4-chloro-phenyl)-4-iodo-benzenesulfonamide (497 mg, 1.0 mmol), [1,1′ Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (30 mg, 0.037 mmol) and dry cesium carbonate (511 mg, 1.57 mmol) in NMP (3 mL), was added DME (3 mL) and dry triethylamine (3 mL) under dry nitrogen. To this stirred mixture was added (4-methoxyphenyl)boronic acid (202 mg) and the mixture was stirred at 55° C. overnight. The reaction was worked up by addition to crushed ice and extracted with ethyl acetate (3×75 mL), and the organic layer was dried (MgSO4), filtered and concentrated. The crude product was chromatographed on silica gel using 10–30% EtOAc/Hexane. 1H NMR (CDCl3) δ 9.64 (br s, 1H, NH), 7.75 (dm, 1H), 7.75 (dm, 2H, J=8.8 Hz), 7.48 (m, 3H), 7.56 (dm, 2H, J=8.4 Hz), 7.51 (m), 7.32 (d 1H, J=2.2 Hz), 7.26 (d, 1H, J=7 Hz), 7.09 (d, 2H, J=8.4 Hz), 3.65 (s, 3H). MS: m/z 478.0 (M+1).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6](=O)[CH2:7][CH:8]([CH3:10])[CH3:9].C([BH3-])#N.[Na+].Cl.[CH3:17][O:18][C:19]([C@@H:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH2:28])=[O:20].Cl>CO>[CH3:17][O:18][C:19]([C@@H:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:28][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:20]
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1N
Reactant: CC(C)CC=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)[C@@H]1CCCCC[C@@H]1NCCC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
Sodium acetate (0.328 g, 4.00 mmol), powdered 4 Å molecular sieves (1.0 g), isovaleraldehyde (0.216 mL, 2.00 mmol) and sodium cyanoborohydride (0.251 mg, 4.00 mmol) were added sequentially to a solution of cis-2-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 2a, 0.415 g, 2.00 mmol) in methanol (10 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, then was acidified to pH=2 by the addition of 1.0 M aqueous hydrochloric acid solution. After stirring for 5 min at 25° C., the mixture was partitioned between half-saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (3×50 mL). The organic layers were washed sequentially with half-saturated aqueous sodium bicarbonate solution (100 mL) and saturated aqueous brine solution (100 mL), then were dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (Analogix SuperFlash Column; 0-40% ethyl acetate in hexanes) to afford the desired product, cis-2-(3-methyl-butylamino)-cycloheptanecarboxylic acid methyl ester (0.340 g, 1.41 mmol, 70%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 0.89 (d, 6H, J=6.5 Hz), 1.33 (q, 2H, J=7.3 Hz), 1.43-1.50 (m, 3H), 1.57-1.66 (m, 3H), 1.72-1.79 (m, 3H), 1.81-1.87 (m, 2H), 2.47-2.54 (m, 1H), 2.59-2.66 (m, 1H), 2.79-2.84 (m, 1H), 2.95-2.99 (m, 1H), 3.67 (s, 3H). LC-MS (ESI) calcd for C14H27NO2 241.20, found 242.4 [M+H+].
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:33])[C@@H:8]([N:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([O:6][C:7](=[O:33])[C@@H:8]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc([N+](=O)[O-])cc1)[C@H](C(=O)OC1CCCC1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(N)cc1)[C@H](C(=O)OC1CCCC1)c1ccccc1
Yield: 90 %

Procedure:
A mixture of Stage 2 product (12 g, 26.4 mmol) and 10% Pd/C (2.0 g) in EtOAc (350 ml) was hydrogenated at room temperature for 18 h. The Pd/C catalyst was filtered off through a pad of celite. The filtrate was concentrated under reduced pressure to yield a white solid (10.1 g, 90% yield). LCMS purity 100%, m/z 425 [M++H]+, 466 [M++H+41]+.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCN(C2CCCCC2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-cyclohexylpiperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17](O)=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[C:4]([O:20][CH3:21])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:46][C@H:47]1[CH:52]2[CH2:53][CH2:54][N:49]([CH2:50][CH2:51]2)[CH2:48]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:49]12[CH2:54][CH2:53][CH:52]([CH2:51][CH2:50]1)[C@H:47]([NH:46][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[O:20][CH3:21])=[N:12][C:11]=13)=[O:18])[CH2:48]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COc1cc(Cl)ccc1-c1nc2c(C(=O)O)cccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Cl)ccc1-c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
A mixture of 2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxylic acid (95 mg, 0.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol), 1-hydroxybenzotriazole (76 mg, 0.62 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (78 mg, 0.39 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.20 mL, 1.4 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxamide (69 mg, 54%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.59 (d, J=7.0 Hz, 1H), 8.19 (dd, J=7.8, 1.0 Hz, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.83 (dd, J=8.2, 1.0 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.15-7.10 (m, 2H), 4.40-4.22 (m, 1H), 4.02 (s, 3H), 3.55-3.50 (m, 1H), 3.20-2.75 (m, 5H), 2.23-2.19 (m, 1H), 2.10-2.00 (m, 1H), 1.80-1.75 (m, 2H), 1.60-1.50 (m, 1H); MS (ESI+) m/z 412 (M+H); HPLC>99% (AUC), tR=13.78 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:14]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH4+].[Cl-]>CO.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:14]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(COc1ccccc1)N1CCCC[C@@H]1c1nc(-c2cccc([N+](=O)[O-])c2)no1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1cccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)c1
Reaction time: 0.5 h

Procedure:
(R)-1-{2-[3-(3-Nitro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-2-phenoxy-ethanone were dissolved in 100 ml MeOH. 50 ml sat. NH4Cl and Zn-powder were added. The suspension was briefly heated to reflux and stirred for 30 min. After filtration the MeOH was evaporated and the product isolated via extraction ethylacetate/water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:15]=[C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].S(O[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=O)(=O)C.O>CN(C)C=O>[CH3:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][N:12]2[C:11](=[O:20])[CH2:10][C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[C:14](=[CH:15][CH2:16][CH2:17][CH2:18]3)[C:13]2=[O:19])=[CH:31][CH:32]=1
Reactant: COc1cccc(C23CCCC=C2C(=O)NC(=O)C3)c1
Reactant: Cc1ccc(CCOS(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C23CCCC=C2C(=O)N(CCc2ccc(C)cc2)C(=O)C3)c1

Procedure:
4a-(m-Methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (6 g) in 75 ml of anhydrous dimethylformamide was added to a 55% suspension of sodium hydride in mineral oil (1.2 g) in 50 ml of dimethylformamide at 70°. The reaction mixture was heated for one hour at 80° and then cooled to 25°. p-Methylphenethyl mesylate (7.0 g) was added and the reaction heated at 70° for 18 hours. It was poured into water and extracted with ether. The residue after evaporation of the ether was chromatographed on 800 g. of Florisil. This yielded 4.4 g, mp 134°-140°; recrystallized from ethanol, mp 149°-151°.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([N+:34]([O-])=O)[CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]>C(O)(=O)C.[Fe]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH2:34])[CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)c([N+](=O)[O-])c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)c(N)c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
To a stirred solution of acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-3-nitro-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (1.71 g, 2.9 mmol) in glacial acetic acid (15 mL) was added iron powder (3.22 g, 57.7 mmol). After stirring at 60° C. for 15 min, the reaction mixture was filtered through a celite bed. The filtrate was concentrated under reduced pressure, and the resulting residue was taken up in ethyl acetate and the solution was washed with water, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to a residue which was purified by silica gel column chromatography to furnish acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[3-(3-amino-4-hydroxy-benzyl)-4-chloro-phenyl]-tetrahydro-pyran-2-ylmethyl ester (1.3 g)
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:25])=[C:8]([CH3:24])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]=1)=[O:11].Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:25])=[C:8]([CH3:24])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][S:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=2)(=[O:33])=[O:32])=[C:14]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]=1)=[O:11]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 68.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (0.516 g, 1.14 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.540 g, 2.28 mmol). Purification on 2% H3PO4 /MeOH treated silica gel, eluting with a 15 & 25% EtOAc/hexane step gradient gave 0.509 g (68%) of the title compound as a brown solid, mp 72-82° C. 1H NMR (DMSO-d6) δ 1.25-1.34 (m, 2 H), 1.50-1.55 (m, 2 H), 1.62-1.74 (m, 4 H), 1.77 (s, 3 H), 2.15 (s, 3 H), 2.95 (quintet, 1 H), 3.88 (s, 2 H), 7.10-7.15 (m, 2 H), 7.20 (d, 1 H), 7.27 (t, 1 H), 7.35-7.37 (m, 2 H), 7.48-7.58 (m, 3 H), 7.96 (dd, 1 H). IR (KBr) 3400, 2950, 1690, 1390 and 1190 cm-1. mass spectrum (-ESI) m/z 651 (M-H). Anal. Calcd. for C32H29BrO8S.0.4H2O: C, 58.17; H, 4.55; N, 0.00. Found: C, 58.20; H, 4.55; N, 0.03.
Reaction SMILES: O1CCCC1.[CH2:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](Cl)=[N:18][OH:19])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].[C:21]([C:23]1[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=1)#[CH:22].C(N(CC)CC)C>O>[CH2:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=3)[O:19][N:18]=2)=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9]
Reactant: C#Cc1cccnc1N
Reactant: CCCCc1ccc(CC(Cl)=NO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1ccc(Cc2cc(-c3cccnc3N)on2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-butyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.665 mmol) described in Manufacturing Example 70-1-3 and 3-ethynyl-pyridin-2-ylamine (50 mg, 0.424 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (232 μL, 1.66 mmol) at room temperature, which was stirred for 8 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (55 mg, 18%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[C@@H:13]([CH2:21][OH:22])[O:12]3)[N:9]=[CH:10][C:3]=12.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:22][CH2:21][C@@H:13]1[C@H:14]2[O:18][C:17]([CH3:19])([CH3:20])[O:16][C@H:15]2[C@H:11]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH:1][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:3]3[CH:10]=[N:9]2)[O:12]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ncc2c(N)ncnc21
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ncc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
Compound 22.2 (4.20 g, 13.66 mmol) in pyrdine (40 mL, 0.33 M) was cooled to 0° C. and treated with benzoyl chloride (12.68 mL, 109.3 mmol) The mixture was warmed to room temperature and stirred for 16 h. The solvent was removed in vacuo and the residue was treated with 2.5 N KOH (40 mL) in pyridine (40 mL) and stirred for 20 min. The mixture was cooled to 0° C. and AcOH was added (6 mL). The solvent was removed in vacuo and the residue was dissolved in EtOAc (150 mL) and washed with H2O (100 mL), saturated NaHCO3 (2×100 mL), and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford compound 22.3 (2.74 g, 49% yield) as a white solid: 1H NMR (CDCl3, 300 MHz) 9.02 (br s, 1H), 8.80 (s, 1H), 8.55 (s, 1H), 7.97 (d, J=7.5 Hz, 2H), 7.62 (app t, J=7.5 Hz, 1H), 7.52 (t, J=7.5 Hz, 2H), 6.65 (s, 1H), 5.25 (m, 1H), 5.07 (d, J=6.0 Hz, 1H), 4.99 (br s, 1H), 4.53 (m, 1H), 3.91 (m, 1H), 3.77 (m, 1H), 1.61 (s, 3H), 1.35 (s, 3H); MS (ESI) m/z 412 [M+H]+.
Reaction SMILES: [CH:1]12[CH:9]3[CH:3]([CH2:4][CH2:5][CH:6]3[CH2:7][CH2:8]1)[C:2]2=[O:10].C1C=CC(=O)/C(=C/NCCN/C=C2/C=CC=CC/2=[O:26])/C=1.OO>C(O)C>[CH:1]12[CH:9]3[CH:3]([CH2:4][CH2:5][CH:6]3[CH2:7][CH2:8]1)[C:2](=[O:10])[O:26]2
Reactant: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Reactant: O=C1C2CCC3CCC1C32
Agent: OO
Solvent: CCO
Product: O=C1OC2CCC3CCC1C32
Temperature: 25 °C
Reaction time: 24 h
Yield: 617.6 %

Procedure:
Into 0.5 ml of ethanol was dissolved tricyclo[4,2,1,03,9]nonane-2-one (13.6 mg, 0.1 mmol). Into this ethanol solution was added the Co (III) (salen) complex (3.7 mg, 5 μmol) having the above formula (XI). Into this solution was added 30% hydrogen peroxide aqueous solution (15 μI, hydrogen peroxide content 0.13 mmol), which was stirred at room temperature for 24 hours. After the completion of the reaction, the mixed liquid was concentrated, and the residue was chromatographed in a silica gel column with hexane/ethyl acetate (=8/2) as a developing solvent, thereby obtaining 2-oxatricyclo[5.2.1.04,10]decane-3-one (4.7 mg, yield 31%) having the above formula (VIII). The enantiomer excess percentage of the product was determined as follows.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:22]=[O:23])=[C:13]([N:15]([CH2:18][CH:19]([OH:21])[CH3:20])C=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:22]=[O:23])=[C:13]([NH:15][CH2:18][CH:19]([OH:21])[CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)CN(C=O)c1cc(OCc2ccccc2)ccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(O)CNc1cc(OCc2ccccc2)ccc1C=O
Temperature: 0 °C

Procedure:
An ice-cooled solution of the product from Step B (298 g, 0.95 mol) in THF (3 L) was treated with 1 M aqueous sodium hydroxide (1.95 L, 1.9 mol) keeping the temperature below 8° C. After the starting material was consumed, the mixture was diluted with brine and extracted twice with ethyl ether. The organic solution was washed with water until neutral and then with brine, dried over sodium sulfate, treated with charcoal and passed through silica (1 kg) with ether and with 1:1 ethyl acetate-hexane to yield, after concentration in vacuo, a yellow solid (207 g, 76%).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([N:12]2[CH2:17]COC[CH2:13]2)=[O:11])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:42][C:43]([NH2:45])=[NH:44])[CH:33]=[CH:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>>[CH3:17][N:12]([CH3:13])[C:10]([CH:6]1[C:5]2[N:45]=[C:43]([NH:42][C:32]3[CH:33]=[CH:34][C:35]([N:36]4[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]4)=[C:30]([O:29][CH3:28])[CH:31]=3)[N:44]=[CH:3][C:4]=2[CH2:9][CH2:8][CH2:7]1)=[O:11]
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C1CCCC(C(=O)N2CCOCC2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(C(=O)N(C)C)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-(morpholine-4-carbonyl)-cyclohexanone (25 mg, 0.11 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (31 mg, 0.084 mmol) using in analogous manner the procedure described in example 45b). Obtained as a white solid (23 mg, 67%). MS ISP (m/e): 407.4 (100) [(M+H)+]. mp 150-152° C.
Reaction SMILES: [CH2:1]([Si:3]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14]O)=[CH:10][C:9]([C:16]([F:19])([F:18])[F:17])=[CH:8][CH:7]=2)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:43]C(Br)(Br)Br>C1COCC1>[Br:43][CH2:14][CH2:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[NH:5][C:4]=1[Si:3]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:1][CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCBr
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A solution 2-(2-(triethylsilyl)-5-(trifluoromethyl)-1H-indol-3-yl)ethanol (0.730 g; 2.13 mmol) in THF (6 mL) was added to a solution of triphenyl phosphine (0.836 g; 3.19 mmol) and perbromomethane (1.06 g; 3.19 mmol) in THF (12 mL) pre-stirred for 1 hour. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 5 to 40% ethyl acetate in heptane) to afford 0.449 g (52%) of the title compound as a yellow oil.