Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:20]=1)#N.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.CC(O)=[O:39].O>C(Cl)Cl>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:20]=1)=[O:39]
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)CCc1cc(C(N)=O)ccc1O2
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1ccc2c(c1)CCc1cc(C=O)ccc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of the intermediate from step 3 (2.5 g, 9.5 mmol) in dry CH2Cl2 (320 mL), cooled at −78° C. and under N2 atmosphere, add DIBAL 10M in toluene (28.4 mmol). Allow the mixture to warm to room temperature and stir overnight. Cool the mixture to 0° C. and add AcOH/H2O. Stir at room temperature for 1 hour. Extract the aqueous layer with CH2Cl2 (×2). Combine the organic layers and dry over Na2SO4. Eliminate the solvent and purify by flash chromatography (eluent: EtOAc/hexane 3/1) to obtain the title compound (1.75 g, 69%). 1H-NMR (MeOD, 300 MHz): 9.91 (s, 1H), 7.81-7.73 (m, 4H), 7.37-7.26 (m, 2H), 3.21 (m, 4). 13C-NMR (MeOD, 300 MHz): 193.2, 162.6, 160.3, 134.4, 133.8, 133.2, 131.9, 131.3, 130.6, 128.8, 123.3, 122.4, 32.9, 32.8.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20]C)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C1C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(OC)cc1C2
Agent: BrB(Br)Br
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(C)=C1c1ccc(O)cc1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9a-butyl-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (76 mg, 0.267 mmol) in anhydrous CH2Cl2 (2 mL) was placed under a nitrogen atmosphere, cooled in an ice bath, and stirred while 1M BBr3 in CH2Cl2 (0.80 mL, 0.80 mmol) was added by syringe. The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) containing 2N HCl (2 mL). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil. This material was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate using 5% MeOH in CH2Cl2 as the developing solvent. The product band was eluted with 10% MeOH in CH2Cl2 and the eluant evaporated under vacuum to give an oil which was lyophilized from benzene to afford 9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@H:19]([O:26]C2CCCCO2)[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C@H:15]([O:33]C2CCCCO2)[CH2:14][C@H:13]1[Cl:40])(=[O:3])[CH3:2]>C(O)(=O)C.O.O1CCCC1>[C:1]([NH:4][C:5](=[O:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:24])[CH3:25])[C@H:15]([OH:33])[CH2:14][C@H:13]1[Cl:40])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](CCC=C(C)C)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@H]1Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](O)CCC=C(C)C)[C@H](O)C[C@H]1Cl
Yield: 59.7 %

Procedure:
460 mg of (13E)-(8R,9R,11R,12R,15R)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-19-methyl-13,18-prostadienoic acid acetylamide was stirred under argon at room temperature for 17 hours with 10 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture was then concentrated under vacuum, and the residue was purified by column chromatography on silica gel with hexane/0-100% ethyl acetate as the eluent, thus obtaining 197 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[Br:18])[NH:14][N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[Br:18])[N:14]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)[N:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cc2[nH]ncc2cc1OCc1ccccc1
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1cc2c(cnn2C2CCCCO2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a solution of 5-(benzyloxy)-6-bromo-1H-indazole (5 g, 16.5 mmol) in THF (30 mL) and DCM (30 mL) is added 3,4-dihydro-2H-pyran (3 mL, 32.8 mmol) and methanesulfonic acid (1 mL, 15.3 mmol). After the reaction mixture is stirred at RT for 2 hours, EtOAc (50 mL) and saturated aqueous NaHCO3 are added. The organic phase is separated, dried over MgSO4, and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (4:1) to give the desired product (2.7 g, 42.2% yield). MS (m/z): 387.0 (M+H).
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)[C:3](OCC)=[O:4].[NH2:16][C:17](N)=[S:18].Cl.[OH2:21]>C(OCCO)C>[CH3:15][C:10]1[CH:9]=[C:8]([CH:2]2[S:18][C:17](=[O:21])[NH:16][C:3]2=[O:4])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: O
Reactant: CCOC(=O)C(Cl)c1ccc(C)c(C)c1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCOCCO
Product: Cc1ccc(C2SC(=O)NC2=O)cc1C
Yield: 60 %

Procedure:
2.26 g of ethyl α-chloro-α-(3,4-dimethylphenyl)acetate and 910 mg of thiourea, in 15 ml of ethylene glycol monoethyl ether, are stirred under reflux for 2 hours. Then, 1 ml of concentrated HCl is added and the mixture is further heated under reflux for 3.5 hours. After cooling, water is added and extraction is carried out with ethyl acetate. The extract is washed with water and dried (MgSO4). After the solvent is distilled off, column chromatography is carried out on the oily residue with 100 g of silica gel. The eluate with chloroform-ethyl acetate (5:1) yields crystals of 5-(3,4-dimethylphenyl)thiazolidine-2,4-dione 1.32 g (60%). Recrystallization from cyclohexane-ethyl acetate gives colorless prisms, m.p. 121°-122° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](/[CH:10]=[CH:11]/[C:12]2[N:13]([CH3:23])[N:14]=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[S:5][C:6]=1[C:7]([OH:9])=O.CN(C(O[N:32]1N=N[C:34]2C=CC=[CH:38][C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[CH:33]([NH:32][C:7]([C:6]1[S:5][C:4](/[CH:10]=[CH:11]/[C:12]2[N:13]([CH3:23])[N:14]=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:3][C:2]=1[CH3:1])=[O:9])([CH3:38])[CH3:34]
Reactant: Cc1nc(/C=C/c2c(-c3ccccn3)nnn2C)sc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(/C=C/c2c(-c3ccccn3)nnn2C)sc1C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 4-methyl-2-[(E)-2-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-yl)-vinyl]-thiazole-5-carboxylic acid (56 mg, 0.17 mmol) and TBTU (60 mg, 0.19 mmol) in DMF (0.9 mL) was added DIPEA (146 μL, 0.86 mmol). Then isopropylamine (16 μL, 0.24 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 1 to 10% methanol in dichloromethane) afforded the title compound (36 mg, 57%) as a light yellow solid after recrystallisation from methanol-water. MS: m/e=369.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.C([Li])CCC.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([OH:24])([C:2]3[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=3)[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: Cn1cc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(C2(O)C(=O)Nc3cc(Cl)ccc32)cn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazole (0.98 g, 6.0 mmol) in tetrahydrofuran (10 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 2.76 mL, 6.90 mmol) (Aldrich) dropwisely. The mixture was stirred at −78° C. for 10 minutes. To the obtained brownish solution was added a solution of 6-chloroisatin (0.5 g, 2.76 mmol) (Crescent) in tetrahydrofuran (5 mL). The reaction mixture was warmed up to room temperature and stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate three times. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate:dichloromethane, 1:1 V/V) to give rac-6-chloro-3-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-1,3-dihydro-indol-2-one as a yellow solid. (Yield 0.22 g, 30%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1C(=O)N([Br:34])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:34][C:17]1[S:16][C:15]([NH:14][C:12](=[O:13])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2ncc(Br)s2)cc1

Procedure:
A solution of 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 65, 202 mg, 510 μmol), NBS (91 mg, 510 μmol), and Bz2O2 (6 mg, 26 μmol), in CCl4 (2 mL) was heated to reflux for 16 h. After removal of the solvent, the residue was partitioned between EtOAc (30 mL) and H2O (30 mL). The organic extracts were washed with saturated aqueous NH4Cl (30 mL), before being dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (CH2Cl2-EtOAc, 2:3) gave the title compound: RTA=3.50 min; m/z (ES+)=516.2 [M+MeCN+H]+.
Reaction SMILES: [F:1][C:2]([F:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C@@H:3]([NH:11][C@H:12]([C:18]12OCC(C)(C[O:23]1)C[O:19]2)[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.Cl.[OH-].[Na+]>C1COCC1.O>[F:33][C:2]([F:1])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C@@H:3]([NH:11][C@@H:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:18]([OH:23])=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1
Reactant: CC(C)(C)C[C@H](N[C@@H](c1ccc(F)cc1)C(F)(F)c1ccccn1)C12OCC(C)(CO1)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@H](N[C@@H](c1ccc(F)cc1)C(F)(F)c1ccccn1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of [2,2-difluoro-1(S)-(4-fluorophenyl)-2-pyridin-2-ylethyl]-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)butyl]amine (265 mg, 0.571 mmol) in a mixture of THF (5 ml) and water (5 ml) was added 1N HCl (2 ml, 2 mmol) and the reaction mixture was stirred at room temperature for 2 h. 1N NaOH (3.6 ml, 3.6 mmol) was added and stirring was continued at room temperature for 4 h. The solvent was evaporated using rotavap and 6N HCl was added dropwise to adjust the pH to 6. The precipitates were filtered and dried to obtain 2(S)-[2,2-difluoro-1(S)-(4-fluorophenyl)-2-pyridin-2-ylethylamino]-4,4-dimethylpentanoic acid (100 mg) as a white solid which was converted to the title compound as described in Example 1, Step 12 above. LC/MS: 443.2 (M−1)−1, 445.4 (M+1)+1, 466.9 (M+Na). 1HNMR (DMSO-d6): δ 8.7 (d, 1H), 8.6 (s, 1H), 7.95 (t, 1H), 7.6 (d, 1H), 7.55 (t, 1H), 7.4 (d, 2H), 7.2 (d, 2H), 4.6 (m, 1H), 2.6 (t, 1H), 1.3 (m, 4H), 0.6 (S, 10H), 0.25 (t, 1H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6]N(C)C)C.C([O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[N:22][CH:21]=1)C.C[O-].[Na+].Cl>C(O)(=O)C.C(O)C.CO>[O:3]=[C:4]1[N:26]([C:23]2[N:22]=[CH:21][C:20]([C:19]([OH:18])=[O:28])=[CH:25][CH:24]=2)[NH:27][CH:6]=[C:5]1[N:10]1[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: CCOC(=O)c1ccc(NN)nc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1ccc(-n2[nH]cc(-n3ccnn3)c2=O)nc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
491 mg (1.8 mmol, 80% purity) of the compound from Example 3A and 289 mg (1.6 mmol) 6-hydrazinonicotinic acid ethyl ester [for the preparation see WO 2006/114213] are stirred in 10 ml acetic acid at RT for 12 h. Thereafter, 120 mg (0.7 mmol) 6-hydrazinonicotinic acid ethyl ester are again added to the reaction mixture and the mixture is stirred again at RT for 13 h. After standing at RT for a further two days, the reaction solution is concentrated in vacuo, the residue is taken up in ethyl acetate, the mixture is washed neutral with saturated sodium bicarbonate solution and the organic phase is dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The intermediate product obtained in this way is dissolved in 10 ml ethanol, 0.3 ml (1.8 mmol) of a 30% strength sodium methylate solution in methanol are added and the mixture is stirred at RT for 17 h. The reaction solution is adjusted to pH 5 with 1 N hydrochloric acid and is subsequently stirred at RT for a further 2 h. It is concentrated in vacuo, acetonitrile is added to the residue, the precipitate which has separated out is filtered off and the residue on the filter is washed with diethyl ether and dried in vacuo. 9.4 ml 0.1 M ethanolic potassium hydroxide solution are added to the ester obtained in this way and the mixture is stirred at RT for 16 h. The reaction solution is adjusted to pH 2 with 1 N hydrochloric acid, the solvent is removed on a rotary evaporator, the residue is taken up in water and the mixture is extracted with ethyl acetate. The crystals which have precipitated out from the aqueous phase are filtered off, the residue on the filter is washed with diethyl ether and the product is dried in vacuo.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](OCC(Cl)(Cl)Cl)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>CS(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Reactant: OC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)N2CCC(O)CC2)CC1
Yield: 34.3 %

Procedure:
A solution of 2,2,2-trichloroethyl 4-(2-tert-butylphenyl)piperazine-1-carboxylate (Example 60, 0.40 g, 1.02 mmol), piperidin-4-ol (0.50 g, 4.94 mmol), and N-ethyl-N-(1-methylethyl)propan-2-amine (0.158 g, 1.22 mmol) in DMSO (5 mL) was stirred for 3 days at 110° C. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give a crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=50:50 to 0:100 then ethyl acetate/methanol=100/0 to 70/30) to provide 1-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}piperidin-4-ol (0.121 g, 34%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:15]=[O:16])=[CH:8][N:9]2[C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1)[CH3:2].CC(=CC)C.O.[O-:23]Cl=O.[Na+]>C1COCC1.C(O)(C)(C)C>[C:12]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[CH:11]=2)[C:7]([C:15]([OH:23])=[O:16])=[CH:8]1)(=[O:13])[NH2:14]
Reactant: [O-][Cl+][O-]
Reactant: CCc1ccc2c(C=O)cn(C(N)=O)c2c1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CCc1ccc2c(C(=O)O)cn(C(N)=O)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Ethyl-3-formyl-indole-1-carboxylic acid amide (720 mg, 3.33 mmol) was dissolved in a mixture of THF (60 mL) and t-butanol (18 mL). 2-methyl-2-butene (2 M solution in THF, 66.6 mL, 133 mmol) was added, followed by a water (16 mL) solution of NaClO2 (80%, 3.76 g, 33.3 mmol) and NaH2PO4 (3.20 g, 26.6 mmol). The resulting solution was stirred at RT for 4 h and THF was concentrated. EtOAc was added and the layers separated. The aqueous layer was acidified by addition of HCl 1N and extracted twice with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane to EtOAc to CH2Cl2/MeOH 8:2) to give the desired compound. tR (HPLC conditions a): 2.17 min. 1H-NMR (400 MHz, CDCl3): δ (ppm): 12.9 (m, 1H), 8.81 (s, 1H), 8.66 (bs, 1H), 8.23 (d, 1H),), 8.09 (m, 2H), 7.70 (dd, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:61]([O:63][CH2:64][Cl:65])=[O:62]>N1C=CC=CC=1.C(OCC)(=O)C>[C:61](=[O:62])([O:63][CH2:64][Cl:65])[O:47][C@H:18]([C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:19][C@@H:20]([NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43]([O:44][CH3:45])=[O:46])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCCl
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)OCCl)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a solution of the product from Example 111 (0.050 g, 0.062 mmol) in pyridine (0.60 mL) at room temperature was added chloromethyl chloroformate (0.007 mL, 0.079 mmol), and the mixture was stirred for 30 minutes. Additional chloromethyl chloroformate (0.007 mL) was added and the reaction was stirred for 30 minutes. The reaction was diluted with ethyl acetate and washed with dilute NaHCO3 and brine. The organic was dried over MgSO4, filtered and evaporated to give the title compound (0.047 g, 84% yield), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:22]1[CH2:23][CH2:24][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH2:20][CH2:21]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Clc1ccnc2ccc(Br)cc12
Product: Brc1ccc2nccc(N3CCN(c4ccccn4)CC3)c2c1

Procedure:
291 mg 6-bromo-4-chloroquinoline and 0.91 mL 4-(2-pyridyl)piperazine were reacted by the same method as in Production Example 74 to give 373 mg of the title compound as a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:15]=[C:16](F)[CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[C:19](=[O:22])([O-])[O-].[K+].[K+].[OH2:25]>CS(C)=O.C1(C)C=CC=CC=1>[C:2]1([O:25][C:2]2[CH:3]=[C:4]([CH:15]=[C:16]([O:22][C:19]3[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=3)[CH:17]=2)[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[O:6])[CH:3]=[CH:4][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)c2cc(F)cc(F)c2)cc1
Reactant: O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(C(=O)c2cc(Oc3ccccc3)cc(Oc3ccccc3)c2)cc1
Yield: 49 %

Procedure:
19.0 g (0.077 mole) of 3,5-difluoro-4′-methoxybenzophenone are dissolved under argon in a mixture of 200 ml of dimethyl sulfoxide and 200 ml of toluene. 28.56 g (0.207 mole) of finely powdered potassium carbonate are added to this solution. The solution is stirred under reflux for 4 hours, the water formed being removed in a water separator. The toluene is then completely distilled off and the reaction mixture is stirred for a further 3 hours at 150° C. A further 28.56 g (0.207 mole) of finely powdered potassium carbonate and 50 ml of toluene are added. The mixture is heated under reflux and the toluene is distilled off. The solution is stirred for a further 4 hours at 150° C. After cooling, the solution is poured onto ice. The solution is neutralised by adding HCl solution (10%). Extraction with diethyl ether is performed several times. The combined organic phases are washed with saturated sodium chloride solution. The product is dried over magnesium, sulfate and the solvent is removed in vacuo. The crude product is chromatographed on silica gel (silica gel 60, 0.040-0.063 mm, Merck) using n-hexane/ethyl acetate (19:1). 14.90 g (49%) of a pale yellow oil are obtained.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([O:46]C)([CH3:45])[CH2:10][C@@H:9]([CH3:48])[C:7](=[O:8])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51].[OH-].[K+].Cl[C:56]([O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][O:67][CH2:68][CH3:69])=[O:57]>O1CCCC1>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:48])[C:7](=[O:8])[C@H:6]([CH3:49])[C@@H:5]([OH:50])[C@@:4]1([OH:52])[CH3:51].[CH2:68]([O:67][CH2:66][CH2:65][O:64][CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][C:56](=[O:8])[O-:57])[CH3:69]
Reactant: CCOCCOCCOCCOC(=O)Cl
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOCCOCCOCCOC(=O)[O-]
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 3 h
Yield: 598.4 %

Procedure:
To a solution of 6-O-methylerythromycin A (10 g) in tetrahydrofuran (50 ml ), were added 95 % potassium hydroxide powder (0.87 g ) and 2 - [2 - (2 -ethoxyethoxy ) ethoxy ]ethyl chloroformate (3.60 g) under ice-cooling. After stirring for 3 hours, 95% potassium hydroxide powder (0.24 g ) and 2- [2-(2 -ethoxyethoxy ) ethoxy ]ethyl chloroformate (0.98 g ) were further added thereto and the mixture was stirred for additional 2 days. The post treatment was performed by the same method as the one described in Example 7. The crude product thus obtained was purified by silica gel column chromatography (elution solvent; acetone : n-hexane =7 : 13 - 2 : 3) and then crystallized from chloroform/n-hexane. Thus 6-0-methylerythromycin A 2 '- {2- [2- (2-ethoxyethoxy ) ethoxy]ethyl}carbonate (8.85 g) was obtained as a white powder.