Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]3[CH2:43][CH2:42]3)=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:41]1([C:38]2[N:37]=[CH:36][C:35]([C:31]3[CH:30]=[C:29]([C:27]4[CH2:26][C:25](=[O:44])[NH:24][C:9]5[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=5[N:7]=4)[CH:34]=[CH:33][CH:32]=3)=[CH:40][CH:39]=2)[CH2:42][CH2:43]1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccc(C4CC4)nc3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M148) (334 mg, 0.524 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (201 mg, 74%).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@H:9]3[S:8][CH:7]=2)=[CH:30]1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: Cn1ccc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cn1cc(CC2=CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)c2ccccc21
Reaction time: 0.25 h

Procedure:
0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is dissolved in a solution of 0.13 g of 1-methylindole in 0.3 ml of trifluoroacetic acid, and the solution is left to stand for 15 minutes at room temperature and diluted with an equal quantity of toluene. The mixture is evaporated to dryness under reduced pressure and the residue is worked up in accordance with the process described in example 6. 3-(1-Methyl-3-indolylmethyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is thus obtained; in a thin layer chromatogram (silica gel), this acid shows Rf values at 0.85 (system n-butanol/acetic acid/water, 67:10:23) and at 0.58 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: [O:1]1[CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4].[C:8](=[O:10])=[O:9]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][O:1][C:8](=[O:9])[O:10]1)=[O:4]
Reactant: O=C=O
Reactant: COC(=O)C1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: COC(C)(C)C
Product: COC(=O)C1COC(=O)O1
Reaction time: 96 h
Yield: 94 %

Procedure:
20 g of the methyl epoxypropionate were mixed with 20 g of tert-butyl methyl ether and 1 g of tetrabutylammonium bromide. The homogeneous mixture was transferred to a 100 ml pressurized reactor and carboxylated for 4 days at 40° C. and a CO2 pressure of 20 bar. After the carboxylation, a two-phase system was obtained; the upper phase consisted of tert-butyl methyl ether, and the lower phase consisted of 4-methoxycarbonyl-2-oxo-1,3-dioxolane (purity 94% (GC), yield 94%).
Reaction SMILES: C(O)C.Br[C:5]1[CH:6]=[CH:7][C:8]2[N:14]([CH2:15][C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH2:13][CH2:12][C:11]([C:21]([OH:23])=[O:22])=[CH:10][C:9]=2[CH:24]=1.B([O-])([O-])O[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:37]([O:36][CH2:35][CH2:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:5]2[CH:6]=[CH:7][C:8]3[N:14]([CH2:15][C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)[CH2:13][CH2:12][C:11]([C:21]([OH:23])=[O:22])=[CH:10][C:9]=3[CH:24]=2)=[CH:32][CH:31]=1)[CH2:38][CH3:39]
Reactant: O=C(O)C1=Cc2cc(Br)ccc2N(Cc2cccs2)CC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccs2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
In toluene (30 ml), ethanol (3 ml) and water (3 ml) were suspended 7-bromo-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (500 mg), 4-propoxyethoxyphenyl borate (615 mg) and potassium carbonate (949 mg), and the suspension was stirred under argon atmosphere for 30 minutes. Then, to the suspension was added tetrakistriphenylphosphinepalladium (111 mg), and the mixture was heated under argon atmosphere at 100° C. for 6 hours. After allowing to cool, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1), which was recrystallized from hexane-ethyl acetate to give 7-(4-propoxyethoxyphenyl)-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (269 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:35])[CH2:21][NH:22][C:23]2([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:25][CH2:24]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:35])[CH2:21][NH:22][C:23]2([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[CH2:24][CH2:25]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: COc1ccc(CC2(NCC(O)c3ccc(OCc4ccccc4)c4[nH]c(=O)ccc34)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CC2(NCC(O)c3ccc(O)c4[nH]c(=O)ccc34)CC2)cc1

Procedure:
258 mg (0.51 mmol) 8-benzyloxy-5-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-ethyl}-1H-quinolin-2-one in 10 mL methanol are hydrogenated with palladium on charcoal as catalyst at 3 bar. Then the catalyst is separated off, the solvent is distilled off and the residue is purified by chromatography (reverse phase, water/acetonitrile gradient). Yield: 12 mg (6%); mass spectroscopy: [M+H]+=381.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[N:9]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=2)[CH2:8][C:7]1=[O:23].[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][OH:37])=[CH:34][CH:33]=1>C(Cl)Cl>[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][O:37][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH2:13][N:9]3[CH2:8][C:7](=[O:23])[N:6]([CH2:5][C:4]4[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=4[O:2][CH3:1])[S:10]3(=[O:12])=[O:11])=[CH:15][CH:16]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)Cl)cc3)S2(=O)=O)c(OC)c1
Reactant: CSc1ccc(CO)cc1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)OCc4ccc(SC)cc4)cc3)S2(=O)=O)c(OC)c1

Procedure:
400 mg (911 μmol) of the title B compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoyl chloride, 140 μL (1.0 mmol) of TEA and 141 mg (914 μmol) of 4-(methylthio)benzyl alcohol in 10 mL of CH2Cl2 are stirred at RT for 18 h. The solvent is removed under reduced pressure and the residue is chromatographed on a Biotage 40M column with 98/2 —CH2Cl2/EtOAc to give 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid 4-methylsulfanyl-benzyl ester: [M+NH4]+=574.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.[OH-].[Na+]>CO>[CH2:1]([CH:8]1[CH2:12][CH2:11]/[C:10](=[CH:18]\[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][CH3:14])/[C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1C=O
Reactant: O=C1CCCC1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1/C=C1\CCC(Cc2ccccc2)C1=O

Procedure:
A Stork reaction between benzyl chloride and the pyrrolidine enamine of cyclopentanone gave 2-benzylcyclopentanone. The boiling point of this intermediate compound was determined to be 121°-125° C. at a pressure of 2 mm Hg. To a solution containing 32 mmole of 2-benzylcyclopentanone and 48 mmole of 2-methoxybenzaldehyde in 20 ml of methanol was added 12 ml of 5% NaOH with stirring at about room temperature. After about 2 hours of stirring, the mixture was cooled and the precipitate was collected by filtration and washed with water. The solid was recrystallized in ethanol to give 2-benzyl-5-(E)-[(2-methoxy) benzylidene] cyclopentanone. The melting point of this intermediate product was determined to be 65°-67° C. A mixture containing 20 mmole of this intermediate, 38 mmole of dimethylamine hydrochloride, 2.4 g of paraformaldehyde and 4 drops of concentrated HCl in 50 ml of ethanol was refluxed with stirring. After about 12 hours, 1.8 g of paraformaldehyde was added and refluxing was continued for about 12 additional hours. The resulting solution was concentrated in vacuo to give a residue. Then 100 ml of water was added to the residue and stirred for about 15 minutes at about room temperature. The precipitate was removed by filtration. The resulting filtrate was treated with 10% NaOH to about pH 10 and extracted with ether. The extract was dried over anhydrous MgSO4 and acidified with ethanolic HCl to give a precipitate. The precipitate was recrystallized in a mixture of methanol and acetone to yield the 2-Benzyl-2-dimethylaminomethyl-5-(E)-[(2-methoxy) benzylidene] cyclopentanone hydrochloride. The melting point of the product was determined to be 175°-177° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH2:18][OH:19])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O>C(N(CC)CC)C>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][S:15][C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH:18]=[O:19])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccccc1SCCN1CCN(c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1ccccc1SCCN1CCN(c2ccccc2)CC1
Yield: 93.1 %

Procedure:
6.0 g of 2-[2-(4-phenylpiperazin-1-yl)ethylthio]benzylalcohol, 2.60 g of oxalyl chloride, 3.2 g of dimethylsulfoxide and 9.3 g of triethylamine are treated in the same manner as described above. 5.55 g of 2-[2-(4-phenylpiperazin-1-yl)ethylthio]benzaldehyde are obtained. Yield: 93%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([N:24]4[CH2:29][CH2:28][N:27]([C:30](OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[CH:19][CH:20]=3)[C:15]2=[O:37])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+].[C:49]1([CH:55]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:56]CBr)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>O>[CH:8]1([N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([N:24]4[CH2:29][CH2:28][N:27]([CH2:30][CH2:56][CH:55]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH2:26][CH2:25]4)=[CH:19][CH:20]=3)[C:15]2=[O:37])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ccn(C4CCCCC4)c(=O)c3c2)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)ccc2ccn1C1CCCCC1
Reaction time: 2 h
Yield: 136 %

Procedure:
Trifluoroacetic acid (1 ml) was added under cooling in an ice bath to the compound (10 mg) obtained in Example 70. The mixture was stirred for 2 hr. A saturated aqueous sodium hydrogencarbonate solution was then added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation. N,N-dimethylformamide (2 ml) was added to the residue to prepare a solution. Potassium carbonate (lO mg) and 3,3-diphenylpropyl bromide (4 mg) were then added to the solution. The mixture was stirred at room temperature overnight. Water was added to the reaction solution. The mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation. The residue was purified by preparative TLC (hexane:ethyl acetate=1:1) to give the title compound (10 mg).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:18]=[C:17]([C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=O)[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:18]=[C:17]([C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=[CH2:1])[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1OC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C1CCCN(C(=O)c2ccc(C(=O)OC)c(OC)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (607 mg) in N,N-dimethylformamide (10 ml) was added potassium-tert-butoxide (191 mg), and the mixture was stirred at room temperature for 30 minutes. Methyl 2-methoxy-4-(2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepin-1-yl)carbonylbenzoate (300 mg) was added to the resulting solution, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and the solution was washed successively with 1N hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The crude product was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give methyl 2-methoxy-4-(2,3,4,5-tetrahydro-5-methylene-1H-1-benzazepin-1-yl)carbonylbenzoate (65 mg).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][C:36]=1[N+:43]([O-:45])=[O:44]>CN(C=O)C>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:6]([C:3]2([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]2)=[O:7])=[CH:37][C:36]=1[N+:43]([O-:45])=[O:44]
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C1(C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
TEA (21.7 mL; 156 mmol) was added to a mixture of 1-(trifluoromethyl)-cyclopropanecarboxylic acid (8.00 g; 51.9 mmol) and TBTU (16.7 g; 52 mmol) in DMF (40 mL). After 1 h at rt, a solution of (4-chloro-3-nitrophenyl)methylamine hydrochloride (11.6 g; 52 mmol) in DMF (70 mL) was added dropwise over 30 min. After 17 h at rt, the mixture was concentrated and the residue partitioned between water and MTBE. The organic layer was washed with water, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give the sub-title compound. Yield: 13.191 g (78%).
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:10].S(=O)(=O)(O)O.O.C(#[N:20])C>>[NH2:20][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: CC#N
Reactant: O[C@@H]1Cc2ccccc2[C@H]1O
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 40 ml of acetonitrile, 3.0 g (20.1 mmol) of trans-(-)-1,2-indandiol (I': trans-configuration: 98.0%; cis-configuration: 2.0%; optical purity: 100% e.e.) was dissolved. At room temperature, 3.2 g (31.7 mol) of 97% sulfuric acid was dropwise added thereto in a period of 30 minutes. After the resulting mixture was stirred at room temperature for 1 hour, the compound (I') disappeared from an HPLC. To the reaction liquid, 20 ml of water was added. Immediately thereafter, the mixture was heated and 42 ml of an acetonitrile/water azeotrope was distilled off under normal pressure. Then, the mixture was subjected to a reflux for 1.5 hours to complete the reaction. The reaction liquid was cooled to room temperature and washed twice with 10 ml of dichloromethane. Then, its pH was adjusted to 10.5 by an addition of an aqueous solution of 25% sodium hydroxide. The grayish white scaly crystal deposited thereby was filtered off under reduced pressure, washed with a small quantity of water, and then dried under reduced pressure to yield 1.77 g of cis-(-)-1-aminoindan-2-ol (V) as a primary crystal. Then, the mother liquid after the deposition of the crystal was extracted with dichloromethane and the extracted phase was concentrated to yield 0.69 g of the compound (V) as a secondary crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C(C)C)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and isobutyryl chloride the title compound was obtained as a light yellow solid (8%), MS: m/e=336 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH3:25])[C:16]2=[O:26])=[CH:11][CH:10]=1)C1C=CC=CC=1.CCOC(C)=O>CN(C=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH3:25])[C:16]2=[O:26])=[CH:13][CH:14]=1
Reactant: Cc1ccnc2c1n(C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccnc2c1n(C)c(=O)n2-c1ccc(O)cc1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.0 g) and 10% Pd—C (0.308 g) in DMF (10 mL)-EtOAc (100 mL) was hydrogenated under balloon pressure at 20° C. for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50%-100% EtOAc in hexane) to give 3-(4-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.30 g) as a light brown solid. This product was subjected to the next reaction without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=1)=[O:19])[C:13]([C:35]1[CH:40]=[CH:39][C:38]([O:41]CC3C=CC=CC=3)=[CH:37][CH:36]=1)=[C:12]2[CH3:49])C1C=CC=CC=1.C(O)C.C1CCC=CC=1>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:24][CH:25]=1)=[O:19])[C:13]([C:35]1[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=1)=[C:12]2[CH3:49]
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(C(=O)c2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: C1=CCCC=C1
Product: Cc1c(-c2ccc(O)cc2)n(C(=O)c2ccc(OCCN3CCCCC3)cc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 0.78 g (0.00120 mol) of [5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (described above) in 5 mL of dry THF, and 5 mL of punctilious ethanol, under N2, was added 1.4 mL (0.0120 mol) of cyclohexadiene and 0.39 g (one-half the mass of the benzyloxy starting material) of 10% Pd/C, and stirred at room temperature overnight. The reaction mixture was filtered and evaporated to dryness in a rotary evaporator. 100 mL of ethyl acetate was added to the crude product. This organic phase was washed with water (2×50 mL), saturated brine, removed, dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The crude product when subjected to HPLC gave 0.30 g of pale-yellow solid.
Reaction SMILES: [CH3:1][S:2][CH3:3].ClN1C(=O)CCC1=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([N:23]3[CH2:27][CH2:26][C@@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]3)=[O:22])[CH:19]=2)C=[CH:13]1>ClCCl>[CH3:1][S:2][C:3]1[C:15]2[C:20](=[CH:19][C:18]([C:21]([N:23]3[CH2:27][CH2:26][C@@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]3)=[O:22])=[CH:17][CH:16]=2)[NH:12][CH:13]=1
Reactant: CSC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)c2ccc3cc[nH]c3c2)C1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CSc1c[nH]c2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc12
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Dimethylsulfane (2.0 mL, 26.74 mmol, 1.1 eq) was added drop wise at 0° C. to a stirred suspension of N-chlorosuccinimide (3.55 g, 26.74 mmol, 1.1 eq) in dichloromethane (20 mL). The mixture was cooled to −20° C., compound 336a) (8.0 g, 24.31 mmol, 1.0 eq) in dichloromethane (50 mL) was added drop wise at this temperature and the mixture was then stirred for 1 h at room temperature. The volatiles were evaporated and the residue was dissolved in xylene (30 mL) and stirred at 120° C. for 16 h. The solvent was removed in vacuo, ethyl acetate was added (50 mL), and the organic phase was washed with water (100 mL), dried over sodium sulfate and evaporated. The residue was purified by column chromatography [100-200 mesh silica, ethyl acetate/pet ether=1:4]. Yield: 5.5 g (60% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:8]=3[NH:9][C:10]=2[CH:11]=1.[OH-].[Na+].I[CH3:22]>C1C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:8]=3[N:9]([CH3:22])[C:10]=2[CH:11]=1
Reactant: CI
Reactant: COc1ccc2c3c([nH]c2c1)-c1ccccc1C3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2c3c(n(C)c2c1)-c1ccccc1C3
Temperature: 40 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of 29a (60.1 mg, 0.26 mmol) in benzene (2 mL) was added aqueous sodium hydroxide (50% by mass, 540 μL), tetrabutylammonium iodide (50 mg, 0.14 mmol), and iodomethane (130 μL, 2.09 mmol). The reaction mixture was stirred vigorously at 40° C. for 16 hours and then at 55° C. for 2 additional hours. Upon cooling to room temperature, the mixture was diluted with benzene (10 mL) and H2O (10 mL), and the aqueous layer was extracted 2×10 mL ethyl acetate. Organic layers were combined, washed 1×15 mL H2O, dried over anhydrous magnesium sulfate and concentrated to yield a brown solid. Crude product was purified by flash column chromatography (20:1 to 10:1 hexanes—ethyl acetate) to give a tan brown solid in 64% yield (40 mg, 0.16 mmol). 1H NMR (600 MHz, CDCl3): δ 7.60 (d, 1H, J=7.8 Hz), 7.51-7.52 (m, 2H), 7.32-7.34 (t, 1H, J=7.2 Hz), 7.18-7.20 (t, 1H, J=7.2 Hz), 6.84-6.85 (m, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 3.66 (s, 2H); 13C NMR (150 MHz, CDCl3): δ 156.0, 147.6, 143.8, 142.7, 135.7, 126.4, 125.4, 123.9, 120.3, 119.6, 118.7, 116.9, 108.9, 93.8, 55.7, 31.1, 30.1. FTIR: cm−1 2935, 1605, 1566, 1492, 1385, 1310, 1263, 1230, 1210, 1040, 812, 755. EI-HRMS: Calcd. for C17H15NO+ [M]+: 249.1154. found 249.1158.