Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:9]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(OCC)(=O)C>CCCCCC>[Cl:7][C:8]1[C:9]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:10][C:11]([NH:14][S:35]([CH3:34])(=[O:37])=[O:36])=[N:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.2 %

Procedure:
To a pyridine (2 ml) solution of the [5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine (106 mg, 0.247 mmol) obtained in Example 196 was added methanesulfonyl chloride (29 μl, 0.370 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 3 days and concentrated under reduced pressure. To the residue thus obtained was added ethyl acetate. The resulting mixture was washed sequentially with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (58 mg, 0.114 mmol, 46%) as a white solid. The resulting white solid was washed with hexane-ether and collected by filtration to give the title compound (28 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Cl[CH:19]([OH:21])[CH3:20]>CS(C)=O>[OH:21][CH2:19][CH2:20][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CC(O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(C=O)c(OCCO)c1

Procedure:
2.5 g of 2-hydroxy-4-methoxybenzaldehyde, 6.8 g of K2CO3, 3.3 ml of chloroethanol and 33 ml of DMSO were heated for 8 hrs. to 80° C. Extraction with ethyl acetate and chromatography on silica gel with methylene chloride-acetone gave 2.1 g of 2-(2-hydroxy-ethoxy)-4-methoxy-benzaldehyde, m.p. 94° C., MS: 196 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Br[CH2:22][CH2:23][Cl:24]>>[Cl:24][CH2:23][CH2:22][N:8]1[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:9]1
Reactant: ClCCBr
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CCCl)c1=O
Yield: 88.8 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 1-bromo-2-chloroethane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 88.8%.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].CCN(C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: COc1ccccc1CN
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-methoxy-benzylamine and DIEA to give 2-(2-methoxy-benzylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 376 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]=[O:36])=[CH:29][CH:28]=1>O1CCCC1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[OH:36])=[CH:31][CH:32]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(CC=O)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A stirring solution of 10.8 mL (0.077 mole) of diisopropylamine in 100 mL of tetrahydrofuran is cooled to 0° C., and 30.8 mL (0.077 mole) of n-butyllithium (2.5M in hexanes) is added dropwise. Upon completion of the addition, the reaction mixture is stirred for about 10 minutes, then 22.3 grams (0.077 mole) of tributyltin hydride is added dropwise at a rate to maintain the reaction mixture temperature at about 0° C. The reaction mixture is then stirred for about 15 minutes. After this time the reaction mixture is cooled to -78° C., and a solution of 13.8 grams (0.077 mole) of 3-(4-fluorophenyl)-3-methylbutyraldehyde in about 15 mL of tetrahydrofuran is added dropwise during a 30 minute period. Upon completion of addition, the reaction mixture is stirred at -78° C. for ten minutes. After this time the reaction mixture is quenched by the dropwise addition of 300 mL of aqueous 10% ammonium chloride. The mixture is then extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, at a temperature of less than 30° C., yielding 36.3 grams of 3-(4-fluorophenyl)-3-methyl-1-tributylstannylbutanol. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:21][CH:22]=3)[CH:13]=[C:12]([CH3:34])[CH:11]=2)=[O:8])=[CH:5][C:4]([CH3:35])=[N:3]1.I[CH2:37][C:38]([NH2:40])=[O:39].C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:40][C:38](=[O:39])[CH2:37][N:19]1[C:20](=[N:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][C:17]([O:16][C:14]2[CH:15]=[C:10]([NH:9][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:35])[CH:5]=3)=[O:8])[CH:11]=[C:12]([CH3:34])[CH:13]=2)=[CH:18]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cc(C)cc(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Yield: 74.6 %

Procedure:
In the same manner as in Reference Example 5 and using 1,3-dimethyl-N-{3-methyl-5-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide (3.88 g, 7.89 mmol), iodoacetamide (1.90 g, 10.27 mmol), N,N-diisopropylethylamine (1.80 mL, 10.3 mmol) and N,N-dimethylformamide (20 mL) as starting materials, the title compound (3.23 g, 75%) was obtained as a pale-yellow oil.
Reaction SMILES: [Si]([C:8]#[C:9][C:10]1[S:14][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:17]=2)=[C:12]([C:29]([NH2:31])=[O:30])[CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:9]([C:10]1[S:14][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:17]=2)=[C:12]([C:29]([NH2:31])=[O:30])[CH:11]=1)#[CH:8]
Reactant: CC(C)(C)[Si](C)(C)C#Cc1cc(C(N)=O)c(Nc2cccc(CN3CCOCC3)n2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(C(N)=O)c(Nc2cccc(CN3CCOCC3)n2)s1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 5-{[tert-butyl(dimethyl)silyl]ethynyl}-2-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (435 mg, 0.95 mmol) in THF (15 mL) was added TBAF (1.0 M in THF, 2.38 mL, 2.38 mmol), and the reaction was stirred at room temperature for 6 h. The solution was diluted with water and extracted with EtOAc (2×). The organic extracts were dried over magnesium sulfate, filtered, combined with silica gel and evaporated. Flash chromatography (dry load, 0-10% MeOH/EtOAc) provided the title compound as a gray solid.
Reaction SMILES: C(O)(=[O:3])C.[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.OO.O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19]([CH3:20])=[O:3])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CC(=O)O
Agent: OO
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
To an acetic acid solution (30 ml) of 4-chloro-4'-methylmercaptomethylbenzophenone (8.3 g), aqueous 30% hydrogen peroxide solution (3.5 ml) was added, and the mixture was stirred for 2 hours while keeping at 10° C. To the reaction solution, water (200 ml) and toluene (200 ml) were added, and then the organic layer was separated, and washed successively with water, an aqueous sodium bicarbonate solution and an aqueous saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate. After distilling off the solvent, the crude product was purified by silicagel column chromatography (developing solvent: acetone:n-hexane=50:50) to obtain 4-chloro-4'-methylsulfinylmethylbenzophenone (5.3 g).
Reaction SMILES: [N+:1](=[CH:3][CH3:4])=[N-:2].[C:5]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH:20]=[CH:21][C:22]#[N:23])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC>[C:5]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:21]([C:22]#[N:23])=[N:2][NH:1][C:3]=1[CH3:4])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC=[N+]=[N-]
Solvent: CCOCC
Product: Cc1[nH]nc(C#N)c1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reaction time: 3 h

Procedure:
A solution of diazoethane in 400 ml of ether (prepared from 16.1 g (0.1 mol) of N-ethyl-N'-nitro-N-nitrosoimino urea,) was added to a solution of 15 g (0.056 mol) of crude 3-(2-benzoyl-4-chlorophenyl)-2-propenonitrile in 100 ml of ether. After standing at room temperature for 3 hr, the excess diazoethane was destroyed by addition of glacial acetic acid. The mixture was washed with saturated sodium bicarbonate solution, was dried and evaporated, at the end azeotropically with toluene. The residue was dissolved in 400 ml of toluene and the solution was heated to reflux for 11/2 hr in presence of 60 g of activated manganese dioxide. The water was separated in a Dean Stark trap. The MnO2 was removed by filtration over Celite and the filtrate was evaporated. The residue (14 g) was chromatographed over 300 g of silica gel using 10% (v/v) of ethyl acetate in methylene chloride. The homogenous fractions were combined and evaporated to yield an oily product.
Reaction SMILES: O.[N+:2]([C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C@H:10]1[CH2:12][C@H:11]1[C:13](O)=[O:14])=O)([O-:4])=[O:3].O.[NH2:20][NH2:21]>C(O)C>[N+:2]([C:5]1[CH:6]=[C:7]([C:8]2[CH:10]3[CH:11]([C:13](=[O:14])[NH:20][N:21]=2)[CH2:12]3)[CH:16]=[CH:17][CH:18]=1)([O-:4])=[O:3]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)[C@H]1C[C@H]1C(=O)O
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1NN=C(c2cccc([N+](=O)[O-])c2)C2CC12
Yield: 69.6 %

Procedure:
4.4 g (17.4 millimoles) of cis-2-(m-nitrobenzoyl)-cyclopropanecarboxylic acid hydrate, 1.05 g (21.0 millimoles) of hydrazine hydrate and 100 ml of ethanol are refluxed for 7 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 2.8 g (70% of theory) of 2-(m-nitrophenyl)-3,4-diazabicyclo[4.1.0]hept-2-en-5-one are obtained as pale yellow crystals, of melting point 220°-221° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:19]([CH3:21])[CH3:20])([CH2:14][CH2:15][CH2:16][NH:17][CH3:18])[C:12]#[N:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(C(C1C=C(OC)C=C(OC)C=1)C#N)(C)C.CC(NCCCCl)=O.[H-].[Na+].Cl.[F:49][C:50]([F:61])([F:60])[C:51]1[CH:52]=[C:53]([CH2:57][CH:58]=O)[CH:54]=[CH:55][CH:56]=1>[Pd].C1(C)C=CC=CC=1>[F:49][C:50]([F:61])([F:60])[C:51]1[CH:52]=[C:53]([CH:54]=[CH:55][CH:56]=1)[CH2:57][CH2:58][N:17]([CH3:18])[CH2:16][CH2:15][CH2:14][C:11]([C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH:19]([CH3:21])[CH3:20])[C:12]#[N:13]
Reactant: CNCCCC(C#N)(c1cc(OC)cc(OC)c1)C(C)C
Reactant: O=CCc1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: CC(=O)NCCCCl
Agent: COc1cc(OC)cc(C(C#N)C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(C(C#N)(CCCN(C)CCc2cccc(C(F)(F)F)c2)C(C)C)c1
Yield: 86.3 %

Procedure:
A mixture of 29.0 g (0.1 mole) of 2-(3,5-dimethoxyphenyl)-2-isopropyl-5-methylaminovaleronitrile (prepared by reacting α-isopropyl-3,5-dimethoxyphenylacetonitrile and 3-methylformamido-1-chloropropane in the presence of sodium hydride and then eliminating the formyl group by means of hydrochloric acid) and 18.8 g (0.1 mole) of 3-trifluoromethylphenylacetaldehyde was reduced catalytically with 400 mg of 5% strength palladium on carbon in 100 ml of toluene under atmospheric pressure at from 25 to 30° C. for 20 hours. After the catalyst had been removed, the toluene solution was washed several times with water and dried with potassium carbonate, after which the toluene was distilled off. The residue was dissolved in isopropanol, and ethanolic hydrochloric acid was added. Crystallization from isopropanol gave 39.9 g (80%) of 5-[(3-trifluoromethylphenethyl)-methylamino]-2-(3,5-dimethoxyphenyl)-2-isopropylvaleronitrile of melting point 136°-138° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[I-].[K+].Br[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19]>O1CCCC1.C(O)(=O)C.O.CN(C)P(N(C)C)(N(C)C)=O>[CH3:21][O:20][C:18](=[O:19])[CH:17]([O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: COC(=O)C(Br)c1ccc(OCOc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C(Oc1cccc(C(C)(C)C)c1)c1ccc(OCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.1 %

Procedure:
A mixture of 3.3 g of 3-tert.-butylphenol and 0.83 g of 60% sodium hydride-oil dispersion in 40 ml of tetrahydrofuran is stirred under argon for 1 hour at room temperature. To the mixture is added 3.65 g of potassium iodide, one ml of hexamethylphosphoramide and dropwise, a solution of 8.51 g of methyl bromo{p-[(p-chlorophenoxy)methoxy]phenyl}acetate in 30 ml of tetrahydrofuran. The mixture is refluxed for 18 hours and poured into 500 ml of water containing 2 ml of acetic acid. The mixture is extracted with ether and the ether extracts washed with sodium bicarbonate solution, 10% sodium bisulfite solution and with saturated sodium chloride solution. The solvent is removed under reduced pressure to give 11.7 g of a gum. Chromatography over silica gel with dichloromethane as eluent gives 6 g of product as a gum.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:27][CH3:28])=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1.S(OC)(O[CH3:33])(=O)=O.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CC(C)=O>[CH3:28][O:27][C:3]1[C:2]([O:1][CH3:33])=[CH:26][N:5]2[C:4]=1[C:9]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=1)=[C:8]([C:24]#[N:25])[CH:7]=[N:6]2
Reactant: COS(=O)(=O)OC
Reactant: COc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of compound from Example 399 (14 mg, 0.038 mmol), dimethyl sulfate (4 μl, 0.042 mmol), K2CO3 (14 mg, 0.101 mmol) in acetone (0.5 ml) was stirred at rt overnight. After regular workup, the title compound (13 mg, 88%) was obtained after silica gel flash column chromatography (100% CH2Cl2). LCMS Found: (M+H)+=387.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13]/[N:14]=[C:15](\[NH2:17])/[CH3:16])=O)[S:10][C:3]=12.C1(C)C=CC=CC=1.ClC1C=CN=C2C=C(C(O)=O)SC=12>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[O:13][N:14]=[C:15]([CH3:16])[N:17]=3)[S:10][C:3]=12
Reactant: C/C(N)=N/OC(=O)c1cc2nccc(Cl)c2s1
Agent: O=C(O)c1cc2nccc(Cl)c2s1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1noc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 110 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
A 50 mL round bottom flask with a reflux condenser was charged with (1 Z)—N′-(((7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl)oxy)ethanimidamide (0.282 g, 1.04 mmol) and toluene (10 ml) and heated to 110° C. and stirred for 18 hours. LC/MS analysis indicated a mixture of the product and 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid. The reaction was diluted with chloroform (30 mL) and washed with water (30 mL), sat. aq. NaHCO3 (30 mL), and brine (30 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield 7-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridine (0.1128 g, 43% yield) as a light yellow solid, which was used without further purification.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([CH2:16][OH:17])[CH2:15][C@@:9]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:10]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd]>[F:28][C:26]([F:27])([F:29])[C:24]1[CH:25]=[C:20]([CH2:19][O:18][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:15][C@H:14]3[CH2:16][OH:17])[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=1
Reactant: OC[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Product: OC[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-hydroxymethyl-1-phenyl-8-azabicyclo[3.2.1]octane (Example 28; 85 mg 0.15 mmol), 10% palladium on charcoal (125 mg, 0.12 mmol) ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +65° C. for 45 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl and recrystallised from ethylacetate:iso-hexane.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:33])[CH2:16][CH2:17][N:18]([CH:20]2[CH2:25][CH2:24][N:23](CC3C=CC=CC=3)[CH2:22][CH2:21]2)[CH3:19])[CH2:11][CH2:10]1)C1C=CC=CC=1>[Pd].O.CO>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[NH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH3:33])[CH2:16][CH2:17][N:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH3:19])[CH2:13][CH2:14]1
Reactant: CN(CCN(C)C1CCN(Cc2ccccc2)CC1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(CCN(C)C1CCNCC1)C1CCNCC1
Reaction time: 6 h
Yield: 73 %

Procedure:
10% Palladium on carbon (125 mg) and concentrated hydrochloric acid (1.2 ml; 14 mmol) were added to a solution in water-methanol (4 ml-8 ml) of N,N′-bis(1-benzyl-4-piperidinyl)-N,N′-dimethylethylenediamine (757 mg; 1.7 mmol) synthesized by the above process, and the mixture was stirred for 6 hours in a bath controlled at 55° C. under hydrogen. The catalyst was removed from the reaction mixture by filtration, and the filtrate was concentrated under reduced pressure. The resultant crude crystals were washed with ethanol, thereby obtaining 497 mg (yield: 71%) of the title compound as a colorless crystalline powder [melting point: 275° C. (decomposition)].
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([OH:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.[OH-].[Na+]>CO.ClCCl>[CH2:22]([C:18]1([OH:21])[CH2:19][CH2:20][N:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=2)[CH2:16][CH2:17]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCC(O)(Cc3ccccc3)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](O)c1nccc(N2CCC(O)(Cc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-1-[4-(4-benzyl-4-hydroxy-piperidin-1-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 174, Step A, 0.20 g, 0.52 mmol) in methanol (5 mL) was added 1 N aqueous sodium hydroxide (1 mL) and stirred for 4 h at ambient temperature. The mixture was diluted with dichloromethane and washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to give the title compound as a foam, 0.12 g (68%). 1H NMR (CDCl3, 300 MHz) δ 1.49 (d, 3H), 1.74 (br s, 2H), 1.82 (m, 2H), 2.08 (m, 2H), 3.42 (m, 2H), 4.42 (br s, 1H), 4.71 (q, 1H), 6.43 (d, 1H), 7.33-7.48 (m, 5H), 8.21 (d, 1H); MS (Cl) 314 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[N:15]1[C:37](=[O:38])[C:34]2[C:35]3[C:36]4[C:31](=[CH:32][CH:33]=2)[C:30]2[C:39]5[C:26]([CH:27]=[CH:28][CH:29]=2)=[CH:25][CH:24]=[CH:23][C:22]=5[C:21]=4[CH:20]=[CH:19][C:18]=3[C:16]1=[O:17])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:46]Br>ClC1C=CC=CC=1>[Br:46][C:27]1[C:26]2[C:39]3[C:30]([C:31]4[C:36]5[C:35]6=[C:18]([C:16]([N:15]([C:6]7[CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[CH:10][C:5]=7[C:1]([CH3:2])([CH3:3])[CH3:4])[C:37](=[O:38])[C:34]6=[CH:33][CH:32]=4)=[O:17])[CH:19]=[CH:20][C:21]=5[C:22]=3[CH:23]=[CH:24][CH:25]=2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c(N2C(=O)c3ccc4c5cccc6cccc(c7ccc(c3c47)C2=O)c65)c1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CC(C)(C)c1ccc(C(C)(C)C)c(N2C(=O)c3ccc4c5cccc6c(Br)ccc(c7ccc(c3c47)C2=O)c65)c1
Reaction time: 2 h

Procedure:
650 mg (1.28 mmol) of N-(2,5-di-tert-butylphenyl)perylene-3,4-dicarboximide (2b) are dissolved in 100 ml of chlorobenzene, the red solution is mixed with 650 mg of anhydrous potassium carbonate, and 0.30 ml of bromine in 10 ml of chlorobenzene is then added dropwise to the mixture. The reaction mixture is stirred at 40°-50° C. for 2 h, the temperature is then increased to 50°-60° C. and maintained there for another 5 h, and the chlorobenzene is then evaporated off on a rotary evaporator, during which substantial amounts of bromine are also removed. A thin-layer chromatogram (toluene/silica gel) shows that no more starting material is present in the residue obtained, which could only be removed with difficulty. Several separations by column chromatography on silica gel using chloroform afford 610 mg of an orange powder which is recrystallized by extraction with ethyl acetate. Yield 570 mg (77%) of orange-coloured small needles having a slight solid fluorescence, m.p. >320° C. Rf (CHCl3 /silica gel)=0.43. UV (CHCl3): λmax (ε)=511 nm (36058), 486 (35564), 357 (3430). Fluorescence (CHCl3): λmax (Irel)=542 nm (1), 572. The position of the bromine substituent could be determined by comparison with the spectrum of 9-bromo-N-(1-hexylheptyl)perylene-3,4-dicarboximide and 1H spectra. The substitution pattern of the comparison substance was determined by a combination of COSY and NOESY spectra.