Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][CH2:15][C:16]1[N:17]2[CH:23]=[N:22][CH:21]=[C:18]2[S:19][CH:20]=1.[CH2:24]([O:27][C:28]([NH:30][S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.O1CCCC1>[CH2:24]([O:27][C:28]([N:30]([CH2:14][CH2:15][C:16]1[N:17]2[CH:23]=[N:22][CH:21]=[C:18]2[S:19][CH:20]=1)[S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26]
Reactant: OCCc1csc2cncn12
Reactant: C=CCOC(=O)NS(N)(=O)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOC(=O)N(CCc1csc2cncn12)S(N)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
Under an argon atmosphere at -38° C., 0.77 ml of diethyl azodicarboxylate was added dropwise to 10 ml of an anhydrous tetrahydrofuran solution containing 550 mg of 3-(2-hydroxyethyl)imidazo[5,1-b]thiazole, 884 mg of N-allyloxycarbonyl-N-aminosulfonylamine and 1286 mg of triphenylphosphine, and the mixture was then stirred at -38° C. to -32° C. for 30 minutes and further stirred for 10 minutes while the solution was heated up to 0° C. The solvent was evaporated under reduced pressure to obtain an oil, and this oil was then dissolved in 50 ml of dichloromethane. Further, extraction was carried out with 2N hydrochloric acid (20 ml×2), and the combined aqueous layer was then washed with 10 ml of dichloromethane. Afterward, the solution was adjusted to pH 9 with anhydrous potassium carbonate, and then subjected to extraction with dichloromethane (30 ml×2). The dichloromethane extract was dried (anhydrous magnesium sulfate:anhydrous potassium carbonate=1:1) and then filtered, and the solvent was evaporated under reduced pressure. Afterward, the resulting oil was purified by a silica gel column chromatograph to obtain 548 mg of the title compound as a milky white amorphous.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[CH:3]=1.ClC1C(C(OCC)=S)=C(C)[N:18]=C(C)C=1.C1COCC1.O1CCOCC1>C(N(CC)CC)C>[NH2:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: CCOC(=S)c1cnc(C)cc1Cl
Reactant: CCOC(=S)c1c(Cl)cc(C)nc1C
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=S)c1cnc(C)cc1N

Procedure:
In accordance with Scheme 1 below, ethyl 4-chloro-2-methylthiopyridine-5-carboxylate (II with A=CH) (prepared according to Todd et al., J. Amer. Chem. Soc. (1943), 65, 350-354; Pesson, M., Eur. J. Med. Chem. (1974), 9(6), 585-590; Shadbolt, R., J. Chem. Soc. (1967), 13, 1172-1178) or ethyl 4-chloro-6-methyl-2-methylthiopyridine-5-carboxylate (II with A=C-Me) (prepared according to the method described in WO 2005/105 801) is reacted with an amine of formula R5—NH2 (in which R5 is as defined previously in relation to formula (I) according to the invention) in an organic solvent such as THF or dioxane, and in the presence of an organic base, for example triethylamine, at room temperature, according to the method described by D. Boschelli et al. in J. Med. Chem. (1998), 41, 4365-4377, to give an ethyl 4-amino-2-methylthiopyridine-5-carboxylate derivative of formula (III).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8](O)=[O:9])=[O:4].B(OC)(OC)OC.[Cl-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[CH2:8][OH:9])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: COB(OC)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H]1CO
Reaction time: 2 h

Procedure:
Add borane-methyl sulfide complex (177 mL, 0.354 mol), slowly, by means of a dropping funnel, to a stirring solution of trans-cyclopropane-1,2-dicarboxylic acid monomethyl ester (Example 3a) (25.5 g, 0.177 mol), trimethyl borate (60.3 mL, 0.531 mol) and tetrahydrofuran (150 mL) at 0° C. After complete addition, allow the reaction to come to ambient temperature and stir for 2 h more. Pour the reaction mixture into a stirring solution of 50% aqueous sodium chloride solution (1.5 L)-concentrated HCl (10 mL). Extract the mixture with ethyl acetate (EtOAc) (3 times), combine the extracts, dry (Na2SO4) and concentrate the solvent to obtain a colorless oil: 22.6 g.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:25][CH2:26][C:27](N(C)C)=[O:28])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[Ce](Cl)Cl.[CH2:51]([Mg]Br)[CH3:52].O1CC[CH2:57][CH2:56]1>>[Si:1]([O:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:25][CH2:26][C:27]([CH2:51][CH3:52])([OH:28])[CH2:56][CH3:57])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Reactant: CN(C)C(=O)CCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl[Ce](Cl)Cl
Product: CCC(O)(CC)CCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 51.7 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(N,N-dimethylaminocarbonylethoxy)-20-methylpregna-5,7,16-triene (133 mg, 0.20 mmol), anhydrous cerous (III) chloride (2.17 g, 8.8 mmol), ethylmagnesium bromide (8.3 ml, 8.0 mmol) and tetrahydrofuran (10 ml) were subjected to reaction using a procedure similar to that of Example 25(2) (at 0° C. for 1 hour), worked up and purified by preparative thin layer chromatography (2 sheets (each 1.0 mm thickness), hexane:ethyl acetate=5:1) to give the titled compound (70.7 mg, 51.7%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl.[CH2:17]([O:19][C:20]([NH:22][C:23]1([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH:45]=[CH2:46])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH2:32][C:31]2=[O:47])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:21])[CH3:18]>C(O)C>[NH2:1][C:2]1[CH:7]=[C:6]([N:26]2[CH2:27][CH2:28][C:23]([CH2:29][N:30]3[CH2:35][CH2:34][N:33]([S:36]([C:39]4[CH:40]=[CH:41][C:42]([CH:45]=[CH2:46])=[CH:43][CH:44]=4)(=[O:38])=[O:37])[CH2:32][C:31]3=[O:47])([NH:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])[CH2:24][CH2:25]2)[CH:5]=[CH:4][N:3]=1
Reactant: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCNCC3)C(=O)C2)cc1
Reactant: Nc1cc(Cl)ccn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCN(c4ccnc(N)c4)CC3)C(=O)C2)cc1
Yield: 20.8 %

Procedure:
2-Amino-4-chloropyridine (132 mg), triethylamine (700 mg) and ethanol (15 ml) were added to 1-{[4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzensulfonyl)-2-piperazinone hydrochloride (250 mg), to react at 155° C. for 20 hours in a sealed tube. The reaction solution was concentrated, a 10% aqueous sodium carbonate solution was added to the residue, the material was extracted with dichloromethane, dried, and concentrated. The resulting residue was dried, concentrated, purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1), and crystallized from dichloromethane-hexane to obtain the title compound (58 mg) as pale yellow crystals.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:9])[CH2:3]1.[CH2:16]([O:18][C:19](=[O:23])[CH:20](Br)[CH3:21])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:23])[CH:20]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:9])[CH2:3]1)[CH3:21])[CH3:17]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C(N[C@@H]1CCNC1)c1ccc(Cl)s1
Agent: Cl
Product: CCOC(=O)C(C)N1CC[C@@H](NC(=O)c2ccc(Cl)s2)C1

Procedure:
6.3 Using general procedure A 5-chloro-thiophene-2-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride was reacted with ethyl-2-bromopropionate to give 2-{(R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidin-1-yl}-propionic acid ethyl ester. Oil. MS 329.1 ([M−H]−)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([O:16][CH3:17])[CH:9]=1>C(#N)C>[CH3:15][O:14][C:12]1[N:11]=[C:10]([O:16][CH3:17])[CH:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: C1CNCCN1
Reactant: COc1cc(Cl)nc(OC)n1
Solvent: CC#N
Product: COc1cc(N2CCNCC2)nc(OC)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Piperazine (1.23 g, 14.32 mmol) was treated with 6-chloro-2,4-dimethoxy pyrimidine (0.5 g, 2.86 mmol) in acetonitrile (5 mL) and the reaction mixture was stirred at room temperature for 6 hours. Subsequently the reaction mixture was poured onto ice-cold water (25 ml) and extracted with ethyl acetate (25 ml). The organic layer was washed with aqueous sodium bicarbonate solution and evaporated to furnish the required compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:8])[CH2:4][C:5](Cl)=[O:6].[CH2:9]([OH:11])[CH3:10].S(Cl)(Cl)=O.S(OCC)(O[CH2:19][CH3:20])=O>C(Cl)Cl>[CH2:9]([O:11][C:5](=[O:6])/[CH:4]=[C:3](/[O:8][CH2:19][CH3:20])\[CH2:2][Cl:1])[CH3:10]
Reactant: O=C(Cl)CC(=O)CCl
Reactant: CCO
Reactant: CCOS(=O)OCC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)/C=C(\CCl)OCC
Temperature: 130 °C
Reaction time: 1 h

Procedure:
206.6 g (0.47 mol) of a 35 percent mixture of 4-chloroacetoacetyl chloride in methylene chloride was cooled to -10° C. Under nitrogen, 147.2 g (3.2 mol) of ethanol was added in 30 minutes, and then 83.3 g (0.7 mol) of thionyl chloride was added in 30 minutes (formation of diethyl sulfite). The temperature was raised to 55° to 60° C. in an hour, and then it was stirred for 1 hour more at 55° to 60° C. Then the excess ethanol and methylene chloride was distilled off at reduced pressure. The residue (raw 4-chloro-3,3-diethoxybutanoic acid ester) was mixed with 0.27 g of methanesulfonic acid and warmed at a pressure of 75 mbars to 125° to 130° C. Thus, the formed ethanol and excess diethyl sulfite were distilled off. The residue (raw 4-chloro-3- ethoxy -but-2E-enoic acid ethyl ester) was taken up in 110.2 g (120 ml) of toluene and the organic phase was washed with 69.8 g of aqueous 16 percent HCl for 30 minutes, with 32.1 g of an aqueous 10 percent sodium chloride solution for 10 minutes, with 134 g of aqueous 10 percent NaOH for 75 minutes and finally with 32.1 g of aqueous 10 percent sodium chloride solution for 10 minutes. The toluene was then evaporated off and the residue was distilled at a pressure of 2 mbars and a temperature of 78° to 80° C. 4-chloro-3-ethoxy-but-2E-enoic acid ethyl ester was obtained in a yield of 80.6 g (88.5 percent) in a purity of 99.8 percent (GC).
Reaction SMILES: NC[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])C.C(Cl)(=[O:31])C>ClCCl>[O:15]=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:4][CH2:3][CH2:28][CH2:27][NH:24][C:25](=[O:31])[CH3:26])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:7]1
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: NCCOc1c(-c2ccccc2)[nH]c(=O)c2ccccc12
Solvent: ClCCl
Product: CC(=O)NCCCOc1c(-c2ccccc2)[nH]c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of 150 mg (0.45 mmol) of 4-(2-amino-ethoxy)-3-phenyl-2H-isoquinolin-1-one (cmpd. 1) dichloromethane (6 mL), triethylamine (190 L, 1.36 mmol) and acetyl chloride (39.3 L, 0.55 mmol) were added under argon atmosphere at 0° C. and the mixture was stirred at room temperature overnight. The reaction mixture was then washed with water, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and the resulting crude was purified by flash chromatography (dichloromethane:methanol, 97:3) affording 64 mg of the title compound (42%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3cccc(Cl)c3)CC2)cc1

Procedure:
1-[1-(3-Chloro-benzyl)-piperidin-4-yl]-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 3-chlorobenzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.98 (m, 2H), 2.18-2.28 (m, 4H), 2.93-2.99 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.57 (s, 2H), 4.77-4.83 (m, 1H), 7.32-7.41 (m, 4H), 7.62-7.64 (m, 2H), 8.04-8.07 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=498.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH:3]([OH:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH3:30][C:2]([CH3:1])([CH3:29])[C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)O)c(C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(C(=O)O)c(C)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of 4-{1-[4-(3,3-dimethyl-2-hydroxybutoxy)-3-methylphenyl]-1-ethylpropyl}-2-methylbenzoic acid, Example 1, (0.50 g, 1.22 mmol) in CH2Cl2 (10 mL) is added a solution of the Dess-Martin reagent (0.57 g, 1.34 mmol) in CH2CL2 (10 mL) dropwise and stirred for 2 h. The reaction is diluted with EtOAc (100 mL), washed with 10% Na2SO3 (2×20 ml), 0.1 M HCl (20 ml), and H2O (20 ml). The organic layer is MgSO4 dried, and concentrated to give the title compound (0.48 g, 1.17 mmol, 95%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1C=O.[CH2:35]([Mg]Br)[CH3:36].[C:39](=O)(O)[O-:40].[Na+].O>ClCCl>[OH:40][CH2:39][CH2:35][CH2:36][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[N:3]1[C:2](=[O:1])[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:20][CH:21]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4]1
Reactant: O=C([O-])O
Reactant: CC[Mg]Br
Reactant: O=Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CCCO
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzaldehyde (Example 529, 0.14 g, 0.32 mmol) was dissolved in dichloromethane (5 mL) and cooled to −78° C. Ethylmagnesium bromide (0.10 mL, 3 M diethyl ether solution, 0.32 mmol, equiv) was added dropwise and the mixture was stirred for 30 minutes at −78° C. Additional ethylmagnesium bromide (0.10 mL, 3 M diethyl ether solution, 0.32 mmol, 1 equiv) was added and the mixture was stirred for an additional 30 minutes at −78° C. The mixture was treated with sodium bicarbonate (3 mL, aqueous saturated) and warmed to ambient temperature, poured into water and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate; then 100:0 to 0:100; ethyl acetate:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.14 (1H, s), 8.46 (1H, d, J=2.4 Hz), 8.18 (1H, d, J=8.0 Hz), 7.84 (2H, d, J=8.7 Hz), 7.78 (1H, d, J=8.7 Hz), 7.73 (1H, m), 7.67-7.60 (2H, m), 7.53 (1H, t, J=7.7 Hz), 7.48 (2H, d, J=8.5 Hz), 7.43 (1H, br t, J=7.6 Hz), 7.38-7.33 (2H, m), 6.53 (1H, m), 5.78 (2H, s), 5.12 (1H, d, J=4.7 Hz), 4.73-4.68 (1H, m), 1.71-1.64 (1H, m), 1.5-1.43 (1H, m), 0.78 (3H, t, J=7.4 Hz) ppm; high resolution mass spectrometry (ES+) m/z 476.2061 [(M+H)+; calculated for C29H26N5O2: 476.2081].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[CH3:25][N:26]([CH3:33])[C:27](=[O:32])[CH2:28][C:29](=O)[CH3:30]>C1COCC1>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:28]([C:27]([N:26]([CH3:33])[CH3:25])=[O:32])=[C:29]([CH3:30])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=3)[C:10](=[S:11])[NH:12]2)=[CH:19][CH:18]=1)#[N:16]
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC1=C(C(=O)N(C)C)C(c2ccc(C#N)cc2)NC(=S)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
3-Trifluoromethylphenyl thiourea (200 mg, 0.91 mmol), 4-cyanobenzaldehyde (238.2 mg, 1.82 mmol) and N,N-dimethyl-3-oxobutanamide (235 mg, 1.82 mmol) are dissolved in 5 ml THF. Ethyl polyphosphate (0.30 g) is added and the reaction mixture is stirred at reflux temperature overnight. After cooling to room temperature, it is quenched with 10 ml of water and extracted with 10 ml ethyl acetate (2×). The combined organic layers are dried with sodium sulfate and the solvent is removed in vacuo. The product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: O1CCCC1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH:12][CH2:13][CH:14]([OH:21])[CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.[H][H].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>O>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][O:21][CH:14]([CH2:13][NH:12][C:11]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:9]([Cl:8])[CH:10]=2)[CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[CH:31][CH:30]=1
Reactant: OC(CNc1ccc(Cl)c(Cl)c1)Cn1ccnc1
Reactant: ClCc1ccc(Cl)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(COC(CNc2ccc(Cl)c(Cl)c2)Cn2ccnc2)cc1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To 400 ml of tetrahydrofuran 8.8 g (0.366 mol) of sodium hydride followed by 92 g (0.320 mol) of 1-[3-(3,4-dichloroanilino)-2-hydroxypropyl]imidazole are added with stirring at room temperature. The formation of hydrogen stops after 1 hour and the reaction mixture is heated and refluxed for 5 hours. After cooling, 44 g (0.273 mol) of 4-chlorobenzylchloride are added. The solution is again heated to boiling temperature and refluxed for 4 hours. After cooling, 10 ml of water are added dropwise under nitrogen and the crystal cake is concentrated at 50° C./12 Torr. The residue is dissolved in 1500 ml of toluene and the solution washed twice with 300 ml of water each, filtered and concentrated to one third of its original volume under reduced pressure. The crystallized product is filtered off, washed with 100 ml of toluene in portions and dried in vacuum at 50° C./12 Torr. The raw substance is recrystallized under filtration with charcoal in a mixture of 300 ml of ethanol and 100 ml of water, filtered off and dried in vacuum at 50° C./12 Torr to yield 55.3 g of 1-[2-(4-chlorobenzyloxy)-3-(3,4-dichloroanilino)-propyl]-imidazole, M.P. 102.5°-103° C.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]3[C:10]=2[C:5](=[CH:6][CH:7]=[CH:8]3)[CH:4]([C:15]#[N:16])[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:28](N)[CH2:29][NH2:30]>>[CH3:1][CH:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]3[C:10]=2[C:5](=[CH:6][CH:7]=[CH:8]3)[CH:4]([C:15]2[NH:30][CH2:29][CH2:28][N:16]=2)[O:3]1
Reactant: CC1OC(C#N)c2cccc3cccc1c23
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1OC(C2=NCCN2)c2cccc3cccc1c23
Temperature: 200 °C
Yield: 9.1 %

Procedure:
3-Methyl-1,3-dihydrobenzo[de]isochromene-1-carbonitrile (100 mg) was mixed with ethylene diamine mono-p-toluenesulfonic acid salt (111 mg) and the mixture was heated to 200° C. After 3 hours reaction was cooled to room temperature. Purification of the mixture by column chromatography with neutral alumina (ethyl acetate-heptane) afforded 11 mg of 2-(3-methyl-1,3-dihydrobenzo[de]isochromen-1-yl)-4,5-dihydro-1H-imidazole that was converted to the title compound using salt formation method A. (Yield 10 mg).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8](=[O:26])[NH:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)([CH3:6])([CH3:5])[CH3:4]>CO.C1COCC1>[C:3]([O:7][C:8](=[O:26])[NH:9][CH:10]([CH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1ccc(C(NC(=O)OC(C)(C)C)C2CCC(=O)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(NC(=O)OC(C)(C)C)C2CCC(O)CC2)cc1
Reaction time: 7 h

Procedure:
Sodium borohydride (12 mg, 0.34 mmol) and 2 drops methanol were added to a solution of [(4-methoxy-phenyl)-(4-oxo-cyclohexyl)-methyl]-carbamic acid tert-butyl ester (33, 110 mg) in THF (5 mL). After stirring for 7 hours the reaction was worked up by washing the solution with saturated sodium bicarbonate solution and brine. After drying the organic phase over sodium sulphate, followed by filtration, evaporation gave 101 mg of the desired cis/trans isomer mixture (34) as a colourless solid, which was used directly in the next stage. Rt=1.36, 1.39 min (Method 5). Detected mass: 219.2 (M—C4H8—CO2—H2O+).