Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[O:14][C:13](=[O:15])[NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[I:28].[NH4+].[Cl-]>C1COCC1>[I:28][C:19]1[CH:20]=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:18]=1[CH2:17][N:12]1[CH2:11][CH2:10][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:14][C:13]1=[O:15]
Reactant: O=C1NCCC(c2ccccc2)O1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1OC(c2ccccc2)CCN1Cc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C

Procedure:
A stirred and cooled (0° C.) suspension of sodium hydride (60% suspension in mineral oil, 14 mg, 0.34 mmol) in THF (2 mL) was treated dropwise with a solution of 6-phenyl-1,3-oxazinan-2-one (24 mg, 0.137 mmol) in THF (2 mL), under an atmosphere of nitrogen. The reaction was stirred for 20 min at 0° C. and 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (Intermediate 11; 50 mg, 0.137 mmol) was added. The reaction was allowed to warm to room temperature and stirred for an additional 3 h. Saturated NH4Cl (1 mL) was added and the resultant mixture was partitioned between H2O (20 mL) and EtOAC (20 mL). The aqueous layer was re-extracted with EtOAc (3×20 mL) and the combined extracts were washed with brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 3-[2-iodo-5-(trifluoromethyl)benzyl]-6-phenyl-1,3-oxazinan-2-one as a colorless oil. LCMS=462.0 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[C:16]([NH2:21])([CH2:19][CH3:20])([CH3:18])[CH3:17]>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:21][C:16]([CH3:18])([CH2:19][CH3:20])[CH3:17]
Reactant: CCC(C)(C)N
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Solvent: CCO
Product: CCC(C)(C)NCCOc1cc(F)cc(S(C)(=O)=O)c1
Yield: 76.3 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and tert-amylamine (1.61 ml, 13.46 mmol) in ethanol (5 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (389 mg, 76.2%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 190.2° C. MS m/z (relative intensity, 70 eV) 303 (M+, 0), 288 (21), 276 (10), 275 (41), 274 (bp), 84 (10).
Reaction SMILES: N1(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)C=CC=N1.Cl.[F:32][C:33]([F:48])([F:47])[C:34]1[N:35]=[CH:36][C:37]([NH:40][C@H:41]2[CH2:45][CH2:44][CH2:43][C@@H:42]2[NH2:46])=[N:38][CH:39]=1.[F:49][C:50]1[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:51]=1[C:52](O)=[O:53]>>[F:49][C:50]1[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:51]=1[C:52]([NH:46][C@H:42]1[CH2:43][CH2:44][CH2:45][C@@H:41]1[NH:40][C:37]1[CH:36]=[N:35][C:34]([C:33]([F:32])([F:47])[F:48])=[CH:39][N:38]=1)=[O:53]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1c(F)cccc1F
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1cccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1c(F)cccc1F

Procedure:
Prepared according to the procedure for 2-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 31) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 213 mg, 0.75 mmol) and 2,6-difluorobenzoic acid (CAS number 385-00-2; 131 mg, 0.83 mmol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][C:5]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[C:4]=2[N:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:12][C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][C:5]4([CH2:13][CH2:14][CH2:15][CH2:16]4)[C:4]=3[N:3]=[C:2]([NH2:1])[N:11]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Nc1nc(O)c2c(n1)C1(CCCC1)CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Reaction time: 3 h

Procedure:
A solution of Example 10C (2.91 g, 13.27 mmol), p-toluenesulfonyl chloride (3.79 g, 19.91 mmol), and 4-(dimethylamino)pyridine (324 mg, 2.65 mmol) in methylene chloride (60 mL) was treated with triethylamine (3.7 mL, 4.40 mmol) at ambient temperature, and the resulting solution was stirred for 3 hours. It was then diluted with methylene chloride (100 mL) and water (50 mL), and the layers were separated. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; then the residue was chromatographed on silica gel (1:2:2 ethyl acetate/methylene chloride/hexane, eluant) to provide the title product. 1H NMR (300 MHz, CD3OD) δ 7.95 (d, 2H), 7.44 (d, 2H), 2.45-2.47 (m, 3H), 2.40-2.45 (m, 2H), 1.99-2.10 (m, 2H), 1.79-1.90 (m, 2H) 1.65-1.75 (m, 6H), 1.52-1.62 (m, 2H); MS (DCI+) m/z 374 (M+H)+.
Reaction SMILES: O.[CH2:2]([N:9]1[C:13]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][N:11]=[C:10]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:29]O>>[CH2:2]([N:9]1[C:13]([CH2:14][C:15]([O:17][CH3:29])=[O:16])=[CH:12][N:11]=[C:10]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cnc(-c2ccccc2)n1Cc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1cnc(-c2ccccc2)n1Cc1ccccc1
Reaction time: 4 h

Procedure:
In 200 ml of methanol was dissolved 2.4 g of 1-benzyl-2-phenylimidazole-5-acetic acid monohydrate, and 1 ml of concentrated sulfuric acid was added to the solution. The mixture was boiled for 4 hours. The reaction solution was evaporated to dryness under reduced pressure, and 50 ml of water containing 3.4 g of sodium bicarbonate and 50 ml of chloroform were added to the residue for shaking. The chloroform layer was washed with water and evaporated to dryness under reduced pressure. The residue was dissolved in a small amount of ether, and hexane was added to the solution, thereby yielding 2 g of methyl 1-benzyl-2-phenylimidazole-5-acetate as colorless crystals, m.p. 78°-79° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]=[CH:5][CH2:4][CH:3]1[CH:8]=[O:9].C=CC=C.[CH:14](=[O:18])/C=C/C.C=O.[OH-].[K+]>O.CO>[CH3:1][CH:2]1[C:3]([CH2:14][OH:18])([CH2:8][OH:9])[CH2:4][CH:5]=[CH:6][CH2:7]1
Reactant: CC1CC=CCC1C=O
Reactant: C/C=C/C=O
Agent: C=CC=C
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1CC=CCC1(CO)CO
Temperature: 60 °C
Yield: 82 %

Procedure:
To a three-necked flask, 327 g of 2-methyl-4-cyclohexene-1-carboaldehyde, a Diels-Alder reaction product of butadiene and crotonaldehyde, 600 ml of methanol and 729 g of 37% of formalin were charged, and then the temperature of this solution was raised to 60° C. with stirring. Next, 252 g of KOH dissolved in 600 ml of distilled water was added dropwise thereto. After stirring for 7 hours, the reaction solution was concentrated under reduced pressure, which resulted in a residue with two phases. The oil phase concentrated to about 150 ml was washed with 300 ml of distilled water. After concentration under reduced pressure, 50 mg of 3,5-di(t-butyl)-4-hydroxytoluene (BHT) was added to the oil phase, and then vacuum distillation was carried out to yield 311 g (yield 82%) of 6-methyl-3-cyclohexene-1,1-dimethanol as a colorless crystal.
Reaction SMILES: [CH2:1]([NH:7][S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OCC)=[O:19])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].C([Al+]CC(C)C)C(C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O>[CH2:1]([NH:7][S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNS(=O)(=O)CCCCCCCC(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCNS(=O)(=O)CCCCCCCC=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, ethyl 8-hexylsulfamoyl-octanoate (No. 6804262; 818.3 mg, 2.44 mmol) was dissolved in toluene (11 mL), and the mixture was cooled to −78° C. While maintaining the temperature at −78° C., a diluted solution of diisobutylaluminum hydride (1.5 M solution in toluene, 1.95 mL, 2.93 mmol) in toluene (2.9 mL) was added dropwise over 25 minutes, and the mixture was stirred at −78° C. for 1.5 hours. The reaction was monitored by LCMS. To this reaction solution was, then, further added a diluted solution of diisobutylaluminum hydride (1.5 M solution in toluene, 0.81 mL, 1.22 mmol) in toluene (0.9 mL) was added dropwise over 10 minutes, and the mixture was stirred at −78° C. for 1 hour. Methanol (0.65 mL) was added to the reaction solution, which was stirred at −78° C. for 10 minutes to stop the reaction. A saturated aqueous solution (3.0 mL) of Rochelle salt and water (9.0 mL) were further added and the mixture was stirred at 0° C. for 1 hour. Insoluble material was filtered off and washed with dichloromethane. The filtrate was then extracted with dichloromethane. The organic layer was washed with water, and dried over anhydrous sodium sulfate, and then filtered. Dichloromethane was distilled off to obtain the target 8-oxo-octane-1-sulfonic acid hexyl amide (ESI (LC/MS positive mode) m/z 292 (M+H); Rt 1.68 min.).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(N(CC)CC)C.C(Cl)(=O)OCC.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1>C(Cl)Cl>[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]([CH2:12][CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:8][C:9]=2[O:10][CH3:11])=[O:46])=[CH:43][CH:42]=1
Reactant: O=C(O)c1ccc(Oc2ccccn2)cc1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CN)c1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CNC(=O)c2ccc(Oc3ccccn3)cc2)c1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a solution of ethyl 2-[(3-aminomethyl-4-methoxyphenyl)-methyl]butyrate hydrochloride (302 mg, 1.00 mmol) [Japanese Patent Application No. 2000-158424] and triethylamine (390 μL, 2.80 mmol) in 10 mL of dehydrated methylene chloride was added ethyl chlorocarbonate (105 μL, 1.10 mmol) under cooling with ice and stirring, and the mixture was stirred for 20 minutes under cooling with ice. Next, 4-(2-pyridyloxy)benzoic acid (237 mg, 1.10 mmol) was added and the mixture was stirred for 1 hour under cooling with ice and for 5 hours at room temperature. Methylene chloride was added to the reaction mixture, which was washed with water, brine, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=3:2 v/v) to obtain 317 mg (68%) of the title compound as a colorless oil.
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:30])=[C:18]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=4)=[O:22])[CH:19]=3)=[N:9][N:8]2[CH:31]=1)(=O)C.[ClH:32].C(OCC)(=O)C>CO>[ClH:32].[NH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([CH3:30])=[C:18]([NH:20][C:21]([C:23]4[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=4)=[O:22])[CH:19]=3)=[N:9][N:8]2[CH:31]=1
Reactant: CC(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
To a suspension of N-(5-{[2-(acetylamino)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (310 mg, 0.73 mmol) in methanol (10 mL) was added 4N hydrochloric acid/ethyl acetate (10 mL, 40 mmol), and the mixture was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/tetrahydrofuran, and then with diethyl ether to give the title compound (240 mg, 78%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]O)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.S(Cl)([Cl:18])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][Cl:18])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCCl

Procedure:
A mixture of 20 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, 34 parts of sulfinyl chloride and 300 parts of trichloromethane is stirred and refluxed for 4 hours. The trichloromethane is evaporated and the residue is crystallized from 4-methyl-2-pentanone (activated charcoal). The product is filtered off (the filtrate is set aside), yielding a first fraction of 8.2 parts of 5-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one. The filtrate, which was set aside, is concentrated and the concentrate is stirred with 2,2'-oxybispropane. The precipitated product is filtered off and dried, yielding a second fraction of 8 parts of 5-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one.
Reaction SMILES: COC(=O)CCCC1OC=C(C2C=CC=CC=2[N+]([O-])=O)N=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])=O.[CH3:35][O:36][C:37](=[O:43])[CH2:38][CH2:39][C:40]([NH2:42])=[O:41]>>[CH3:35][O:36][C:37](=[O:43])[CH2:38][CH2:39][C:40]1[O:41][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[N:42]=1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CCC(N)=O
Agent: COC(=O)CCCc1nc(-c2ccccc2[N+](=O)[O-])co1
Product: COC(=O)CCc1nc(-c2ccccc2[N+](=O)[O-])co1
Yield: 35.7 %

Procedure:
Using a method similar to the procedure described for the preparation of 4-[4-(2-nitro-phenyl)-oxazol-2-yl]-butyric acid methyl ester; reaction of 2-bromo-2′-nitroacetophenone (15.43 g, 63.2 mmol) with succinamic acid methyl ester (14.4 g, 110 mmol) gives 3-[4-(2-nitro-phenyl)-oxazol-2-yl]-propionic acid methyl ester (6.24 g, 36%). MS (ES): (M+1)+ 277.1 m/z.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH:47]([O:51][CH3:52])[CH2:46]2)[CH:8]([CH3:54])[CH:7]([OH:55])[CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3].[H][H]>CO.[Pd]>[OH:39][C:20]12[O:35][CH:24]([CH:23]([O:36][CH3:37])[CH2:22][CH:21]1[CH3:38])[CH:25]([O:33][CH3:34])[CH2:26][CH:27]([CH3:32])[CH2:28][C:29]([CH3:31])=[CH:30][CH:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:56])[CH2:6][CH:7]([OH:55])[CH:8]([CH3:54])[CH:9]([C:43]([CH3:53])=[CH:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH:47]([O:51][CH3:52])[CH2:46]1)[O:10][C:11](=[O:42])[CH:12]1[N:17]([CH2:16][CH2:15][CH2:14][CH2:13]1)[C:18](=[O:41])[C:19]2=[O:40]
Reactant: [H][H]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCCC(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Pd]
Solvent: CO
Product: CCCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCCC(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Yield: 89.1 %

Procedure:
To a solution of the product of Example 43 (28 mg) in methanol (10 ml) was added 10% Pd-on-C (5 mg) and the resulting suspension was then stirred in an atmosphere of hydrogen for 2 hours at 0° C. The reaction mixture was then filtered and volatiles were removed in vacuo. Chromatography on silica then gave the title compound as a foam (25 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH:11](=O)[CH2:12][CH2:13][CH3:14].[BH4-].[Na+].C(OCC)(=O)C>CO>[CH2:11]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]#[N:1])=[CH:4][CH:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCC=O
Reactant: N#Cc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCNCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 g 4-Aminomethyl-benzonitrile and 3.75 ml Butyraldehyde were dissolved in 40 ml methanol. 3.0 g molecular sieves 4 Angström were added and the mixture was stirred at room temperature for two hours. Then 2.2 g sodium borohydride were added and the mixture was stirred for an additional hour at room temperature. 250 ml ethyl acetate were added, and the reaction was quenched by addition of 4 ml water. The reaction mixture was filtered through a pad of celite and MgSO4. The filtrate was evaporated in vacuo to provide 3.7 g crude 4-Butylaminomethyl-benzonitrile. This material was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]=[CH:5]1.[Mg].Cl.[CH3:11][C:12]([CH3:14])=[O:13]>C1COCC1>[CH:4]1([CH2:3][CH2:2][C:12]([CH3:14])([OH:13])[CH3:11])[CH2:8][CH2:7][CH:6]=[CH:5]1
Reactant: CC(C)=O
Reactant: ClCCC1C=CCC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(O)CCC1C=CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
5.3 g (40.6 mmol) of 3-(2-chloroethyl)-1-cyclopentene (obtained according to Hill et al. in J. Org. Chem., 1969, 3681), dissolved into 30 ml of dry THF, were added dropwise into a three necks 200 ml flask containing 1.2 g (48.7 mmol) of magnesium and 5 ml of dry THF. After a 2 hours stirring at room temperature, 2.8 g (48.7 mmol) of acetone were slowly added to the reaction mixture. 15 Minutes after the addition of the acetone, the reaction mixture was slowly hydrolysed using 1 M aqueous HCl, and extracted with ether. Then, the organic phase was washed twice with water and twice with brine, dried over MgSO4 and concentrated. The crude product was purified by chromatography over silica (eluant: cyclohexane/ethyle acetate=9/1). It was thus obtained 2.7 g of the title compound (yield=47%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH:12]([N:15]1[CH2:18][CH:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)([CH3:14])[CH3:13].[OH-].[K+]>CCOCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:18][CH:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:16][NH:15][CH:12]([CH3:13])[CH3:14]
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(C)N1CC(OCc2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)NCC(COc1ccc2ccccc2c1)OCc1ccccc1
Temperature: 180 °C
Yield: 84 %

Procedure:
A mixture of 17.3 parts of β-naphthol, 20.5 parts of 1-(iso-propyl)-3-benzyloxyazetidine, and 1.1 parts of potassium hydroxide was heated under nitrogen gas at 180° C. for 8 hours with agitation. The reaction mixture was cooled and dissolved in 100 parts of ether. The solution was washed with 50 parts of 2 N-sodium hydroxide aqueous solution and dried over anhydrous sodium sulfate. Ether was distilled off and the residue was subjected to distillation to yield 29.3 parts of 1-(β-naphthoxy)-2-benzyloxy-3-(iso-propylamino)-propane boiling at 185°-190° C. under 1 mm Hg. The yield was 84%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][C@H:27]3[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@H]3CC[C@H](O)CC3)c2c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (140 mg, 0.38 mmol, prepared in analogy to the one in Example 2-1), trans-4-aminocyclohexanol (45 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (15 mg, 0.038 mmol), sodium tert-butoxide (38 mg, 0.39 mmol) and 1,4-dioxane (2 mL) was heated with stirring in a 5 mL of microwave process vial for 2 hours at 120° C. under microwave irradiation. The mixture was filtered and washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98-7.83 (m, 2 H), 7.76 (s, 1 H), 7.64-7.44 (m, 2 H), 7.29 (d, J=8.34 Hz, 1 H), 7.21 (d, J=8.84 Hz, 1 H), 6.22 (d, J=8.34 Hz, 1 H), 6.06 (s, 1 H), 5.09 (brs, 2 H), 4.68 (d, J=4.29 Hz, 1 H), 3.62 (brs, 3 H), 3.49 (d, J=4.55 Hz, 1 H), 2.34 (s, 3 H), 2.03-1.83 (m, 4 H), 1.63-1.45 (m, 2 H), 1.35 (brs, 2 H), 1.24 (brs, 1 H), 1.18 (brs, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Br[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:34]([CH2:33][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:5]2[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)#[N:35]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC#N)cc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.6 %

Procedure:
A mixture of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.5 g, 5.9 mmol), bromoacetonitrile (0.5 ml, 7.2 mmol), potassium carbonate (1.0 g, 7.2 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 12 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl {[6-(cyanomethoxy)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (1.4 g, yield 52%) as pale-yellow crystals.