Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CN1C(=O)CCC1.[F:16][C:17]1[CH:18]=[C:19]([CH2:23][NH2:24])[CH:20]=[CH:21][CH:22]=1.CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Br:8][C:4]1[N:3]=[C:2]([NH:24][CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: NCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Fc1cccc(CNc2cccc(Br)n2)c1
Temperature: 117.5 °C
Reaction time: 168 h

Procedure:
A mixture of 2,6-dibromopyridine (7.1 g, 30.0 mmol), NMP (16 ml), (3-fluorophenyl)methanamine (4.13 g, 33.0 mmol) and Hunig's Base (5.76 ml, 33.0 mmol) was flushed with argon. The crude reaction mixture mixture was stirred at 115-120° C. for about 168 hours. LC/MS was used to monitor the reaction. The crude mixture was then cooled to room temperature, and then diluted with 250 ml of ethyl acetate, washed with saturated sodium bicarbonate (2×), water (2×), saturated, salt solution (1×), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography using a 120 g column, eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to yield, 7.11 grams of the titled compound as a free base, which was used in the next step without further purification. LCMS (m/z): 281.1/283.1 (MH+), retention time=1.03 min.
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.[C:28](Cl)(=O)[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>C(Cl)Cl>[CH2:28]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C(\CCCCCOCc1cccnc1)=C(\c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (0.8 g, 3 mmoles) was dissolved in methylene chloride (10 ml), and pyridine (2 ml) and nicotinoyl chloride hydrochloride (0.55 g, 3 mmoles) were added. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (1:1) as the developing solvent to give 1-nicotinyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (1.0 g, 89.6%) (Compound Id-21) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[C:11]1(B(O)O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C:19]2[C:20]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)c1ccc(Br)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cccc3ccccc23)[nH]1
Yield: 81.6 %

Procedure:
Argon gas was bubbled 15 min through a solution of 5-bromo-1H-pyrrole-2-carboxylic acid methyl ester (10.0 mmol, 2.04 g), 1-naphthylboronic acid (30.0 mmol, 5.16 g), 2M aqueous sodium carbonate (20 ml), and DMF (150 ml). The mixture was then treated with tris(dibenzylidienacetone)dipalladium (0) (0.50 mmol, 0.46 g), and triphenylarsine (2.0 mmol, 0.61 g), then heated to reflux under argon for 12 h. The mixture was partitioned between ethyl acetate (500 ml) and water (150 ml). The organics were filtered through celite, washed with brine (3×50 ml), then concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 2.05 g (81%) of 5-naphthalen-1-yl-1H-pyrrole-2-carboxylic acid methyl ester. 1H NMR (CDCl3) δ 9.37 (1H, s), 8.22-8.17 (1H, m), 8.16-7.89 (2H, m), 7.59-7.50 (4H, m), 7.88 (1H, dd, J=3.9, 2.7), 6.22 (1H, dd, J=3.8. 2.6), 3.88 (3H, s).
Reaction SMILES: ClCCN(N=O)[C:5](N=[N+]=[N-])=[O:6].NN1[CH2:18][CH2:17]CCC1.[CH3:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH:24]S(O)(=O)=O>ClCCl>[CH:5]([O:6][CH2:17][CH3:18])=[O:24].[CH3:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: [N-]=[N+]=NC(=O)N(CCCl)N=O
Reactant: NN1CCCCC1
Reactant: O=S(=O)(O)O
Solvent: CCCCC
Solvent: ClCCl
Product: CCOC=O
Reaction time: 1 h
Yield: 21 %

Procedure:
To a solution of 0.1 mole N-(2-chloroethyl)-N-nitrosocarbamoylazide in 75 ml dichloromethane is added in drops at -5 degC. (°C.) under stirring within 2 hours a solution of 0.2 mole N-aminopiperidine in 20 ml of a mixture of 4 parts by volume dichloromethane and 1 part by volume n-pentane. After the addition, the stirring is continued for one hour and a whitish-yellow precipitate is obtained. Subsequently it is shaken out with the same volume of 0.1 N H2SO4. The organic phase is dried over Na2SO4 and concentrated on the rotary evaporator. From ethyl formate/n-pentane we obtain on standing in the deep freezer yellow crystals which are homogeneous in thin-layer chromatography, after recrystallization from the same solvent mixture (silicagel foils, solvent system n-pentane/diethylether/dichloromethane 5:2:2)
Reaction SMILES: [ClH:1].Cl.Cl.N1C=C(CN2C3C=CC([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=C1.Cl.[NH:41]1[CH:45]=[C:44]([CH2:46][N:47]2[C:53]3[CH:54]=[CH:55][C:56](C#N)=[CH:57][C:52]=3[CH2:51][N:50]([S:60]([CH3:63])(=[O:62])=[O:61])[C@H:49]([CH2:64]C3C=CC=CC=3)[CH2:48]2)[N:43]=[CH:42]1>>[ClH:1].[ClH:1].[NH:41]1[CH:45]=[C:44]([CH2:46][N:47]2[C:53]3[CH:54]=[CH:55][C:56]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:57][C:52]=3[CH2:51][N:50]([S:60]([CH3:63])(=[O:62])=[O:61])[C@H:49]([CH2:64][C:26]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[CH2:48]2)[N:43]=[CH:42]1
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: Cl
Product: CS(=O)(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccncc1
Yield: 99 %

Procedure:
Example 365 was prepared as a light yellow solid in 99% yield from Compound B of Example 226 and D-(4-pyridyl)alanine by the following sequence: Compound C of Example 226; Compound D of Example 226; Compound B of Example 264; Compound D of Example 264.
Reaction SMILES: [CH3:1][C:2]1([C:5]2[CH:6]=[C:7]([NH2:17])[N:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26].ClC([O-])=O>C1COCC1.O>[Cl:30][C:29]([Cl:32])([Cl:31])[CH2:28][O:27][C:25](=[O:26])[NH:17][C:7]1[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=[C:5]([C:2]2([CH3:1])[CH2:3][CH2:4]2)[CH:6]=1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Treat a cooled (0° C.) solution of the 5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (5.68 g, 25 mmol) and pyridine (2.2 mL, 27.5 mmol) in THF (3 mL/mmol) with 2,2,2-trichloroethyl chloroformate (3.7 mL, 27.5 mmol). Maintain the reaction temperature at 0° C., and after 2 hours, add small portions of chloroformate (0.3 mL) and pyridine (0.2 mL). One hour later, dilute the reaction with water (150 mL) and extract with EtOAc (3×100 mL). Wash the combined organic phases with water (100 mL), saturated aq. NaHCO3 (50 mL), and saturated aq. sodium chloride (50 mL). Recrystallize the crude syrup from ethyl acetate/hexanes to provide the title compound as a white solid (8.18 g, 20.3 mmol; 81%). LCMS (ES+): m/z=402.2/404.2 [M+H].
Reaction SMILES: BrCC[C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(OCC)C>[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH:17]1[CH2:5][CH2:4][CH2:14][CH2:13][C:5]1[CH:4]=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9]
Reactant: O=C1NC(=O)c2cc(CCBr)ccc21
Reactant: CN1CCNCC1
Solvent: CCOCC
Product: CN1CCNCC1CCCCc1cccc2c1C(=O)NC2=O

Procedure:
4-Bromoethylphthalimide (564 mg; 2.0 mmoles) and N-methylpiperazine (0.44 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])#[CH:12].N>>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:12]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1ccccc1F
Agent: N
Product: Fc1ccccc1-c1cc(-c2cccnc2)no1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-2-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.34-7.56 (m, 2H), 7.58-7.74 (m, 3H), 8.02 (td, J=7.6, 1.7 Hz, 1H), 8.47 (dt, J=7.9, 2.0 Hz, 1H), 8.77 (dd, J=4.9, 1.5 Hz, 1H), 9.23 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 241 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:14]4[C:19]=3[CH:18]=[C:17]([OH:20])[CH:16]=[CH:15]4)=[N:8][C:4]=2[CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].O.C(COC)OC>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[C:23]1([C:2]2[CH:22]=[CH:21][C:5]3[NH:6][C:7]([NH:9][C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[C:19]=4[CH:18]=[C:17]([OH:20])[CH:16]=[CH:15]5)=[N:8][C:4]=3[CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccc2cccc(Nc3nc4cc(Br)ccc4[nH]3)c2c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Oc1ccc2cccc(Nc3nc4cc(-c5ccccc5)ccc4[nH]3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 8-(5-bromo-1H-benzo[d]imidazol-2-ylamino)naphthalen-2-ol (18 mg, 0.05 mmol, Example 14), phenylboronic acid (12 mg, 0.1 mmol, Aldrich), PdCl2(PPh3)2 (3.5 mg, 0.005 mmol, Aldrich), Na2CO3.H2O (12 mg, 0.1 mmol), dimethoxyethane (0.35 mL), H2O (0.15 mL) and EtOH (0.1 1 mL) was subjected to microwave irradiation at 120° C. with stirring for 10 min. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound. MS (ESI, pos. ion) m/z: 352 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:7])[CH3:6].[Cl:19][CH2:20][CH2:21][C:22](Cl)=[O:23].O>ClC(Cl)C>[C:5]([N:8]1[C:14]2[CH:15]=[C:16]([C:22](=[O:23])[CH2:21][CH2:20][Cl:19])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCCCc2ccccc21
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(=O)N1CCCCc2ccc(C(=O)CCCl)cc21
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Aluminum chloride (30.8 g, 231 mmol) was added to a solution of 1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepine (17.5 g, 92.5 mmol) and 3-chloropropionyl chloride (13.2 ml, 139 mmol) in dichloroethane under cooling with water-bath, and then the mixture was stirred at 50° C. for 1 day. The reaction solution was poured into iced water and extracted with dichloromethane. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=1:1) and crystallized from hexane, whereby the title compound (8.47 g) was obtained as colorless powder with a mp. of 106 to 107° C.
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21].O>O1CCCC1>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 59.5 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.050 g, 4.066 mmol) in tetrahydrofuran (16 ml), lithium hydroxide monohydrate (0.161 g, 3.84 mmol) was added and the mixture was stirred at room temperature for approximately 1.2 hours. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.903 g, 2.27 mmol) in tetrahydrofuran (3 ml), and water (0.57 ml) were added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, approximately half of the solvent was evaporated from the solution under reduced pressure. Ethyl acetate and water were added to the solution and the solution was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP 27 g, ethyl acetate:hexane=1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300SP: 6 g; ethyl acetate:hexane=1:4), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (0.719 g; 1.35 mmol; yield: 59.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([C@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([C@H:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](OS(C)(=O)=O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In ethyl acetate (40 ml) was dissolved (2S,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (2.5 g). To the solution were added, under ice-cooling, triethylamine (1.82 ml) and methanesulfonyl chloride (1.51 g). The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added ethyl acetate (40 ml), which was washed with water and dried (anhydrous magnesium sulfate), followed by concentration to give (2S,3R)-2-(2,4-difluorophenyl)-3-methanesulfonyloxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol as an oily product. This product was dissolved in methanol (40 ml), to which was added, under ice-cooling, a 28% methanol solution of sodium methylate (2.04 g). The mixture was stirred for 30 minutes at room temperature, then the reaction mixture was concentrated under reduced pressure. To the concentrate was added ethyl acetate (100 ml), which was washed with water, followed by drying (anhydrous magnesium sulfate). The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel chromatography (eluent: ethyl acetate-dichloromethane=4:1) to give (2S,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (1.62 g) as a colorless oily product. This product became a colorless solid in a freezer. m.p. 41°-43° C. [α]D23 =+5.8° (c=1.0 in methanol)
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:52][CH2:51][CH2:50][CH2:49][CH2:48][CH3:47])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCCCCN
Product: CCCCCNC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-amylamine (Fluka) to give the title product. LC-MS (ES+) 734 [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[O:30]=[C:31]1[NH:35][CH2:34][CH:33]([C:36]([NH2:38])=[O:37])[CH2:32]1.[C:39](=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>ClCCl.[Cu]I.COCCOCCOC>[O:29]=[S:20]1(=[O:28])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:4]2[CH:3]=[C:2]([NH:38][C:36]([CH:33]3[CH2:32][C:31](=[O:30])[NH:35][CH2:34]3)=[O:37])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:39])[CH:10]=3)[N:5]=2)[CH2:18][CH2:19]1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: O=C([O-])[O-]
Reactant: NC(=O)C1CNC(=O)C1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOCCOC
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C3CNC(=O)C3)c2c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 3.6 %

Procedure:
A mixture of 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (500 mg, 1.19 mol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1), 5-oxopyrrolidine-3-carboxamide (307 mg, 2.39 mmol), copper(I) iodide (23 mg, 0.12 mmol), potassium carbonate (497 mg, 3.60 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.038 mL, 0.24 mmol) and diethylene glycol dimethyl ether (10 mL) was heated with stirring in a 10 mL microwave process vial for 3 hours at 140° C. under microwave irridiation. The mixture was diluted with dichloromethane, washed with water. The aqueous layer was back extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 40 mg of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-5-oxopyrrolidine-3-carboxamide as light brown solid. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (s, 1 H), 7.88 (m, 3 H), 7.81 (s, 1 H), 7.70 (s, 1 H), 7.64 (td, J=1.2, 7.6 Hz, 1 H), 7.47 (d, J=8.8 Hz, 1 H), 7.46 (dd, J=0.8, 7.6 Hz, 1 H), 7.38 (dd, J=1.6, 8.4 Hz, 1 H), 5.08 (s, 2 H), 4.42 (brs, 2 H), 3.73-3.57 (m, 4 H), 3.43 (dd, J=6.0, 9.6 Hz, 1 H), 3.32 (s, 1 H), 2.48 (m, 1 H), 2.42 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:21]([O:23][CH3:24])=[O:22])=[O:15])[CH:5]=[CH:4][C:3]1=2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:48]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[CH2:28][Br:48])[C:21]([O:23][CH3:24])=[O:22])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(C)c(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(CBr)c(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of methyl 3-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl)methyloxy]-4-methylbenzoate (7.02 g, 16.7 mmol), benzoyl peroxide (0.02 g) and N-bromosuccinimide (4.28 g, 24 mmol) in carbon tetrachloride (370 ml) was heated at reflux and irradiated with a 1000 W lamp for forty five minutes. 350 ml of water and 250 ml of dichloromethane were added. After separation of the phases once settling had taken place, the organic phase was washed twice with 350 ml of water and dried over magnesium sulfate. After concentration on a rotary evaporator at 40° C. under vacuum, the three products obtained were purified by flash chromatography (CH2Cl2) and then by HPLC (70% CH2Cl2, 30% heptane). The properties of the monobromo benzyl compound were as follows:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:27][NH:28][CH2:29][CH2:30][NH:31][CH3:32]>C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([N:28]([CH3:27])[CH2:29][CH2:30][NH:31][CH3:32])(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: CNCCNC
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNCCN(C)S(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1.00 eq), is dissolved in DCM (30 ml). The solution is degassed with N2 and cooled down to 0° C. Triethylamine (1 ml; 7.42 mmol; 5.00 eq) followed by N,N′-dimethylethylenediamine (0.79 ml; 7.42 mmol; 5.00 eq) are added. After 30 minutes at 0° C., the reaction is complete. The reaction mixture is washed with NaHCO3 sat. (twice) and water (twice). The organic phase is dried over MgSO4, filtered and concentrated under vacuum, affording Compound (19) as a beige solid (457 mg; 79%).