Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:11]1[C:15]2[CH:16]=[CH:17][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:19][C:14]=2[NH:13][C:12]1=[O:29])([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.Br[CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:33]1=2.C([O-])([O-])=O.[Na+].[Na+].O.CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:31]=[C:32]3[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[CH2:36][O:35][C:34]4[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:33]3=4)=[CH:19][C:14]=2[NH:13][C:12]1=[O:29])([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: Fc1ccc2c(c1)OCc1ccccc1C2=CBr
Reactant: CC(C)(CN1CCOCC1)n1c(=O)[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(CN1CCOCC1)n1c(=O)[nH]c2cc(C=C3c4ccccc4COc4cc(F)ccc43)ccc21
Yield: 59.8 %

Procedure:
Mix 1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (900 mg of 60% purity, 1.34 mmol), 11-bromomethylene-3-fluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 520 mg, 1.7 mmol), 2N Na2CO3 (4 mmol) in dioxane (10 mL). Sparge with nitrogen for 10 min and then add tetrakistriphenylphosphine Pd (0) (98 mg, 0.08 mmol) and heat at 90-100° C. 5 days. Cool the reaction and shake with water/EtOAc. Dry (MgSO4) and concentrate to give 1.05 g crude product. Purify by column chromatography using 2% 2N NH3 in MeOH/methylene chloride to give 400 mg (80%) title compound as an off-white solid. MS (es) 500 (M+1), 498 (M−1); HPLC (ISO80-10M) t=1.95 min (100%); 1NMR (CDCl3) 8.17 (s, 1H), 7.49 (t, 1H, J=7.5 Hz), 7.46 (d, 1H, J=7.0 Hz), 7.37 (t, 1H, J=7.0 Hz), 7.26 (t, 1H, J=7.5 Hz), 7.14 (d, 1H, J=7.5 Hz), 6.91 (d, 1H, J=8.5 Hz), 6.89 (s, 1H), 6.81 (d, 1H, J=7.5 Hz), 6.70 (td, 1H, J=11.7, 4.1 Hz), 6.66 (s, 1H), 6.56 (dd, 1H, J=10.1, 2.6 Hz), 6.03-4.76 (br d, 2H), 3.85-3.70 (m, 6H), 2.73 (t, 4H, J=4.2 Hz), 1.13 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:31])[CH:29]=[CH2:30].[CH2:32](OCC1OC1)[CH:33]1[O:35][CH2:34]1>C(#N)C>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:32][CH:33]([OH:35])[CH2:34][O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:31])[CH:29]=[CH2:30])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(=O)OCCCCO
Reactant: C(OCC1CO1)C1CO1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CC(=O)OCCCCOCC(O)COc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A reaction mixture containing 4-hydroxybenzophenone (14.9 g, 75 mmol), acetonitrile (40 mL), potassium carbonate (7.8 g, 56.25 mmol) and 4-hydroxybutylacrylate glycidylether (7.5 g, 37.5 mmol) was heated to reflux. The mixture was allowed to stir at reflux temperature for 24 hours. The mixture was cooled to room temperature and filtered to remove the undissolved potassium carbonate. The filtrate was evaporated under reduced pressure. The residual oil was diluted with ethyl acetate (250 ml) and extracted with a mixture of an aqueous solution of sodium hydroxide (1N) and distilled water (4/1). The organic layer was separated, dried over MgSO4, filtered and evaporated to provide 15.1 g of a yellow oil. The product was purified on a SVP D40 Merck Np Column using dichloromethane/n-hexane (50/50) as eluent, to afford 5.5 g of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36](O)=[O:37])([CH3:35])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[F:70][C:71]([F:75])([F:74])[CH2:72][NH2:73]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([CH3:35])([C:36](=[O:37])[NH:73][CH2:72][C:71]([F:75])([F:74])[F:70])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: NCC(F)(F)F
Reactant: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a mixture of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.065 mmol), EDCI (18.7 mg, 0.098 mmol), HOBt (15 mg, 0.098 mmol) and DIPEA (75 mg, 0.6 mmol) in THF (2 mL) was added 2,2,2-trifluoroethylamine hydrochloride (25 mg, 0.185 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (19 mg).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][C:7]1=[O:20])[CH3:4].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24](C)[C:23]=1[SH:29].Br[CH2:31]CBr>CCOCC>[ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:8][C:7]1([C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([S:29][CH3:31])[CH:22]=1)[OH:20])[CH3:4]
Reactant: CN(C)CC1CC(CCc2ccccc2)CCC1=O
Reactant: Cc1cccc(Br)c1S
Reactant: BrCCBr
Agent: Cl
Solvent: CCOCC
Product: CSc1cccc(C2(O)CCC(CCc3ccccc3)CC2CN(C)C)c1
Yield: 23 %

Procedure:
The base of compound (48) was reacted with 1-bromo-3-methyl-sulphanyl-benzene corresponding to the conditions described in Example 1. In departure from the conditions described in Example 1, ether was used as the solvent and 1,2-dibromoethane was added to the reaction batch in order to increase the yield. The crude product was purified with diisopropyl ether via a silica gel column and was taken up in 2-butanone. After the addition of trimethylchlorosilane/water, compound (51) was obtained in a yield of 23% theoretical.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:33][C:4]2[C:5]3[N:6]=[CH:7][N:8]([C:9]=3[N:10]=[C:2]([Cl:1])[N:3]=2)[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([OH:18])[C@H:12]2[OH:13])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: COC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 2,6-dichloro-9-(2,3-di-O-acetyl-5-O-methyl-β-D-ribofuranosyl)-purine (61, 505 mg, 1.2 mmol) and cyclopentylamine (1.8 mmol, 178 μL). The mixture was purified by column chromatography (eluens 2% MeOH in CH2Cl2). Yield 364 mg (0.95 mmol, 79%), mp 124–126° C.; Rf 0.15 (eluens 2% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 8.33 (bs, 1H, NH), 8.30 (s, 1H, H-8), 5.81 (d, 1H, J=4.46 Hz, H-1′), 5.51 (d, 1H, J=3.36 Hz, OH-2′), 5.29 (d, 1H, J=3.32 Hz, OH-3′), 4.59–4.29 (m, 2H, CH, H-2′), 4.41–3.99 (m, 2H, H-3′,4′), 3.56–3.52 (m, 2H, H-5′), 1.94–1.92 (m, 2H, cyclopentyl), 1.71–1.50 (m, 4H, cyclopentyl); MS m/z 384 (M+H)+; Anal. (C16H22ClN5O4.0.1 CH2Cl2) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH2:7][CH2:8][N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH2:22][C:10]2=3)=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[ClH:1].[CH2:18]1[C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:31][CH:30]=3)[C:10]=2[CH2:22][CH2:21][NH:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccc(Cl)cc3)c3ccccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Clc1ccc(OCCn2c3c(c4ccccc42)CCNCC3)cc1
Reaction time: 1 h
Yield: 189.1 %

Procedure:
tert-Butyl 6-[2-(4-chlorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.622 g, 1.41 mmol) was dissolved in CH2Cl2 (10 mL) at rt. CF3CO2H (4 mL) was added, then the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was taken up in EtOAc and washed with 1 N NaOH. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product (0.541 g) was dissolved in EtOAc (2 mL) and 1 N HCl in Et2O (2 mL) was added. The solvents were removed under vacuum and Et2O (10 mL) was added to the residue. The resulting mixture was sonicated and the finely powdered salt was collected by filtration. 4-Chlorophenyl 2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl ether hydrochloride (0.503 g) was obtained in 94% yield. 1H NMR (300 MHz, CD3OD) δ 3.16-3.20, 3.35-3.50, 4.22, 4.59, 6.76, 7.07, 7.18, 7.18, 7.43, 7.48; MS (ESI+) for C20H21ClN2O m/z 341.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][N:6]([CH3:26])[C:7](=[O:25])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[CH3:2].N.C([BH3-])#[N:31].[Na+]>>[ClH:16].[CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][N:6]([CH3:26])[C:7]([C:8]1[NH:31][C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]2[C:10]=1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12]2)=[O:25])[CH3:2]
Reactant: CCN(CC)CCN(C)C(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: [BH3-]C#N
Agent: N
Agent: [Na+]
Product: CCN(CC)CCN(C)C(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Product: Cl

Procedure:
In accordance with the procedure described in Example 3, 16.0 g. of o-benzoyl-p-chlorophenylglyoxylic acid [2-(diethylamino)ethyl]methylamide are reacted with 4.1 g. of ammonia and 1.6 g. of sodium cyanoborohydride. The ether extract containing the free base is concentrated to about 300 ml. and treated with ethereal hydrochloric acid. The precipitated hydrochloride is recrystallized from ethanol, and there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid [2-(diethylamino)ethyl]methylamide hydrochloride in the form of felt-like greenish crystals having a melting point of 208°-210° C. (decomposition).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([N:13]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:25]=1)[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:10]([CH3:12])[CH3:11].[C:41](=O)([O:44]C)[O:42][CH3:43]>>[CH3:43][O:42][C:41](=[O:44])[CH2:30][C:28]1[CH:27]=[C:26]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)[N:25]=[C:24]([N:13]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[CH:29]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A solution of LDA (1.8 M in THF/heptane/ethyl benzene, 340 mL, 0.6 mmol) was added slowly to a stirred solution of isobutyl-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-trifluoromethyl-phenyl)-amine (135 g, 0.3 mmol) under N2 at −78° C. After 30 minutes dimethyl carbonate (55 mg, 0.6 mmol) was added. After stirring at −78° C. for 30 minutes, the solution was allowed to warm up slowly and stirred at 0° C. for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl (1 mL). The mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2 (2×). The combined extracts were washed with brine, then dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (40-80% CH2Cl2 in heptane) to give the product as light yellow oil (75 mg, 49%). 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=7.91 Hz, 2H), 7.70 (d, J=8.29 Hz, 2H), 7.65 (d, J=8.29 Hz, 2H), 7.40 (d, J=8.29 Hz, 2H), 7.14 (s, 1H), 6.50 (s, 1H), 3.96 (d, J=7.16 Hz, 2H), 3.69 (s, 3H), 3.51 (s, 2H), 2.05-2.22 (m, 1H), 0.98 (d, J=6.78 Hz, 6H). MS m/e 511.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](I)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:17][C:18]1[S:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Br:17][C:18]1[S:22][C:21]([C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH:14]=[C:13]([CH3:15])[N:12]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Br)s1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(I)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Br)s2)n1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-2-iodo-6-methylpyridine (example A.52) (1.0 g, ca. 80% pure, ca. 2.75 mmol) and commercially available 5-bromthiophene-2-boronic acid (0.568 g, 2.75 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.480 g, 46%). MS (ISP) 397.9 [(M+H)+], 400.0 [(M+2+H)+], 402.1 [(M+4+H)+] and 404.2 [(M+6+H)+].
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:17]2[S:16][CH:15]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:17]2[S:16][CH:15]=1
Reactant: Oc1cccc(O)c1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccc(O)cc3O)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 0.055 g of resorcinol in 0.3 ml of trifluoracetic acid is mixed with 0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the solution is left to stand for 15 minutes at room temperature. It is diluted with an equal quantity of toluene and then evaporated to dryness under reduced pressure. 3-(2,4-Dihydroxybenzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is obtained by working up the residue in accordance with the process indicated in example 6; this acid shows the following Rf values in a thin layer chromatogram (silica gel): 0.66 (system n-butanol/acetic acid/water, 75:7.5:21), 0.70 (system n-butanol/acetic acid/water, 67:10:23) and 0.52 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([C:19]#[N:20])[CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27](OB(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:18][O:17][C:12]1[CH:11]=[C:10]([C:19]#[N:20])[C:9]2[C:14]([CH:13]=1)=[CH:15][CH:16]=[C:7]([C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=1)[CH:8]=2
Reactant: COc1cc(C#N)c2cc(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: COc1cccc(OB(O)O)c1
Product: COc1cccc(-c2ccc3cc(OC)cc(C#N)c3c2)c1
Yield: 25 %

Procedure:
The compound is prepared by the reaction of 8-cyano-6-methoxynaphthalene-2-yl trifluoromethanesulfonate (466 mg, 1.4 mmol, 1 eq) with 3-methoxyphenylboric acid (260 mg, 1.7 mmol, 1.2 eq) according to method A over night. Purification by column chromatography with hexane/ethyl acetate 7/3 as the eluent yielded the desired compound in a yield of 25%, 113 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:11]([CH2:33][C@H:34]([C:38](O)=[O:39])[CH:35]([CH3:37])[CH3:36])[O:10][C:9]1([CH3:42])[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:45][C:46](=[O:54])[C:47]([CH2:52][CH3:53])([CH2:50][CH3:51])[CH2:48][NH2:49])C>>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:11]([CH2:33][C@H:34]([C:38](=[O:39])[NH:49][CH2:48][C:47]([C:46]([OH:45])=[O:54])([CH2:50][CH3:51])[CH2:52][CH3:53])[CH:35]([CH3:36])[CH3:37])[O:10][C:9]1([CH3:41])[CH3:42])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Reactant: CCOC(=O)C(CC)(CC)CN
Product: CCC(CC)(CNC(=O)[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](Cc1ccc(OC)c(OCCCOC)c1)C(C)C)C(C)C)C(=O)O

Procedure:
The starting material is prepared analogously to Example 124 b) from 3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine (Example 124 c) and 3-amino-2,2-diethylpropionic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1C[CH2:5][CH2:4][CH2:3]1.[Br:7][CH2:8][CH2:9][CH2:10][CH3:11].[F-].[K+]>>[Br-:7].[CH2:3]([N+:2]1([CH3:1])[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: CN1CCCC1
Agent: [F-]
Agent: [K+]
Product: CCC[N+]1(C)CCCC1
Product: [Br-]

Procedure:
Propylmethylpyrrolidinium bromide was prepared by Menshutkin reaction of N-methylpyrrolidine with 1-bromobutane. 21.5 g of the adduct formed by the IB-4 complex with KF were added to 20.8 g of [C4H8N(CH3)C3H7]Br in 100 ml of acetone. The suspension was stirred by means of a magnetic stirrer for 48 hours. The KBr formed during the reaction was eliminated by filtration and the precipitate was washed with two portions of 20 ml of acetone. The solvent was eliminated and a viscous liquid was recovered, corresponding to the formula:
Reaction SMILES: [CH:1]([C:4]1[C:5]2[CH:6]=[C:7]([CH3:28])[C:8]([NH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[CH:9][C:10]=2[C:11]([CH3:15])([CH3:14])[CH2:12][CH:13]=1)([CH3:3])[CH3:2].[CH:29](=O)[CH3:30]>>[CH2:29]([N:16]([C:8]1[C:7]([CH3:28])=[CH:6][C:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:9]=1)[C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=1)[CH3:30]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C(C)C)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C(C)C)=CCC3(C)C)cc1
Yield: 85.3 %

Procedure:
Following General Procedure D, ethyl 4-(5-isopropyl-3,8,8-trimethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 48, 0.10 g, 0.26 mmol) was reacted with acetaldehyde (0.15 mL, 2.6 mmol) to give 0.090 g (90%) of the title compound as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C1COCCN1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Temperature: 100 °C
Yield: 34.8 %

Procedure:
A stirred suspension of 100 mg (0.22 mmol) (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide, 145 mg (0.44 mmol) cesium carbonate and a few crystals of 2,6-di-tert-butyl-p-cresol in 0.39 ml (4.44 mmol) morpholine in a thick-walled glass pressure tube fitted with a teflon cap was heated at 100° C. for 16 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. Flash chromatography (1/1 acetone/hexane) followed by trituration in ether afforded 35 mg (35%) (+)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-2-morpholin-4-yl-isonicotinamide as a white solid. [α]D20=+63.7° (c=0.63, CHCl3), ES-MS m/e (%): 457 (M+H+, 100).
Reaction SMILES: CS[C:3]1[CH:4]=[C:5]([CH2:9]O)C=C[CH:8]=1.[CH3:11][S:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=1.C(OC)(=[O:25])C=C>>[CH3:11][S:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=1.[CH3:11][S:12][C:13]1[CH:14]=[C:15]([C:19]2([C:20]#[N:21])[CH2:9][CH2:5][C:4](=[O:25])[CH2:3][CH2:8]2)[CH:16]=[CH:17][CH:18]=1
Reactant: CSc1cccc(CO)c1
Reactant: C=CC(=O)OC
Agent: CSc1cccc(CC#N)c1
Product: CSc1cccc(C2(C#N)CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared according to the process described in Example 183 via the intermediates (3-methylsulfanylphenyl)methanol (MS (ESI+): 155) and (3-methylsulfanylphenyl)acetonitrile (MS (ESI+): 164). In step c), the reaction mixture was not heated under reflux after the addition of the methyl acrylate, but stirred for 16 h at room temperature. From 2.9 g of (3-methylsulfanylphenyl)acetonitrile, 0.85 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-:11].[Al+3].[Cl-].[Cl-].[CH3:15][C:16]1[C:20]2[C:21]([OH:29])=[C:22]([CH2:26][CH2:27][CH3:28])[CH:23]=[C:24]([Cl:25])[C:19]=2[O:18][CH:17]=1>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[O:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([CH2:26][CH2:27][CH3:28])=[C:21]([O:29][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([Cl:11])=[CH:3][CH:4]=4)[C:20]=3[C:16]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCCc1cc(Cl)c2occ(C)c2c1O
Reactant: [Cl-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Solvent: ClCCCl
Product: CCCc1cc(Cl)c2oc(C(=O)c3ccc(Cl)cc3)c(C)c2c1OC(=O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
A solution of p-chlorobenzoyl chloride (3.5 gm; 20mmoles) in ethylene dichloride (10 mL) was added slowly to a cooled suspension of aluminium chloride (5.36 gm; 40mmoles) in ethylene dichloride (200 mL). After stirring for a period of 15 minutes, 3-methyl 4-hydroxy-5-propyl-7-chlorobenzofuran (1.5 gm; 7mmoles) in ethylenedichloride (10 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 5 hours. It was cooled with an ice-bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the agueous phase was extracted with methylene chloride. The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with 15% ethylacetate in hexane yielded 2.63 gm (75%) of 2-(p-chlorobenzoyl)-methyl-4-(p-chlorobenzoyloxy)-5-propyl-7-chlorobenzofuran, mp. 177°-182° C.