Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][C@H:7]([CH2:21][O:22]C(=O)C)[C@H:6]1[O:26]C(=O)C)(=O)C.[Br:30]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>CN(C)C=O.O.C(O)(=O)C.CO>[Br:30][C:11]1[N:10]([C@H:9]2[C@H:5]([OH:4])[C@H:6]([OH:26])[C@@H:7]([CH2:21][OH:22])[CH2:8]2)[C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=2[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OC[C@H]1C[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CN(C)C=O
Product: OC[C@H]1C[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 90 °C

Procedure:
(1S, 2R, 3R, 5R)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (2.00 g, 4.51 mmol) was dissolved in dry N,N-dimethylformamide (9 mL) and heated to 90° C. N-bromosuccinimide (1.62 g, 9.02 mmol) was added in four portions over 5 hours. . Volatiles were evaporated in vacuo. The residue was chromatographed on silica gel and product was eluted with 30-50% ethyl acetate-hexanes as a yellow glass (1.00 g, 43%); 1H-NMR(DMSO-d6) consistent with structure. This sample was deblocked with sodium carbonate (203 mg, 1.9 mmol) in water (3 mL)-ethanol(15 mL)-methanol (15 mL) at ambient temperature for 5 hours. The pH was adjusted to 7 with acetic acid. The solution was evaporated to dryness in vacuo and the residue was triturated with water to give white powder which was chromatographed. Elution of a silica gel column with 10-12% methanol-chloroform gave (1S, 2R, 3R, 5R)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol as white powder after solidification from 1:1 ethanol-methanol (410 mg, 54%), m.p. 212-215° C.; 1H-NMR(DMSO-d6) and mass spectrum identical with those of racemate described in Example 4; [α]20 589-31.2°, [α]20 578-32.3 °, [α]20 546-37.3 ° (c=0.260, methanol).
Reaction SMILES: I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]4)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)=[O:31].C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:8][C:5]1[C:4]2[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]4)=[CH:10][S:11][C:3]=2[C:2]([C:36]2[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=2)[CH:30]=[O:31])=[CH:7][N:6]=1
Reactant: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ncc(-c2cccc(C=O)c2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A mixture of 7-iodo-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine (100 mg, 0.196 mmol), 3-formylphenyl boronic acid (40 mg, 0.267 mmol), and PdCl2(dppf)-CH2Cl2 adduct (9 mg, 0.011 mmol) in 1,4-Dioxane (1.5 mL) and saturated aqueous sodium bicarbonate (0.6 mL, 0.600 mmol) was degassed with Nitrogen for 10 minutes in a microwave vial. The vial was then capped and the mixture was stirred at 120° C. in the microwave for 30 min. LCMS showed complete and relatively clean conversion to the desired product. The mixture was cooled, poured into water (15 mL), and extracted with ethyl acetate (2×15 mL). The extracts were washed with brine (1×15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g SiO2, 20%-100% EtOAc in hexanes gradient over 35 minutes) to give 3-{4-amino-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-7-yl}benzaldehyde (66 mg, 0.135 mmol, 68.9% yield) as a tan solid. LC/MS (ES) m/z=490 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=1.[H-].[Na+]>CN(C)C=O>[CH3:31][N:23]([C:21]1[CH:22]=[C:17]([O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH:18]=[CH:19][C:20]=1[N+:32]([O-:34])=[O:33])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Yield: 82.7 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 3-benzyloxyphenol (5 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6 g), sodium hydride (55 wt. %, 1.1 g) and anhydrous N,N-dimethylformamide (40 ml) and the reaction mixture was purified to give the title compound (7.8 g).
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=CC(S(N)(=O)=O)=CC=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccc(S(N)(=O)=O)cc2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)cc1
Yield: 82 %

Procedure:
4-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzenesulfonamide. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (63 mg, 0.095 mmol) and 4-bromobenzenesulfonamide following General Procedure A. Flash chromatography (2-20% EtOAc/hexanes) yielded the title compound as a white solid (41 mg, 82%): 1H NMR (CDCl3, 500 MHz) δ 8.05 (d, 2H, J=8.5 Hz), 7.83 (d, 2H, J=8.5 Hz), 7.49 (s, 1H), 7.36-7.32 (m, 2H), 7.25-7.22 (m, 3H), 5.39 (s, 2H), 4.92 (t, 1H, J=6.0 Hz), 2.67 (t, 2H, J=7.5 Hz), 2.03-1.96 (m, 2H), 1.74-1.67 (m, 2H), 1.46-1.38 (m, 6H), 0.97 (s, 9H), 0.18 (s, 3H), 0.07 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 166.6, 149.9, 141.7, 132.8, 129.6, 128.8, 128.7, 128.4, 127.6, 126.0, 124.9, 124.5, 69.1, 36.8, 36.3, 31.8, 29.6, 26.1, 26.1, 25.5, 18.6, −4.5, −4.6.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][CH2:13]OC(C)=O.C([O-])([O-])=O.[Na+].[Na+].O>CCO.S(=O)(=O)(O)O.[Cl-].[Na+].O>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)Cc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1cccc(I)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 2-(3-iodophenyl)acetic acid (1.05 g, 4.0 mmol, commercially available) in EtOH (12 mL) was treated with 2 drops of concentrated sulfuric acid. The resultant solution was heated at reflux for 90 min, cooled to RT and poured into hexanes (50 mL) and EtOAc (50 mL). The organics were with saturated Na2CO3 (2×50 mL), H2O (50 mL), brine (50 mL), dried (MgSO4) and concentrated to yield ethyl 2-(3-iodophenyl)acetate (1.11 g, 95% yield). MS (ESI) m/z: 291.0 (M+H+).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[K+].ClCCl>O>[C:10]1([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:9]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCNC1
Reactant: ClCc1cc(-c2ccccc2)ccn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: c1ccc(-c2ccnc(CN3CCCC3)c2)cc1
Reaction time: 1 h

Procedure:
The product from stage (i) (14.0 g) was added to a solution of pyrrolidine (17.0 ml) in water (80 ml) at 22°. The solution was stirred for 1 h at 22° and then potassium hydroxide (40 g), dichloromethane (200 ml) and water (200 ml) were added. The mixture was stirred for 0.25 h and the phases were separated. The aqueous phase was extracted with dichloromethane (100 ml) and the combined organic extracts were washed with water (2×100 ml), saturated brine, dried and evaporated to leave an oil (15.2 g), a portion of which (0.5 g) was purified by flash chromatography eluting with dichloromethane, ethanol and ammonia (200:8:1) to give the title compound as an oil (0.4 g). T.l.c. Silica (Dichloromethane, ethanol and ammonia 200:8:1) Rf 0.4.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2.CN(C)C=O.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:28][C:27]([NH:31][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)([CH3:30])[CH3:29]
Reactant: CC(C)(C)N
Reactant: ClCCOc1ccccc1C=Cc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NCCOc1ccccc1C=Cc1cccc2[nH]ccc12
Temperature: 120 °C

Procedure:
A mixture of 1.65 g of the product of Step A, 20 ml of dimethylformamide, 15 ml of tert.-butylamine and 770 mg of potassium carbonate was heated for 4 hours at 120° C. and was then diluted with 100 ml of water. The mixture was extracted with ethyl acetate and the extracts were washed with water, dried, concentrated under reduced pressure at 50° C. The residue was chromatographed on silica (eluent: ethyl acetate-triethylamine 9-1) to obtain 1.7 g of N-(1,1-dimethylethyl)-2-[2-[2-(1H-indol-4-yl)-ethenyl]-phenoxy]-ethanamine (trans E).
Reaction SMILES: [Cl:1][C:2]1([Cl:18])[C@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26].O>CCOCC>[Cl:1][C:2]1([Cl:18])[C@H:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:11]1[CH:12]=[CH:13][C:14]([O:17][C:25](=[O:27])[CH3:26])=[CH:15][CH:16]=1
Reactant: Oc1ccc([C@H]2[C@@H](c3ccccc3)C2(Cl)Cl)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: CC(=O)Oc1ccc([C@H]2[C@@H](c3ccccc3)C2(Cl)Cl)cc1
Yield: 31.1 %

Procedure:
A 10 mL solution of 1,1-dichloro-cis-2-(p-hydroxyphenyl)-3-phenylcyclopropane (Compound 9) (0.009 mol) and pyridine (0.79 g, 0.01 mol) in Et2O was heated under nitrogen to a gentle reflux, while acetyl chloride (0.78 g, 0.01 mol) was added dropwise slowly via a cannula. A white precipitate was noted immediately, and the mixture was refluxed for 1 h. The reaction flask was cooled while 5 mL of water was added dropwise. Et2O was used to extract the aqueous layer, and the combined Et2O layers were washed with 5% H2SO4, followed b a saturated NaHCO3 solution. Drying with anhydrous Na2SO4, and evaporation of ether gave a dark-yellow oil, which was chromatographed on a silica gel column and eluted with (3:1) CH2Cl2 /petroleum ether to provide a light-yellow oil (0.9 g, 31%). 1H NMR (CDCl3) δ 2.28 (s, 3H, OCOCH3), 3.30 (s, 2H, ArCH), 7.04 (s, 5H, ArH), 7.28 (m, 4H, ArH).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]1[C:7]([NH2:13])=[N:8][CH:9]=[C:10]([CH3:12])[N:11]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:13]([C:7]1[C:6]([CH3:5])=[N:11][C:10]([CH3:12])=[CH:9][N:8]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Cc1cnc(N)c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(N=C=S)c(C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
Thiophosgene (1.59 mL, 20.9 mmol) was added dropwise to a stirred mixture of 3,5-dimethylpyrazin-2-amine (1.98 g, 16.1 mmol) in tetrahydrofuran (20 mL) and saturated aqueous sodium hydrogen carbonate (20 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a brown solid (866 mg, 5.24 mmol, 33%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:11]2[CH2:12][C:13]([CH2:16][O:17][CH3:18])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[CH3:32][C:33]1[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>>[CH3:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:6]([C:8]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[C:11]3[CH2:12][C:13]([CH2:16][O:17][CH3:18])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:37][CH:38]=1
Reactant: Cc1ccc(N)nc1
Reactant: COCC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Solvent: O=C(O)C(F)(F)F
Product: COCC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(C)cn3)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-(4-methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (228a) and 5-methyl-pyridin-2-ylamine. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=8.59 Hz, 1 H) 8.09 (s, 1 H) 7.92 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 7.65 (dd, J=8.59, 2.02 Hz, 1 H) 7.19 (s, 1 H) 7.13 (s, 2 H) 7.09-7.11 (m, 1 H) 3.43-3.53 (m, 2 H) 3.41 (s, 3 H) 3.16 (d, J=16.42 Hz, 1 H) 3.06-3.10 (m, 3 H) 2.80 (d, J=16.67 Hz, 1 H) 2.34 (s, 3 H) 1.48 (s, 3 H); LCMS for for C25H26N2O6S m/z 483.00 (M+H)+; Anal. Calcd. for C25H26N2O6S.0.37 TFA: C, 58.95; H, 5.18; N, 5.34; Found: C, 58.92; H, 5.07; N, 5.34.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]1[CH:25]=[CH:26][CH:27]=[C:20]1[CH:19]([CH3:28])[NH:18]2>>[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]1[CH:25]=[CH:26][CH:27]=[C:20]1[CH:19]([CH3:28])[N:18]2[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: CC1Nc2cc(Br)ccc2-n2cccc21
Product: COc1ccc(C(=O)N2c3cc(Br)ccc3-n3cccc3C2C)c(OC)c1

Procedure:
7-Bromo-5-(2,4-dimethoxybenzoyl)-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from 2,4-dimethoxybenzoyl chloride and 7-bromo-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (see Example 106, Step 1) according to the procedure of Example 106, Step 2. The product was purified via Biotage Horizon® (25S, silica, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane) and isolated as a white foam. MS (ESI) m/z 427/429 ([M+H]+); HRMS: calcd for C21H19BrN2O3, 426.0579; found (ESI+), 427.0642.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=S)#[N:2].[NH2:13][C@@H:14]1[C:19]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=2[O:17][C:16]([CH3:27])([CH3:26])[C@H:15]1[OH:28].Cl.CN(C)CCCCCN=C=N>CN(C)C=O>[C:1]([N:3]=[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:13][C@@H:14]1[C:19]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=2[O:17][C:16]([CH3:26])([CH3:27])[C@H:15]1[OH:28])#[N:2]
Reactant: N#CNC(=S)Nc1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Agent: CN(C)CCCCCN=C=N
Agent: Cl
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)Nc2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.6 %

Procedure:
To a solution of N-cyano-N'-phenylthiourea (2.11 g, 11.9 mmol) and (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.0 g, 9.1 mmol), title B compound, in dimethylformamide (20 mL) under argon was added 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide hydrochloride (2.23 g, 11.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then partitioned between 1N hydrochloric acid and ethyl acetate. The organic phase was separated and the aqueous phase was reextracted with ethyl acetate. The combined organic extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate/hexanes (7:3) to give a colorless solid which was triturated with ether to yield the title compound (0.35 g), m.p. 215°-216° C.: [α]D25 =-33.5° (c=1, MeOH); 1H NMR (DMSO-d6) δ 9.28 (s, 1 H), 7.58 (d, J=8.0 Hz, 3 H), 7.35 (m, 4 H), 7.15 (m, 1 H), 6.90 (d, J=8.2 Hz, 1 H), 5.92 (br s, 1 H), 4.92 (t, J=9.0 Hz, 1 H), 3.72 (br d, J=5.9 Hz, 1 H), 1.41, 1.18 (s, 3 H each); 13C NMR (DMSO-d6) 159.2, 156.3, 137.5, 132.6, 132.5, 129.0 124.8, 124.7, 123.6, 119.0, 117.8, 117.0, 102.6, 80.4, 70.9, 51.9, 26.6, 18.6; IR (KBr) 2226, 2179, 1609, 1582, 1491, 1267 cm-1.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C@@H:10]([NH:15]N2CCC[C@@H]2COC)[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:8][N:7]=[C:6]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH3:4].B.C1COCC1.Cl>C1COCC1>[CH2:1]([N:5]1[C:9]([C@H:10]([NH2:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:8][N:7]=[C:6]1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H](NN1CCC[C@@H]1COC)c1cnc(-c2ccccc2)n1CCCC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCC[C@@H](N)c1cnc(-c2ccccc2)n1CCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 193 (1.43 g, 3.6 mmol) under argon in anhydrous THF (25 mL) at room temperature is slowly added borane-THF complex (1 M in THF, 54 ml, 54 mmol). The mixture is then refluxed under argon for 16 h. After cooling to room temperature, 10% HCl (20 mL) is added very slowly and the mixture is stirred for 2 h at room temperature. The organic solvent is removed under reduced pressure and the residue is extracted with ether. The aqueous phase is saturated with solid potassium carbonate and extracted with sthyl acetate. The residue obtained after removal of the solvent is purified by column chromatography to afford the desired product as a colorless oil. Yield: 0.6 g; LC-MS (MH+): 286.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[CH3:21][C:22]1[C:23]([C:28]([OH:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1.[F:31][C:32]1[CH:41]=[CH:40][C:35]([C:36](OC)=[O:37])=[CH:34][CH:33]=1>C1COCC1.O>[F:31][C:32]1[CH:41]=[CH:40][C:35]([C:36](=[O:37])[CH2:21][C:22]2[C:23]([C:28]([OH:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:34][CH:33]=1
Reactant: Cc1cccnc1C(=O)O
Reactant: COC(=O)c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(Cc1cccnc1C(=O)O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
To generate LDA: To a chilled (ice-acetone bath) solution of diisopropylamine (5.1 mL, 36 mmol) in dry THF (30 mL) was added n-BuLi (1.45 M solution in hexanes, 24 mL, 35 mmol) drop-wise and under an atmosphere of nitrogen. The solution was stirred for 15 minutes before being added to a suspension of 3-methylpyridine-2-carboxylic acid (1.5 g, 11 mmol) in THF (50 mL) drop-wise, at −78° C. and under an atmosphere of nitrogen. The dark purple mixture was stirred at −78° C. for 30 minutes and then at −5° C. for 30 minutes. After this time the mixture was re-cooled to −78° C. and a solution of methyl 4-fluorobenzoate (1.6 mL, 12 mmol) in THF (15 mL) was added. The dark brown mixture was stirred at −78° C. for 1.5 hours and then at 0° C. for 2.5 hours. The mixture was then poured into chilled water (50 mL) and washed with ethyl acetate (3×35 mL). The aqueous layer was acidified to pH 2 with HCl and extracted with ethyl acetate (3×75 mL). The three extracts were combined and concentrated in vacuo to yield 3-[2-(4-fluorophenyl)-2-oxoethyl]pyridine-2-carboxylic acid as a pale yellow solid (1.5 g, 53% yield). ESI-MI m/z [M+H]+ 259.95. 1H NMR (400 MHz, DMSO) δ 8.61 (dd, J=4.7, 1.6 Hz, 1H), 8.14 (dd, J=8.9, 5.5 Hz, 2H), 7.86 (dd, J=7.8, 1.6 Hz, 1H), 7.62 (dd, J=7.7, 4.7 Hz, 1H), 7.40 (t, J=8.9 Hz, 2H), 4.78 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:20][C:21]1[N:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:23][N:22]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:20][C:21]2[N:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[CH:25][N:26]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2cnc(CBr)nc2)cc1
Reactant: CCOC(=O)CCc1ccc(O)c2ccccc12
Product: CCOC(=O)CCc1ccc(OCc2ncc(-c3ccc(C(F)(F)F)cc3)cn2)c2ccccc12

Procedure:
A] In analogy to the procedures described in example 5C] and 5D], 3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester [Helvetica Chimica Acta (2001), 84(8), 2198-2211] was reacted with 2-bromomethyl-5-(4-trifluoromethyl-phenyl)-pyrimidine (example 11C]) to give 3-{4-[5-(4-trifluoromethyl-phenyl)-pyrimidin-2-ylmethoxy]-naphthalen-1-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][N:8]([C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[C:22](=[S:24])[CH3:23])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C>CC#N>[C:22]([C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([N:8]([CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:7][C:6]([OH:26])=[O:5])=[O:25])(=[S:24])[CH3:23]
Reactant: CC(=S)c1c(Cl)cccc1C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=S)c1c(Cl)cccc1C(=O)N(CC(=O)O)C1CCCC1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
N-(2-Thioacetyl-3-chlorobenzoyl)-N-cyclopentylglycine t-butyl ester (20.6 g, 0.05 mol) was dissolved in 150 ml CH3CN. Sodium iodide (11.3 g, 0.075 m) was then added. The resulting slurry was covered with nitrogen and warmed to 55° C. Chlorotrimethylsilane (8.15 g, 0.075 m) was then added in one portion. The reaction was stirred 30 minutes at 55° C. under nitrogen atmosphere. The heat source was removed and the reaction cooled to room temperature in an ice bath. Water (60 ml) and CH2Cl2 (100 ml) were then added. The aqueous layer was quickly withdrawn and the organic layer washed 2×75 ml H2O, 2×75 ml Na2S2O3 and 2×75 ml brine. The organic layer was then dried (MgSO4), filtered and concentrated to yield a dark yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([C@@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]2=[O:25])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>C(Cl)Cl>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:7]([CH2:6][C:5]2[CH:26]=[CH:27][C:2]([NH:1][C:40]([CH:37]3[CH2:39][CH2:38]3)=[O:41])=[CH:3][CH:4]=2)[C@@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]2=[O:25])(=[O:10])=[O:9])=[CH:16][CH:15]=1
Reactant: Nc1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1)C1CC1

Procedure:
N-(4-Amino-benzyl)-4-chloro-N-((R)-2-oxo-azepan-3-yl)-benzenesulfonamide (0.024 g, 0.06 mmol) was dissolved in CH2Cl2 (1 ml) and Hünig's base (0.01 ml, 0.07 mmol) and cyclopropanecarbonyl chloride (0.007 ml, 0.07 mmol) were added. After 30 min at r.t. the solvent was removed under reduced pressure and the residue dissolved in ethyl acetate and washed with 5% KHSO4/10% K2SO4, brine, dried (Na2SO4), filtered and concentrated. The crude was purified using preparative RP(C18) chromatography: lyophilisate 9 mg; MS: m/e=493.4 (MNH4+).