Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][C:15]4[O:16][C:17]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[N:18][N:19]=4)=[CH:6][CH:7]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Cc1nnc(-c2ccccc2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cc4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, Step 2, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-5-phenyl-[1,3,4]oxadiazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCOCc1ccccc1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1ccc(CNCCCOCc2ccccc2)cc1

Procedure:
A solution of 6.0 g (22 mmol) of 4-bromomethyl-2'-cyanobiphenyl, 5.8 g (35 mmol) of 3-benzyloxypropylamine and 3.6 g of triethylamine in 50 ml of 1,4-dioxane is heated to boiling under reflux for 18 hours. After working up analogously to Example 23a), an oil is obtained which, after flash-chromatographic purification (ethanol:ethyl acetate: 1:4), gives the title compound (TLC system B7; Rf value 0.39).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[OH-:21].[Ca+2].[OH-:23]>ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6](=[O:23])(=[O:21])[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Dissolve 570 mg (2 mmoles) of the ester of Example 2 in a mixture of 2.3 gm of m-chloroperbenzoic acid and 75 cc of chloroform and stir for 12 hours at room temperature. Basify with calcium hydroxide. Filter and evaporate to dryness. Chromatograph the residue over silica gel eluding with 30% ethyl acetate in benzene. Collect the sulfone fractions and evaporate to dryness. Stir the residue in ether for 30 minutes, filter and dry to obtain the title product (m.p. 300°-302° C.), sintered around 295° C.).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH2:24])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C(N(CC)CC)C>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 55.9 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (300 mg), triethylamine (80 mg) and isobutyryl chloride (90 mg) were treated as in Example 133 to give the title compound (200 mg) as white needles (yield: 58%).
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17]Br)(OC(C)(C)C)=O.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl>[CH2:19]([NH:23][CH2:17][C:9]1[NH:8][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)n1c(CBr)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCNCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a stirred solution of 1-BOC-2-bromomethylbenzimidazole (2.00 g, 6.4 rnmol) in dry THF (20 mL) was added n-butylamine (1.2 g, 15.4 mmol). After stirring at RT overnight, the mixture was concentrated. The residue was taken up in H2O and extracted with CH2Cl2. The organic extracts were dried over MgSO4 and concentrated to give a brown residue, which was dissolved in CH2Cl2 (15 mL) and treated with TFA (5 mL). The resulting mixture was stirred at RT overnight then was concentrated. The residue was taken up in H2O, and the solution was neutralized with 2.5 N NaOH. CH2Cl2 extraction, drying (MgSO4), concentration, and silica gel chromatography (2% MeOH/CH2Cl2) gave the title compound as a yellow oil (0.91 g, 70%): 1H NMR (250 MHz, CDCl3) δ 0.79 (t, J=7.2 Hz, 3H), 1.23 (m, 2H), 1.54 (m, 2H), 3.35 (t, J=7.2 Hz, 2H), 4.55 (s, 2H), 7.25 (m, 2H), 7.48 (m, 1H), 7.75 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:13][CH2:14][O:15][C:16]3[C:17]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]4)=[N:18][CH:19]=[CH:20][N:21]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:35][C:36](OC(C)=O)=[O:37]>N1C=CC=CC=1>[C:36]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:13][CH2:14][O:15][C:16]3[C:17]([N:22]4[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]4)=[N:18][CH:19]=[CH:20][N:21]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:37])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc3ccc(N)nc23)CC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2cccc(OCCOc3nccnc3N3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product obtained in Step 1 (502 mg, 1.08 mmol) was dissolved in pyridine. Ac2O (0.42 mL 4.45 mmol) was added, and the reaction mixture seas stirred under inert atmosphere at room temperature for 5 h. Concentration in vacuo afforded a yellow oil, which was purified by column chromatography using EtOAc/Et3N (95:5) as eluent to give the title product as a yellow solid: yield 531 mg (97%); MS m/z 509 (M+H)+. Anal. (C26H32N6O5.0.4 H2O) C, H, N
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([OH:15])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].F[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH2:1]([C:5]1[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([O:15][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCCc1cc2ccccc2c(O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCCCc1cc2ccccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 67 %

Procedure:
3-Butyl-2-phenyl-1-naphthalenol (172) (0.30 g, 1.09 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMSO at 100° C. to give 0.28 g (67%) of the title compound (173) as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.77 (t, J=7.3 Hz, 3H), 1.15-1.30 (m, 2H), 1.40-1.55 (m, 2H), 2.58 (t, J=7.8 Hz, 2H), 6.68 (d, J=8.6 Hz, 2H), 7.08-7.14 (m, 2H), 7.19-7.26 (m, 3H), 7.39 (t, J=7.4 Hz, 1H), 7.50 (1, J=7.3 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.71 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 9.79 (s, 1H). LCMS (APCI): m/z 381 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2c(cc1Cl)C(=O)NCC2
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc2c(cc1Cl)C(=O)N(c1cnccc1C)CC2
Yield: 52.4 %

Procedure:
7-Chloro-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (I-86d: 200 mg, 0.946 mmol) was reacted with 3-iodo-4-methylpyridine (228.2 mg, 1.042 mmol), 1,4-dioxane (5 mL), copper iodide (18 mg, 0.094 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (13.4 mg, 0.095 mmol) and potassium phosphate (603.3 mg, 2.84 mmol) for 48 hours at 120° C. to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 150 mg of the product (52.4% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:44][C:45]#[N:46]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:44][C:45]#[N:46])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1,3-dibenzyl-2-phenyl-1H-indol-5-yl)-phenol (0.542 g, 1.163 mmol) was reacted with K2CO3 (0.225 g, 1.628 mmol) and bromoacetonitrile (0.195 g, 1.628 mmol) in acetone (10 ml) to give the product (0.486 g, 0.963 mmol, 83%) as a viscous, yellow oil. 1H NMR (DMSO-d6) δ 4.08 (s, 2H), 5.19 (s, 2H), 5.36 (s, 2H), 6.89 (d, J=7.3 Hz, 2H), 7.10-7.24 (m, 10H), 7.37-7.51 (m, 7H), 7.57 (d, J=8.9 Hz, 2H), 7.63 (s, 1H); [ESI(+)], m/z 505 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)[CH2:6][CH2:5]2.C=O.[C:18](O)(=O)C.[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:15][CH2:14][N:13]([CH3:18])[CH2:12]1)[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2C1CCNC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(N2CCc3cc(Br)ccc32)C1
Reaction time: 14 h
Yield: 66.5 %

Procedure:
A solution of compound 2 (1.0 g, 3.743 mmol) in dry methanol (10 mL) was treated with HCHO (0.36 g, 4.491 mmol, 37% in water) followed by acetic acid (0.53 mL, 9.357 mmol) and NaCNBH3 (0.28 g, 4.491 mmol) at room temperature and the resulting mixture was stirred for over night (14 h). The reaction was basified with 2 N NaOH solution (50 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined organic layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol:CH2Cl2, 5:95) to obtain compound 3 (0.7 g, 66.6%) as a syrup. 1H NMR (CDCl3) δ 7.12-7.08 (m, 2H), 6.35 (d, 1H, J=9.0 Hz), 4.19-4.10 (m, 1H), 3.45-3.39 (m, 2H), 2.91 (t, 2H, J=8.1 Hz), 2.70-2.63 (m, 3H), 2.51-2.43 (m, 1H), 2.34 (s, 3H), 2.19-2.07 (m, 1H), 1.93-1.81 (m, 1H); ESI-MS (m/z, %): 281, 283 (MH+, 100).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH2:9][CH2:10][Br:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:12]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][Br:11])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCCC=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: BrCCCC(c1ccccc1)c1ccccc1
Yield: 91.8 %

Procedure:
1,1-diphenyl-4-bromobutene (10.0 g) is dissolved in absolute ethanol (100 ml) and palladium on carbon (400 mg) is added. The reaction mixture is placed under hydrogen atmosphere (P=3.3 bar) for 6 hours. The mixture is filtered on kelite, the filtrate is concentrated to obtain the desired product as an orange oil (9.24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2.[C:30](Cl)(=[O:32])[CH3:31].C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:7]2)(=[O:32])[CH3:31]
Reactant: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 56.9 %

Procedure:
A stirred mixture of (3R)-3-(7-amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide (400 mg, 1 mmol) and acetyl chloride (0.1 mL, 1.4 mmol) in tetrahydrofuran (5 mL) was heated to reflux for 2 h. To the mixture was added 50% sodium hydrogen carbonate (40 mL) and ethyl acetate (50 mL). The organic layer was washed with sodium hydrogen carbonate (sat, 20 mL), brine (20 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silica Gel, 1.5:1 ethyl acetate:methylene chloride) to give (3R)-3-[7-(acetylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide as a white solid (0.25 g, 57% yield); mp, 88-90° C.; 1H NMR (CDCl3)˜1.43 (t, J=6.9 Hz, 3H, CH3), 2.22 (s, 3H, CH3), 2.90 (s, 3H, CH3), 3.04 (dd, J=5.5, 16 Hz, 1H, CHH), 3.09 (s, 3H, CH3), 3.52 (dd, J=9.5, 15 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.26 (d, J=17 Hz, 1H, CHH), 4.44 (d, J=17 Hz, 1H, CHH), 5.58 (dd, J=5.5, 9.4 Hz, 1H, NCH), 6.81-6.84 (m, 1H, Ar), 6.92-7.01 (m, 3H, Ar), 7.41 (t, J=7.8 Hz, 1H, Ar), 8.41 (d, J=8.3 Hz, 1H, Ar), 10.37 (s, 1H, NH); 13C NMR (CDCl3)˜14.65, 24.84, 35.47, 36.16, 37.31, 48.71, 53.54, 55.85, 64.44, 111.35, 112.44, 116.83, 117.40, 117.97, 119.10, 131.72, 132.84, 137.65, 141.53, 148.46, 149.06, 168.98, 169.41, 169.57; Anal Calcd for C24H29N3O5+0.7H2O: C, 63.76; H, 6.78; N, 9.29; H2O, 2.79. Found: C, 63.89; H, 6.64; N, 9.14; H2O, 2.70.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.C([Li])CCC.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C(OCC)C.C1COCC1>[Br:7][C:5]1[N:6]=[C:2]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)[S:3][CH:4]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Brc1csc(Br)n1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1nccc(-c2nc(Br)cs2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To a cooled (−78° C.) solution of 2,4-dibromothiazole (24)(0.73 g, 3.0 mmol) in anhydrous diethylether (7 ml) was added n-butyllithium (2.5M in hexane, 1.5 ml, 3.28 mmol) in a dropwise fashion via syringe. The yellow solution was stirred at −78° C. for 15 minutes before the addition of a suspension of 2-chloropyrimidine (20)(2.73 mmol, 0.313 g) in anhydrous diethylether (8 ml). The mixture was allowed to warm to room temperature and maintained like this, with stirring for 16 hours. The mixture was quenched carefully by dropwise addition of water (0.061 ml, 3.41 mmol) in THF (0.7 ml) and then DDQ (0.681 g, 3.0 mmol) added to effect aromatization. The mixture was cooled to 0° C. and 3M NaOH (aq) (2.28 ml, 6.83 mmol) added which caused a sticky solid to adhere to bottom of the reaction vessel. The solvents were collected, dried (MgSO4), filtered and concentrated in vacuo to give the title compound (0.58 g, 69.8%) in suitably clean form to be used without further purification. m/z (LC-MS, ESP): 327 [M+H]+, R/T=3.73 mins.
Reaction SMILES: P(Br)(Br)Br.BrCCC1C2C(C)(C)CCC(C)(C)C=2C=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-].[CH3:42][C:43]1([CH3:76])[CH2:52][CH2:51][C:50]([CH3:54])([CH3:53])[C:49]2[CH:48]=[C:47]([CH:55]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:56])[CH:46]=[CH:45][C:44]1=2.[CH2:77]([O:79][C:80]([C:82]1[CH:89]=[CH:88][C:85]([CH:86]=O)=[CH:84][CH:83]=1)=[O:81])[CH3:78]>CCOCC.CCCCCC.C1(C)C(C)=CC=CC=1.N1C=CC=CC=1>[CH2:77]([O:79][C:80](=[O:81])[C:82]1[CH:89]=[CH:88][C:85](/[CH:86]=[C:55](/[C:47]2[CH:46]=[CH:45][C:44]3[C:43]([CH3:76])([CH3:42])[CH2:52][CH2:51][C:50]([CH3:53])([CH3:54])[C:49]=3[CH:48]=2)\[CH3:56])=[CH:84][CH:83]=1)[CH3:78]
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(C=O)cc1
Agent: BrP(Br)Br
Agent: CC1(C)CCC(C)(C)c2c(CCBr)cccc21
Agent: [Br-]
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-naphthalene is reacted with acetyl chloride and aluminium chloride in nitrobenzene to give (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) methyl ketone. Reduction of this ketone with lithium aluminium hydride in ether yields 5,6,7,8-tetrahydro-α-5,5,8,8-pentamethyl-2-naphthalene-methanol which is converted by treatment with phosphorus tribromide in ether/hexane in the presence of a small amount of pyridine into 2-bromoethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene. This bromoethyl compound is converted by treatment with triphenylphosphine in xylene while heating for 12 hours into [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide which, in a Wittig reaction with 4-ethoxycarbonyl-benzaldehyde, yields p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoic acid ethyl ester of melting point 90°-91° C. This ester is reduced with lithium aluminum hydride in ether/tetrahydrofuran to give p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzyl alcohol of melting point 123°-124° C. (from methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:27][CH2:26][C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]3[O:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:28]=1.[Br:29]N1C(=O)CCC1=O>O1CCCC1>[Br:29][C:8]1[N:7]([C@@H:10]2[O:27][CH2:26][C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]2[O:12][C:13](=[O:15])[CH3:14])[C:6]2[CH:28]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2ccc(Cl)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2ccc(Cl)cc21
Yield: 129.4 %

Procedure:
The title compound was prepared according to General Procedure IV using 6-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.20 g, 0.41 mmol), 30 ml tetrahydrofuran (Aldrich Sure Seal, Milwaukee), and a total of 0.30 g (0.17 mmol) of N-bromosuccinimide that was added over 0.5 h. The product from work-up by General Procedure IV was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with dichloromethane containing 1.0% methanol to give 2-Bromo-6-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.11 g, 0.22 mmol, 54%); MS (AP+): m/z (rel. intensity) 511 (0.10, M+23 (Na)) 1H NMR (DMSO-d6) δ8.16 (s,1H), 7.60-7.58 (d, 1H, J=8.7 Hz), 7.28-7.26 (dd, 1H, J=1.9 Hz, J=8.6 Hz), 5.95-5.92 (d, 1H, J=9.7 Hz), 5.67-5.60 (m, 3H), 4.13-4.09 (dd, 1H, J=5.3 Hz, J=9.2 Hz), 4.00-3.90 (overlapping dd, 1H) 2.20 (s, 3H), 1.98 (s, 3H), 1.74 (s, 3H).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.Cl.[CH3:16]O>>[NH2:4][C:5]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:16])=[O:8]
Reactant: CO
Reactant: CC(=O)Nc1cc(I)ccc1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc(I)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 16.1 g of 2-acetylamino-4-iodobenzoic acid (m.p. 233°-5° C; synthesized in accordance with U.S. Pat. No. 4,762,838) in 325 ml of absolute methanol is saturated at 0° C. with dry hydrogen chloride gas. The mixture is heated to the boil for 15 hours, cooled to room temperature, resaturated using dry hydrogen chloride gas, and allowed to stand at room temperature for 24 hours. The solvent is evaporated in vacuo, the residue is taken up in dichloromethane, and the organic phase is washed with a saturated aqueous sodium hydrogen carbonate solution until free from acid. The organic phase is dried over Na2 SO4, and evaporated in vacuo. This gives 13.8 g of methyl 2-amino-4-iodobenzoate of m.p. 63°-7° C.
Reaction SMILES: S.[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:35][C:36]3[N:40]([CH2:41][C:42](=[O:52])[NH:43][C@H:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH3:45])[C:39]4[CH:53]=[CH:54][C:55]([C:57]#[N:58])=[CH:56][C:38]=4[N:37]=3)[C:23](=[O:34])[C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[N:59]1C=CC(CCN)=C(CCN)C=1CCN>>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]([CH2:35][C:36]3[N:40]([CH2:41][C:42](=[O:52])[NH:43][C@H:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH3:45])[C:39]4[CH:53]=[CH:54][C:55]([C:57]([NH2:59])=[NH:58])=[CH:56][C:38]=4[N:37]=3)[C:23](=[O:34])[C:24]3[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:29]=3)=[CH:20][CH:21]=2)[CH2:11][CH2:10]1)=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: NCCc1ccnc(CCN)c1CCN
Reactant: COC(=O)c1ccc(C(=O)N(Cc2nc3cc(C#N)ccc3n2CC(=O)N[C@@H](C)c2ccccc2)c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Agent: S
Product: COC(=O)c1ccc(C(=O)N(Cc2nc3cc(C(=N)N)ccc3n2CC(=O)N[C@@H](C)c2ccccc2)c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Hydrogen sulfide was blown into a solution of (S)-2-[N-[4-(1-tert-butoxycarbonylpiperidin-4-yloxy)phenyl]-N-(4-methoxycarbonylbenzoyl)-aminomethyl]-5-cyano-1-(1-phenylethylcarbamoylmethyl)benzimidazole (284 mg) in a mixture of pyridin-triethylamine (5:1) (10 ml) with ice-cooling, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated and the residue was treated with hydrogen chloride-ethanol. Thereto were added acetone (6 ml), methanol (6 ml) and methyl iodide (0.229 ml), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was dissolved in ethanol (12 ml). Ammonium acetate (43 mg) was added, and the mixture was stirred at 75° C. for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=95:5-90:10) and dried under reduced pressure to give the title compound (113 mg).