Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:33]=[CH:32][C:9]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[O:25][N:24]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[CH2:16][CH2:15]2)=[O:11])=[CH:8][C:7]=1[OH:34].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:5][C:6]1[CH:33]=[CH:32][C:9]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[O:25][N:24]=[C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:22]=3)[CH2:16][CH2:15]2)=[O:11])=[CH:8][C:7]=1[O:34][CH2:2][CH2:3][OH:4]
Reactant: O=C(NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1)c1ccc(Cl)c(O)c1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1)c1ccc(Cl)c(OCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromoethanol (0.012 mL) was added to a mixture of the compound prepared in Example 55 (50 mg) and potassium carbonate (49 mg) in N,N-dimethylformamide (0.8 mL). The mixture was stirred at room temperature overnight, then 50° C. for six hours. The reaction was cooled to room temperature and was adjusted to pH 7 via the addition of aqueous 3% hydrochloric acid. The mixture was extracted twice with ethyl acetate and the organic phases were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methanol:ethyl acetate=1:19) to obtain the title compound (10 mg) having the following physical data.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[Cl:24])[CH:16]=2)=[O:14])[CH2:9]1>>[CH3:6][N:7]([CH:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[Cl:24])[CH:16]=2)=[O:14])[CH2:9]1)[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: CN(C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1)S(C)(=O)=O

Procedure:
The title compound was prepared from methanesulfonyl chloride and (3-methylamino-pyrrolidin-1-yl)-(7-chloro-thieno[3,2-b]pyridin-2yl)-methanone by a procedure analogous to Example 64C. MS: 374/376 (MH+); HPLC Rf: 4.14 min.; HPLC purity 98%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][CH:46]([N:49]3[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:44][CH2:45][CH:46]([N:49]5[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:53][CH2:54]5)[CH2:47][CH2:48]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 64 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.70 g, 1.52 mmol), 2-(methyloxy)-4-(4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}-1-piperidinyl)aniline (0.60 g, 1.52 mmol), p-toluenesulfonic acid (0.69 g, 3.64 mmol) and iPrOH (15 mL) were heated in the microwave at 175° C. for 25 min. LCMS indicated the reaction had proceeded to completion and the reaction mixture was concentrated onto silica gel. Flash chromatography afforded the title compound (0.80 g, 64%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.40 (bs, 1H), 8.45 (s, 1H), 8.33-8.31 (m, 1H), 8.19 (d, J=5.5 Hz, 1H), 8.07-8.03 (m, 1H), 7.83-7.79 (m, 1H), 7.74-7.70 (m, 1H), 7.60 (at, J=7.9 Hz, 1H), 7.48-7.35 (m, 3H), 7.24-7.16 (m, 2H), 7.00-6.94 (m, 1H), 6.67 (d, J=2.2 Hz, 1H), 6.50-6.44 (m, 2H), 3.79 (s, 3H), 3.75-3.68 (m, 2H), 3.25 (t, J=6.6 Hz, 2H), 3.01 (s, 3H), 2.70-2.60 (m, 5H), 2.45-2.24 (m, 5H), 1.86-1.79 (m, 2H), 1.55-1.44 (m, 2H). MS (ES+, m/z) 822 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[C@H:10]([CH:33]([CH3:35])[CH3:34])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:50]=[N+:51]=[N-:52])(CCCC)CCCC)CCC>>[CH3:16][CH2:15][CH2:14][CH2:13][C:12]([N:11]([C@H:10]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:36])[CH:33]([CH3:35])[CH3:34])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[C:26]([C:31]3[N:52]=[N:51][NH:50][N:32]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:23][CH:24]=1)=[O:17]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
L-valine benzyl ester hydrochoride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester so formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester. N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester is treated with tributyltin azide to give valsartan benzyl ester. Valsartan benzyl ester is subjected to catalytic hydrogenation using for example palladium-charcoal as catalyst to give valsartan.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[N+]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O>>[C:1]([C:14]1[CH:15]=[CH:16][C:17]2[C:12](=[CH:17][CH:12]=[CH:13][CH:14]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc2ccccc2c1

Procedure:
One such method by which they can be prepared involves the reaction of and unsubstituted or substituted naphthalene with acetyl chloride in nitrobenzene in the presence of about three molar equivalents of aluminum chloride to afford the corresponding 2-acetylnaphthalene derivative. The resulting derivative is heated with morpholine in the presence of sulfur at 150°C; the resulting product is refluxed with concentrated hydrochloric acid to furnish the corresponding 2-naphthylacetic acid derivative.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:39]1([N:43]2[CH2:49][CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40]1>CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[CH:39]1([N:43]2[CH2:49][CH2:48][CH2:47][N:46]([C:15]([CH:13]3[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:14]3)=[O:17])[CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40]1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: C1CC(N2CCCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a stirred solution of 1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid (500 mg, 2.13 mmol) in DMF/DCM (1:10) (11 ml) was added HOBt (287 mg, 2.13 mmol) and EDCI (490 mg, 2.56 mmol). The resulting suspension was stirred at RT for 10 mins before dropwise addition of 1-cyclobutyl-1,4-diazepane (328 mg, 2.13 mmol) in DCM (3 ml). After stirring for 16 h at RT the reaction was shown to be complete by TLC and the solvent was evaporated at reduced pressure. The residue was treated with saturated aqueous NaHCO3 (10 ml) and the resulting aqueous extracted with EtOAc (3×7.5 ml). The combined organic phases were dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 99:1 to 97:3 gradient of DCM/2M NH3 in MeOH) provided the title compound (475 mg, 60% yield) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:18][CH2:19][C:13]=2[C:12]=1OS(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:22])([F:24])[F:23])[CH2:18][CH2:19][C:13]=2[C:12]=1[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(F)cn1
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(F)cn3)c2CC1)C(F)(F)F
Yield: 62.6 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 2-aminomethyl-5-fluoro-pyridine (230 mg, 1.8 mmol) and a solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.2 mmol) in toluene (4 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography to give 7-chloro-6-[(5-fluoro-pyridin-2-ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (302 mg, 64%). GC-MS m/z: 402 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:19]=1.CO.[BH4-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][NH:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:19]=1
Reactant: Fc1ccccc1C1=NCCNc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccccc1C1NCCNc2ccc(Br)cc21
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A round bottomed flask was charged with 7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (47 mg), methanol (5 mL) and acetic acid (1 mL). The resulting mixture was treated with sodium borohydride in small portions while stirring at room temperature. The addition of sodium borohydride was continued until the starting material was consumed. The reaction was then concentrated to dryness and taken up in a saturated solution of sodium bicarbonate. The aqueous mixture was stirred for 10 minutes then extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to an oil. Silica gel purification provided 7-bromo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (30 mg) as a colorless oil. H1 NMR (d6-dmso): 7.47 (t, 1H), 7.34 (q, 1H), 7.10-7.25 (m, 3H), 6.88 (d, 1H), 6.40 (s, 1H), 5.66 (d, 1H), 5.04 (br s, 1H), 3.20 (m, 1H), 2.95 (m, 1H), 2.76 (m, 2H), 2.60 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17]C(=O)C.O.[C:23]1(C)[CH:28]=CC(S(O)(=O)=O)=C[CH:24]=1>CC(O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([O:12][CH:23]([CH3:28])[CH3:24])[CH3:11])[C:7]([C:13]([F:14])([F:15])[F:16])=[CH:6][C:5]=1[NH2:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1cc(C(C)O)c(C(F)(F)F)cc1NC(C)=O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1cc(C(C)OC(C)C)c(C(F)(F)F)cc1N
Temperature: 80 °C
Reaction time: 18 h
Yield: 43.7 %

Procedure:
A solution of 2-acetylamino-5-(1-hydroxy-ethyl)-4-trifluoromethyl-benzoic acid methyl ester (500 mg, 1.64 mmol) in i-PrOH (5 mL) was treated by addition of p-toluenesulfonic acid monohydrate (99.9 mg, 0.517 mmol) and stirred at 80° C. for 18 h. The reaction mixture was cooled then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 5:1 hexanes/EtOAc) to give title product (69 mg, 14% yield) as colorless crystals. m.p.: 87-90° C., API-ES: m/z 306 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[H-].[Na+]>O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CN2CCC(Oc3ccccn3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
A mixture of 60.65 H (318 mmoles) 1-phenylmethyl-4-piperidinol, 500 ml dimethylformamide, 46.25 g, that is 41 ml (475 mmoles) 2-fluoropyridine and 17 g 50% sodium hydride in mineral oil is heated at 100° C. for 1 h. The mixture is cooled in an ice bath, 20 ml water are added, the mixture is stirred for 30 min and concentrated to a residual volume of about 200 ml. 1 1 iced water is added, the mixture is stirred at 0° C. for 30 min, and the precipitate is filtered off, washed and dried. 90.71 g 1-phenylmethyl-4-(2-pyridinyloxy)piperidine are thus isolated. Melting point: 75° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH3:17])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CNc1ccc(C)cc1
Product: COc1cc2nc(Cl)nc(N(C)c3ccc(C)cc3)c2cc1OC

Procedure:
The title compound was prepared from 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol) and N-methyl-p-tolylamine (49 mg, 0.386 mmol) by a procedure similar to Example 1b and was isolated as white powder (8 mg, 8%). 1H NMR (CDCl3): 7.27 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.08 (s, 1H), 6.26 (s, 1H), 3.92 (s, 3H), 3.61 (s, 3H), 3.28 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].I[CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14].ClCCl>O1CCCC1>[CH3:14][O:13][Si:12]([CH2:11][CH2:10][CH2:9][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)([O:17][CH3:18])[O:15][CH3:16]
Reactant: c1c[nH]cn1
Reactant: CO[Si](CCCI)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[Si](CCCc1ncc[nH]1)(OC)OC
Reaction time: 4 h

Procedure:
5 g (73 mmol) of imidazole were dissolved in 100 ml of tetrahydrofurane and 1.73 g (73 mmol) of sodium hydride were added. The suspension was stirred for 4 hours, after which 10 ml of iodopropyltrimethoxy silane (52 mmol) were added and the reaction mixture was heated under reflux for 18 hours. 15 ml of dichloromethane were then added and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the product was distilled off at 150-155° C. at 8 mbar. The yield was 8.2 g (60%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[F:21][C:22]([F:32])([F:33])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:26][CH:25]=1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc(OC(F)(F)F)cc2)c1
Yield: 47.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 4-trifluoromethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (212 mg, yield: 47.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Br[C:29]1[N:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:31][CH:30]=1>CCCCCCC.C(OCC)(=O)C>[CH2:38]([O:37][C:35]([C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[N:34]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)c1cccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)n1

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and ethyl 6-bromo-2-pyridinecarboxylate (commercially available) using a gradient of n-heptane:ethyl acetate (100:0 to 60:40). Light yellow foam (89%). MS (Turbo Spray): m/z=540.2 [M+H].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:2]([CH3:1])(=[O:4])=[O:3])=[C:21]([CH3:26])[CH:20]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(OCCN2CCc3ccc(N)cc3CC2)ccc1N
Solvent: c1ccncc1
Product: Cc1cc(OCCN2CCc3ccc(NS(C)(=O)=O)cc3CC2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methanesulphonyl chloride (0.18 ml) was added dropwise to a solution of 7-amino-3-[2-(4-amino-3-methylphenoxy)ethyl]-1,2,4,5-tetrahydro-3H-3-benzazepine (0.36 g) in pyridine (30 ml) cooled to 0°, and the mixture was then stirred at room temperature for 72 hours. The solvent was evaporated in vacuo and the residue was taken up in methylene chloride and washed three times with saturated aqueous sodium bicarbonate and three times with brine. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo to give an oil which was triturated with methylene chloride to give a solid. Recrystallisation of the solid from ethanol/ethyl acetate gave the title compound, yield 0.28 g, m.p. 173°-174°.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:10][O:9][C:7]([C:5]1[O:6][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(Br)o1
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: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2)o1
Yield: 38 %

Procedure:
A mixture of methyl 5-bromofuroate (1 g, 5 mmoles), phenylboronic acid (1 g, 8.2 mmoles), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.17 mmoles), sodium carbonate (1.5 g, 17.4 mmoles) in toluene (100 ml) was refluxed for 16 hours. After cooling, the solvent was evaporated and the yellow residue was partioned between water (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (3×30 ml) and the combined organic layers washed with water (1×30 ml) and dried (MgSO4). The residue was purified by flash chromatography (20% ethyl acetate/70% cyclohexane and 10% diethyl ether/90% cyclohexane) to afford (7) (384 mg). This ester was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1.[CH3:18][N:19](C)C=O.C(Cl)(Cl)Cl.[C-]#N.[Na+]>O>[O:16]=[C:7]1[C:6]2[CH:17]=[C:2]([C:18]#[N:19])[CH:3]=[CH:4][C:5]=2[CH2:11][O:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: CN(C)C=O
Reactant: O=C1c2cc(Br)ccc2COc2ccccc21
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc2c(c1)C(=O)c1ccccc1OC2

Procedure:
Reflux a mixture of 9.13 gm. (0.0316 mole) of 9-bromo-6,11-dihydro-11-oxodibenz[b,e]oxepin, 6.03 gm. (0.0673 mole) of cuprous cyanide and 32 ml. of dimethylformamide for 4 hours with vigorous stirring. Cool the reaction mixture and shake with a mixture of 45 ml. of chloroform, 32 ml. of saturated sodium cyanide solution and 32 ml. of water until all solids have dissolved. Separate the organic layer and wash with aqueous sodium cyanide solution and water. Dry over anhydrous magnesium dulfate. Remove the solvent to obtain the title product (yield 7.43 gm., m.p. 116°-127° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](CC(CC)CC)(C)C)[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:28]#[C:29][C:30]3[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH3:41][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:28]#[C:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:39][CH:40]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O[Si](C)(C)CC(CC)CC)c2)=CCC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O)c2)=CCC3(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-((2,2-diethylethyl)-dimethylsiloxy)-phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound H) 60.0 mg (0.114 mmol) in 1.0 ml of THF at room temperature was added 91.5 mg (0.35 ml, 0.35 mmol) of tetrabutylamonium flouride (1 M solution in THF). After stirring overnight, the solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, followed by column chromatography (4:1, Hexanes:EtOAc) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.98 (2H, d, J=7.8 Hz), 7.52 (2H, d, J=8.3 Hz), 7.39-7.21 (4H, m), 6.93 (1H, d, J=7.5 Hz), 6.84 (1H, d, 7.1 Hz), 6.83 (1H, s), 6.01 1H, t, J=4.7 Hz), 4.91 (1H, s), 4.39 (2H, q, J=7.1 Hz), 2.35 (2H, d, J=4.7 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1C1C=C2C(=CC=1)C(=O)NC=C2.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[NH:29][C:28]([CH3:35])=[CH:27]2>>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:27]1[C:26]2[C:31](=[CH:32][CH:33]=[CH:24][CH:25]=2)[C:30](=[O:34])[NH:29][C:28]=1[CH3:35]
Reactant: Cc1cc2cc(Br)ccc2c(=O)[nH]1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]ccc3c2)c1
Product: COC(=O)c1ccc(C)c(-c2c(C)[nH]c(=O)c3ccccc23)c1

Procedure:
The sub-title compound was prepared by the method of intermediate 3 using the product of step i).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[NH2:16][OH:17]>CC(O)C.O>[Br:1][C:2]1[C:3]([S:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:5]=[N:16][OH:17])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)Sc1c(Br)cccc1C=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)Sc1c(Br)cccc1C=NO
Temperature: 67.5 °C

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-benzaldehyde (6.7 g, 25 mmol) and hydroxylamine hydrochloride (7.9 g, 116 mmol) in 2-propanol (200 mL) and water (40 mL) was heated to 65-70° C. overnight. 2-Propanol was evaporated and water (150 mL) was added to the residue followed by saturated aqueous sodium bicarbonate to bring the pH to ˜8.5. The mixture was extracted with DCM (3×80 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to afford the title compound, which was used immediately without further purification. 1H NMR (300 MHz, CD3OD): δ 1.28 (s, 9H), 7.25-7.35 (t, J=7.8 Hz, 1H), 7.79 (d, J=6.6 Hz, 1H), 7.89 (d, J=6.3 Hz, 1H), 8.83 (s, 1H).