Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19](=[O:21])[CH3:20])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.O.C1C(=O)N([Br:45])C(=O)C1>C(Cl)Cl.C1COCC1>[Br:45][CH2:20][C:19]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[C:9]([C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:8])[CH:18]=[CH:17]2)=[O:21]
Reactant: CC(=O)c1cccc2ccc(C(=O)N3CCOCC3)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc2ccc(C(=O)N3CCOCC3)nc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 1-(2-(morpholine-4-carbonyl)quinolin-8-yl)ethanone (0.438 g, 1.54 mmol) in DCM (5 mL) at 0° C. was added TEA (0.28 ml, 2.00 mmol) followed by TBSOTf (0.39 mL, 1.70 mmol). The resulting mixture was stirred at 0° C. for 50 min. The mixture was then partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted with DCM (3×). The combined organic layers were then dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a brown oil. The resulting oil was taken up in THF (8 mL) and treated with water (0.44 mL, 24.7 mmol) and NBS (288 mg, 1.62 mmol). The resulting solution was stirred at RT for 20 min. The reaction mixture was then partitioned between water and Et2O, and the organic layer was separated and sequentially washed with saturated NaHCO3, water, and brine, then dried over MgSO4, filtered, and concentrated in vacuo to give a 2-bromo-1-(2-(morpholine-4-carbonyl)quinolin-8-yl)ethanone as a greenish-brown solid. This material was used in the subsequent step without purification, assuming the theoretical yield: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (d, J=8.6 Hz, 1H), 8.29 (dd, J=8.1, 1.3 Hz, 1H), 8.11 (dd, J=7.2, 1.4 Hz, 1H), 7.77-7.85 (m, 2H), 3.72 (s, 4H), 3.61-3.62 (m, 2H), 3.57-3.59 (m, 2H), 3.51-3.57 (m, 2H). m/z (ESI, +ve ion) 363.0/365.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[C:14]1([NH:24][CH2:25][CH2:26][NH2:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:24][CH2:25][CH2:26][NH:27][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NCCNc1cccc2ccccc12
Product: O=C(NCCNc1cccc2ccccc12)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(naphthalen-1-ylamino)ethylamine. The product was purified by mass directed purification to give the title compound as a brown solid. δH (CD3OD): 3.55 (2H, t), 3.80 (2H, t), 6.68 (1H, d), 7.04 (1H, s), 7.14 (1H, d), 7.28 (1H, t), 7.36–7.42 (2H, m), 7.65 (1H, s), 7.70–7.74 (1H, m), 7.98–8.02 (1H, m), 8.58 (1H, s); m/z (ES+)=365 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:45][C:46]2[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=2)=[O:43])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCc1nnc(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1nnc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-ethyl-1,3,4-thiadiazole (41 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 53 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH2:23].C1COCC1>>[CH3:22][NH:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Solvent: C1CCOC1
Product: CNc1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), 2.0 M methylamine in THF (2.0 ml, 4 mmol) by a procedure similar to that of Example 122 (53.7%). 1H NMR (CDCl3): 7.45 (d, J=7.8 Hz, 1H), 7.39-7.33 (m, 1H), 7.11-7.07 (m, 2H), 6.90-6.87 (m, 3H), 6.69-6.64 (m, 1H), 4.95 (brs, 1H), 3.82 (s, 3H), 3.50 (s, 3H), 3.11 (d, J=5.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH2:22])=O)=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:8][C:7]=2[CH:31]=1.[Si]([N:36]=[N+:37]=[N-:38])(C)(C)C>COCCOC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]4[NH:22][N:38]=[N:37][N:36]=4)=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[S:8][C:7]=2[CH:31]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(N)=O)cc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: COCCOC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3nnn[nH]3)cc2)cc1
Temperature: 180 °C
Yield: 88.2 %

Procedure:
To a microwave vial, (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (75 mg, 0.174 mmol) and Bu2SnO (4.33 mg, 0.02 mmol) were suspended in DME (3 mL). The vial was charged with TMSN3 (0.023 mL, 0.17 mmol) and the reaction was heated for 60 min at 180° C. under microwave irradiation. The reaction mixture was filtered to remove solids and concentrated onto silica gel. The crude material was purified by column chromatography (SiO2, 1-20% MeOH/DCM) to afford (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-tetrazole (66 mg, 0.15 mmol, 83% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.45-7.61 (m, 5 H), 7.32 (d, J=2.02 Hz, 1 H), 7.15 (d, J=9.09 Hz, 1 H), 6.98 (d, J=16.67 Hz, 1 H), 6.86-6.93 (m, 2 H), 6.78-6.86 (m, 3 H), 3.78 (s, 3 H), 3.69 (s, 3 H), LC/MS (m/z. MH+): 457.4.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH:15]([CH2:17][CH3:18])[CH3:16])=[N:5][CH:4]=[C:3]1[C:19]([O:21]CC)=O.[NH3:24]>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH:15]([CH2:17][CH3:18])[CH3:16])=[N:5][CH:4]=[C:3]1[C:19]([NH2:24])=[O:21]
Reactant: CCOC(=O)c1cnc(-c2ccccc2OC(C)CC)[nH]c1=O
Reactant: N
Product: CCC(C)Oc1ccccc1-c1ncc(C(N)=O)c(=O)[nH]1
Yield: 87.7 %

Procedure:
A steel bomb containing ethyl (±)-1,6-dihydro-6-oxo-2-(2-sec-butoxyphenyl)pyrimidine-5-carboxylate (3.76 g.) and liquid ammonia (ca. 45 ml.) was heated on a steam bath for four hours. The ammonia was removed. A solution of the residue in ice-water was acidified with concentrated hydrochloric acid. The precipitate was recrystallized from methanol to give the title compound (2.99 g., 87.7% yield), m.p. 183°-185°.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][N:9]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[N:7]=1)=[O:2].[BH4-].[Na+].C(O)(=O)C>CO.O1CCCC1>[OH:2][CH2:1][C:3]1[S:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][N:9]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[N:7]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(C=O)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(CO)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of (2S,4R)-2-(2-formylthiazol-4-yl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.26 g) in a mixture of methanol (30 ml) and tetrahydrofuran (30 ml) was added sodium borohydride (94 mg) at 0° C. After stirring at 0° C. for 30 minutes, acetic acid (0.6 ml) was added to the solution. After the mixture was evaporated, the residue was dissolved in ethyl acetate, washed with water, saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated to give (2S,4R)-2-[2-(hydroxymethyl)thiazol-4-yl]-4-(methanesulfonyloxy)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.09 g).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([OH:28])=O)=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C:7]2([CH2:33][CH3:34])[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.[N:40]1(OC(N(C)C)=[N+](C)C)[C:44]2[CH:45]=[CH:46]C=[CH:48][C:43]=2N=N1.[CH:57]([N:60](C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:40][CH:44]5[CH2:43][CH2:48][N:60]([CH3:57])[CH2:46][CH2:45]5)=[O:28])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C:7]2([CH2:31][CH3:32])[CH2:33][CH3:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCC1(CC)C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC1(CC)C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)c4c3OCC4)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.2 %

Procedure:
7-[(8-Cyclopentyl-7,7-diethyl-5-methyl-6-oxo-pteridin-2-yl)amino]-2,3-dihydrobenzofuran-4-carboxylic acid 42b (50 mg, 0.11 mmol) was dissolved in 20 mL of dichloromethane followed by the addition of O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (35 mg, 0.11 mmol), diisopropylethylamine (31 mg, 0.24 mmol) and 1-methyl-piperidyl-4-yl-amine (13 mg, 0.11 mmol) successively. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was added with 50 mL of saturated sodium carbonate solution and extracted with dichloromethane (100 mL×2). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound 7-[(8-cyclopentyl-7,7-diethyl-5-methyl-6-oxo-pteridin-2-yl)amino]-N-(1-methyl-4-piperidyl)-2,3-dihydrobenzofuran-4-carboxamide 42 (10 mg, yield: 16.0%) as a white solid.
Reaction SMILES: CC1(C)[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][OH:29])=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:30][CH2:31][CH2:32][CH2:33][C@H:4]2[O:3]1.C(N(CC)CC)C>C(Cl)Cl.Cl>[OH:29][CH2:28][CH2:27][O:26][C:24]1[CH:23]=[CH:22][C:21]2[N:17]([CH2:16][C:14]3[CH:13]=[CH:12][C:10]4[N:11]=[C:7]([NH:6][C@@H:5]5[CH2:30][CH2:31][CH2:32][CH2:33][C@H:4]5[OH:3])[S:8][C:9]=4[CH:15]=3)[CH:18]=[N:19][C:20]=2[CH:25]=1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(OCCO)ccc43)cc2s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCOc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a stirred mixture of 2-((1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)ethanol (70 mg, 0.15 mmol) from the previous step in DCM (5 mL) at 0° C. was added methanolic HCl (3 drops). The reaction mixture was stirred at 0° C. for 10 min. The mixture was adjusted to pH˜7 by the addition of triethylamine and concentrated under reduced pressure. The residue was purified directly by reverse-phase preparative HPLC to afford ((1R,2R)-2-((6-((5-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (30 mg, 47%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.62 (s, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.16-7.18 (m, 2H), 6.84 (m, 1H), 5.41 (s, 2H), 4.83 (br s, 1H), 4.72 (d, J=4.5 Hz, 1H), 3.98 (t, J=9.6 Hz, 2H), 3.71 (d, J=4.5 Hz, 2H), 3.52 (m, 1H), 3.33 (br s, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.61-1.63 (m, 2H), 1.22-1.28 (m, 4H); LCMS (ESI) m/z 439 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=O)[CH2:13][CH2:14][C:15](=[O:17])[NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH2:26].CN(C)C=O.C1(OP(N=[N+]=[N-])(=O)OC2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C>[CH3:22][O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH:26][C:18](=[O:20])[C@H:12]([CH2:13][CH2:14][C:15](=[O:17])[NH2:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of Nα -benzyloxycarbonyl-L-glutamine, 56 g., and L-tryptophan methyl ester hydrochloride, 56 g., in 300 ml. of dimethylformamide at 5° C. is added diphenylphosphorazidate, 47.5 ml., in 100 ml. of dimethylformamide dropwise over ten minutes followed by 61.6 ml. of triethylamine over one hour. The mixture is stirred in an ice bath for three hours and at room temperature for 18 hours. After evaporation the residue is dissolved in 1 l. of ethyl acetate and washed successively with 500 ml. of 1N hydrogen chloride solution, 500 ml. of a saturated solution of sodium bicarbonate and 500 ml. water. The ethyl acetate layer is separated, dried, evaporated and 74.2 g. of Nα -benzyloxycarbonyl-L-glutaminyl-L-tryptophan methyl ester is obtained by recrystallization from methanol; m.p. 197°-198° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH:21]1[CH3:20])=[O:18]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: CC1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Yield: 5 %

Procedure:
The product is prepared according to the procedure described in example 68, using 550 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 400 mg of 2-methylindoline and 500 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 320 μl of pyridine and 8.0 ml of N,N-dimethylformamide. 37 mg of 3-methyl-2-[2-(2-methyl-2,3-di hydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]#[N:19])=[CH:11][C:5]=2[N:4]=1.[CH3:20][NH:21][CH3:22].C(OCC)(=O)C>C1COCC1>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3]([CH2:2][N:21]([CH3:22])[CH3:20])=[N:4][C:5]=2[CH:11]=1)#[N:19]
Reactant: N#Cc1ccccc1-c1ccc2[nH]c(CCl)nc2c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1nc2cc(-c3ccccc3C#N)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2-Chloromethyl-5-(2-cyanophenyl)-1H-benzimidazole (1.31 mole, 0.350 g) was dissolved in 2 ml THF and cooled to 0° C. Dimethylamine (1 ml) was added. The solution was stirred at room temperature for 20 minutes. Ethyl acetate was added. The organic phase was washed with water, dried over sodium sulfate, and concentrated to yield 270 mg of 5-(2-cyanophenyl)-2-dimethylaminomethyl-1H-benzimidazole. (MS)
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCc1ccc(Cl)cc1
Yield: 62.5 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chloro-benzyloxy)-phenylamine (0.029 g, 0.08 mmol) was treated with 4-chlorophenyl isocyanate (0.014 g, 0.09 mmol, 1.2 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 63 (0.027 g, 0.05 mmol, 65%) as a white solid. LCMS m/z (%)=545 (M+H79Br35Cl35Cl, 65), 547 (M+H79Br35Cl37Cl37Br35Cl35Cl, 100), 549 (M+H81Br35Cl37Cl79Br37Cl37Cl, 45), 551 (M+H81Br37Cl37Cl, 6). 1H NMR (400 MHz, acetone-d6) δ: 8.23 (s, 1H), 8.17 (s, 1H), 7.66 (dd, J=2.7, 9.0 Hz, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.50 (s, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.37 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.9 Hz, 2H), 7.22 (d, J=9.0 Hz, 1H), 5.14 (AB quartet, J=12.3, 24.8 Hz, 2H), 3.69 (s, 3H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:23][CH3:24]>CO>[I-:23].[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N+:19]([CH3:24])([CH3:22])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCC(C2c3ccccc3CCc3ccccc32)CC1
Reactant: CI
Solvent: CO
Product: C[N+]1(C)CCC(C2c3ccccc3CCc3ccccc32)CC1
Product: [I-]
Yield: 82.8 %

Procedure:
Dissolved 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-methyl-piperidine (1.0 g, 3.4 mmol) in 10 mL of methanol. Added iodomethane (0.71 g, 5.0 mmol), and stirred at room temperature for 18 hours. Filtered the precipitate to give 1.22 g (83% yield) of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1,1-dimethyl-piperidinium iodide as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([OH:7])[CH2:5][OH:6].[CH3:8][C:9]1([CH3:33])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]3[N:22]=[C:23]([N:26]4[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]4)[S:24][CH:25]=3)[CH:12]=[CH:11][C:10]1=2.Cl>>[CH3:8][C:9]1([CH3:33])[CH2:18][CH2:17][C:16]([CH3:19])([CH3:20])[C:15]2[CH:14]=[C:13]([C:21]3[N:22]=[C:23]([N:26]4[CH2:31][CH2:30][CH:29]([NH:1][CH2:2][CH2:3][C@H:4]([OH:7])[CH2:5][OH:6])[CH2:28][CH2:27]4)[S:24][CH:25]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: NCC[C@H](O)CO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(=O)CC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCC[C@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously starting from 22 mg (0.21 mmol) of (S)-4-aminobutane-1,2-diol and 80 mg (0.21 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[CH2:5][C:4]1=[O:65])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:75]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][C:79]=1[S:84](Cl)(=[O:86])=[O:85])([O-:77])=[O:76]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:84]([C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][C:78]=3[N+:75]([O-:77])=[O:76])(=[O:85])=[O:86])[CH:46]([O:51][CH:52]([CH3:53])[CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([O:57][Si:58]([C:61]([CH3:62])([CH3:63])[CH3:64])([CH3:59])[CH3:60])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C(OC(C)C)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (80 mg) in dry methylene chloride (1 ml) was added an excess of diisopropylethyl amine (36 μl) and o-nitrophenylsulfonyl chloride (39 mg) followed by addition of 4-dimethylaminopyridine (22 mg). The mixture was stirred at room temperature for 5 hours at which time it was diluted with ethyl acetate, extracted from half saturated sodium bicarbonate solution and washed with brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol to give the title compound (87 mg).