Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>O1CCCC1.C(O)(=O)C.[Pd]>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:21])=[O:20])=[CH:17][CH:18]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1cc(CCc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O

Procedure:
A solution of 2-hydroxy-5-[2-[4-[(2-pyridinylamino)sulfonyl]phenyl]ethenyl]benzoic acid (3 g, 7.5 mmol) in tetrahydrofuran (100 ml) and acetic acid (100 ml) was hydrogenated over palladium on charcoal (10%, 0.3g) and hydrogen at atmospheric pressure and room temperature for 27 h. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in a solution of sodium hydroxide (0.3g) in acetone (30 ml) and water (30 ml). The solution was acidified with hydrochloric acid at ca 50° C. After cooling, the product crystallized yielding 1.6 g (52%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[CH2:3].[NH3:11]>>[NH2:11][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:1])[CH3:3]
Reactant: N
Reactant: C=C(C)c1ccc(O)cc1
Product: CC(C)(N)c1ccc(O)cc1

Procedure:
A 0.10-g sample of 4-(1-methylethenyl)phenol is exposed to excess, gaseous ammonia for about one day at 50° C. After excess ammonia is purged, a quantitative yield of 2-amino-2-(4-hydroxyphenyl)propane is obtained. No 1-amino-2-(4-hydroxyphenyl)propane is detectable by 60 MHz proton NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]2)[CH3:22])[C:5]2[N:9](COCC[Si](C)(C)C)[C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[CH:20]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH3:22])[C:5]2[NH:9][C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[CH:20]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c1n(COCC[Si](C)(C)C)c(=O)n2C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2c1[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-((1-(6-chloro-1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (16.5 mg, 0.025 mmol) was dissolved in trifluoroacetic acid (40% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The crude piperidine was eluted with 2M ammonia in methanol and concentrated. The crude product was dissolved in acetonitrile (1 mL) and treated with formalin (50 μL) followed quickly by sodium cyanoborohydride (3.2 mg, 0.05 mmol). To this was added two small drops of acetic acid over 5 minutes. The reaction was concentrated and the residue taken up in ethyl acetate, washed with saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. The crude product was dissolved in ethanol (10 mL) and heated at reflux overnight. The reaction was concentrated and purified by preparative HPLC (28% B isocratic method, TFA/ACN) to give 9.0 mg (64%) as a colorless film. 1H-NMR (CD3OD, 500 MHz) δ 7.43 (dd, J=8.9, 4.9 Hz, 1.5H), 7.33 (dd, J=8.9, 5.2 Hz, 0.5H), 7.13 (m, 1.5H), 7.04 (m, 1.5H), 6.72 (d, J=1.8 Hz, 0.7H), 6.67 (d, J=1.8 Hz, 0.3H), 4.5 1 (q, J=6.4 Hz, 1H), 3.15-3.52 (m, 9H), 2.40-3.00 (m, 7H), 2.08 (m, 2H), 1.38 (d, J=6.4 Hz, 3H). Mass spec.: 432.1 (MH)+.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:24])=[CH:18][C:17]=3[F:36])[CH:12]=[CH:11][N:10]=2)=CC=1.CCOC(C)=O>CO.C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:24])=[CH:18][C:17]=2[F:36])[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)n2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1nccc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)n1
Yield: 64.2 %

Procedure:
The title compound was prepared from 1-(4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea (Example 15, 20 mg, 0.039 mmol) using a similar procedure described for Example 16. Flash chromatography on SiO2 using EtOAc then 1-2% MeOH in CH2Cl2 as eluents gave the title compound (10 mg, 62%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.01 (s, 1H), 10.52 (s, 1H), 8.20 (d, 1H, J=6.0 Hz), 7.70 (dd, 1H, J=12.1, 2.0 Hz), 7.36-7.30 (m, 6H), 7.16 (dd, 2H, J=8.8, 8.8 Hz), 6.45 (d, 1H, J=6.1 Hz), 3.73 (s, 2H); MS(ESI+) m/z 400.09 (M+H)+.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH:13]=[CH:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C[N+]1([O-])CC[O:20]CC1.OS([O-])=O.[Na+].[OH2:29]>C1COCC1.CC(O)(C)C.[Os](=O)(=O)(=O)=O>[OH:29][CH:13]1[CH:14]([OH:20])[CH2:15][N:11]([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:12]1
Reactant: O
Reactant: O=C(OCc1ccccc1)N1C=CCC1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C(OCc1ccccc1)N1CC(O)C(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 500 mL RBF, the Cbz Pyrroline (15 g, 73.8 mmol) was dissolved in a mixture of 100 mL THF, 60 mL t-BuOH and 40 mL water for addition of the NMO (30.6 ml, 148 mmol) solution followed by the osmium tetraoxide (0.925 ml, 0.074 mmol) solution. Heated in a 70 C. oil bath. Solution slowly went from yellow to brown. After 2 h, cooled to RT and added 50 mL 10% aqueous NaHSO3. Concentrated and partitioned between 100 mL brine and 100 mL EtOAc. Separated layers and extracted with 100 mL EtOAc. Dried over MgSO4, filtered and concentrated to 22.3 g of thick yellow oil. Flash column chromatography from 50-100% EtOAc in hexane provided compound 9. NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.22 (s, 2H), 4.42 (m, 4H), 3.63 (m, 2H), 3.42 (m, 3H), 3.20 (m, 1H).
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=1)[N:9]=2.[S:33]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([CH3:36])(=[O:35])=[O:34]>ClCCl.CO>[CH:30]1([CH2:29][N:7]2[C:6]([N:40]3[CH2:41][CH2:42][N:37]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:38][CH2:39]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:32][CH2:31]1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCN(S(C)(=O)=O)CC4)n(CC4CC4)c3n2)cn1
Reaction time: 3 h

Procedure:
A dimethyl sulfoxide solution (1.0 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-N-methylpyrimidin-2-amine (140.5 mg, 0.29 mmol) and N-mesylpiperazine (190.2 mg, 1.16 mmol) was heated at 140° C. and stirred for 3 hours. N-Mesylpiperazine (190.2 mg, 1.16 mmol) was added, the resulting mixture was further stirred for 5.5 hours and left standing to cool followed by the addition of dichloromethane-methanol (10:1), and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.CO.[CH3:21][NH2:22]>>[NH2:1][C@H:2]([C:15]([NH:22][CH3:21])=[O:17])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1

Procedure:
A mixture of Tyr(3-tBu)-OMe (12 g, 48 mmol) and a 40% methylamine methanol solution (80 ml) was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, giving Tyr(3-tBu)-NHMe (T2) (12 g) as a crude product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C:15](=[O:18])([O-])[O-].[Na+].[Na+].CS(C)=O.Cl.[CH:26]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][CH2:27]2>CC1CCCO1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:32]2[CH:26]3[CH2:31][CH2:30][CH:29]2[CH2:28][CH2:27]3)=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9].[CH3:7][CH:2]1[CH2:3][CH2:4][CH2:15][O:18]1
Reactant: O=C([O-])[O-]
Reactant: C1CC2CCC1N2
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Temperature: 55 °C

Procedure:
4-fluoro-1-nitro-2-(trifluoromethyl)benzene (18) (901 g) was added into a 30 L jacketed vessel. Sodium carbonate (959.1 g) and 5 L dimethylsulfoxide (DMSO) was added and the mixture was stirred under a nitrogen atmosphere. 7-azabicyclo[2.2.1]heptane hydrochloride (7a) (633.4 g) was added to the vessel in portions. The temperature of the mixture was gradually raised to 55° C., and the reaction was monitored by HPLC. When the substrate was less than 1% AUC, the reaction was considered complete. The mixture was then diluted with 10 vol. 2-methyltetrahydrofuran and washed with 5.5 vol. water three times until no DMSO remained in the aqueous layer as determined by HPLC, to give 7-[4-nitro-3-(trifluoromethyl) phenyl]-7-azabicyclo[2.2.1]heptane (19) in 2-methyltetrahydrofuran (approximately 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[Br:9].[Br:10]Br.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[Fe].ClCCl>[Br:10][C:5]1[CH:4]=[C:3]([Br:9])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: BrBr
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Fe]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(F)c(Br)cc1Br
Reaction time: 1 h
Yield: 83.1 %

Procedure:
2,4-difluorobromobenzene (3 g, 15.5 mmol) and 260 mg of iron filings were placed in a two-neck flask, and 15 ml of dichloromethane was then added thereto. The two-neck flask was cooled in an ice bath, and a solution including bromine (1 ml, 18.7 mmol) and 15 ml of dichloromethane was added dropwise to the two-neck flask using an isobaric funnel. Next, the contents in the two-neck flask were heated under reflux for 3 hours. During heating, brown gas was produced. Then, the temperature was reduced to 20° C., and 50 ml of a sodium metabisulfite (Na2S2O5) aqueous solution (10%) was mixed with the contents in the two-neck flask by stirring for 1 hour for terminating the reaction therein. Thereafter, the contents in the two-neck flask were washed several times with deionized water to collect an organic layer, the organic layer was dehydrated using sodium sulfate (Na2SO4), and the solvent in the organic layer was removed, followed by column chromatography (SiO2, n-hexane), thereby obtaining white crystals (3.5 g, 83% yield).
Reaction SMILES: C1CC[CH:4]([N:7]=C=NC2CCCCC2)CC1.[NH:16]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:17]([C:20]([OH:22])=O)[CH2:18][OH:19].CN.[C:32]([O:35]C(=O)C)(=O)[CH3:33]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[C:32]([O:19][CH2:18][C@H:17]([NH:16][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:20]([NH:7][CH3:4])=[O:22])(=[O:35])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CNC(=O)[C@H](COC(C)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.4 %

Procedure:
A three-neck, 3 L flask was dried under N2, cooled, equipped with an overhead stirrer and charged with a solution of DCC (20.6 g, 0.1 mol) in CH2Cl2 (0.65 L). This was cooled to 0° C. and solid Boc-Ser-OH (20.06 g, 0.1 mole) was added in one portion. This mixture was stirred for 5 min. Methylamine (33% w/w solution in EtOH, 12.5 mL, 0.1 mol) was added dropwise over 10 min maintaining the internal temperature below 8° C. The reaction was stirred for an additional 10 min, the cooling bath was emptied, and the reaction was stirred for 12 h; LC-MS (3 min) tR=0.75 min, m/z 241 (M+Na) indicated full conversion. DMAP (1.0 g, 0.008 mol) then acetic anhydride (105.0 mL, 1.1 mol) were added using an external water bath to moderate the exotherm (internal temp <30° C.). The reaction was stirred for 60 min. Celite (25 g) and Et2O (1 L) were added, the mixture was cooled to 0° C. and filtered through a pad of Celite and then a pad of SiO2. The filtrate was evaporated under reduced pressure. The resulting oil was chased with tolulene (3×100 mL) and separated by chromatography on a SiO2 column to yield (2S)-3-acetoxy-2-(t-butoxycarbonylamino)-N-methylpropanamide (20.4 g, 78%). LC-MS (3 min) tR=0.75 min, m/z, 283 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(Cl)cccc23)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc2c(C3CCNCC3)c[nH]c12
Temperature: 90 °C
Reaction time: 72 h
Yield: 199.9 %

Procedure:
A 100 mL round bottom flask was charged with 4-nitrophenyloxycarbonyloxyethyl polystyrene (4.0 g, 4.3 mmol), 7-chloro-3-(1-tert-butoxycarbonylpiperidin-4-yl)-1H-indole (2.7 g, 8.1 mmol), diisopropylethylamine (3.5 mL, 20.2 mmol), 4-dimethylaminopyridine (0.5 g, 4 mmol) and dry dimethyl formamide (50 mL). The mixture was stirred at 90° C. for 72 h. After cooling to room temperature, the resin was filtered off and washed with dry dimethyl formamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL glass cylinder with a fritte and a three way junction in the bottom. The resin was then treated for 20 minutes with 60 mL of a 1:1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2%, w/w) and methionine (0.2%, w/w), using a flow of nitrogen to agitate the resin (Caution: Generation of carbon dioxide). The resin was filtered off and washed with dry dichloromethane (25 mL), a 1:1 mixture of dichloromethane:triethylamine (3×25 mL) and dry dichloromethane (3×25 mL). The resin was dried in vacuo (20° C., 20 h) to yield the title resin (3.8 g).
Reaction SMILES: O(C[C@H:10]([OH:12])C)[Si](C(C)(C)C)(C)C.N[C:14]1C=CN(C)N=1.[CH3:20][O:21][C:22](=[O:42])[C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=[C:25]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37](=[O:41])[N:38]([CH3:40])[CH3:39])=[CH:33][CH:32]=2)[CH:24]=1>>[CH3:20][O:21][C:22](=[O:42])[C:23]1[CH:28]=[C:27]([O:29][CH2:14][O:12][CH3:10])[CH:26]=[C:25]([O:30][C:31]2[CH:32]=[CH:33][C:34]([C:37](=[O:41])[N:38]([CH3:39])[CH3:40])=[CH:35][CH:36]=2)[CH:24]=1
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(C(=O)N(C)C)cc2)c1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Product: COCOc1cc(Oc2ccc(C(=O)N(C)C)cc2)cc(C(=O)OC)c1

Procedure:
The compound of Production Example 122 was obtained as a colorless amorphous substance by the same method as in Production Example 2, a corresponding method, or a combination thereof with an ordinary method, using (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane, 3-amino-1-methyl-1H-pyrazole and 3-(4-dimethylcarbamoyl-phenoxy)-5-hydroxy-benzoic acid methyl ester obtained by deprotection of the methoxymethyl group of 3-(4-dimethylcarbamoyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester obtained by converting the formyl group of 3-(4-formyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester obtained in the same manner as Production Example 1, using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester and p-formylphenylboric acid, to carboxyl, followed by condensation with dimethylamine.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>N1C=CC=CC=1>[O:5]=[C:4]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[CH3:8])[CH:3]=[C:2]([CH3:7])[CH3:1]
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1ccccc1N
Solvent: c1ccncc1
Product: CC(C)=CC(=O)Nc1ccccc1C

Procedure:
3-Methylbut-2-en-oylchloride (24.2 g) was added dropwise to a stirred solution of 2-methylaniline (20 g) in anhydrous pyridine (200 cm3) cooled to 0°. After 1 hour solvent was evaporated in vacuo to yield a solid which was recrystallised from ether/petroleum ether (boiling range 40-60) to afford the title compound, m.p. 105 (29.5 g).
Reaction SMILES: [ClH:1].[CH2:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[CH2:18]=O>C(O)(=O)C>[Cl:1][CH2:18][CH:2]=[C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: C=C1c2ccccc2CCc2ccccc21
Reactant: C=O
Reactant: Cl
Solvent: CC(=O)O
Product: ClCC=C1c2ccccc2CCc2ccccc21

Procedure:
In the same manner as in (2) in Example 2, hydrogen chloride gas was bubbled into the mixture of 20.6 g (0.1 mol) of 10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene (4c), 41 g of acetic acid, and 4.5 g (0.15 mol) of paraformaldehyde. After reaction was conducted, the reaction product was extracted with toluene, neutralized with a saturated sodium bicarbonate solution, and washed with water. Further, this product was dried with sodium sulfate anhydride, concentrated and then recrystallized from hexane to obtain 23.4 g of the compound (5c).
Reaction SMILES: [C:1]1([NH2:12])[CH:2]=[CH:3][CH:4]=[C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)C>[C:1]1([NH:12][C:13](=[O:15])[CH3:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1CCCCC2
Solvent: CCO
Product: CC(=O)Nc1cccc2c1CCCCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product from Example 132A (1.6 g, 9.92 mmol) in ethanol (30 ml) was added a solution of acetic anhydride (1.872 ml, 19.85 mmol) in EtOH (30 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was taken up in EtOAc (100 mL) and the organic solution was washed with H2O, dried and concentrated. The residue was purified by chromatography on silica gel eluting with 15% EtOAc/hexanes to provide the title product. 1H NMR (CDCl3) δ 1.54-1.71 (m, 6H), 1.77-1.89 (m, 2H), 2.20 (s, 3H), 2.72-2.76 (m, J=5.55 Hz, 1H), 2.78-2.85 (m, J=10.71 Hz, 2H), 6.97-7.11 (m, 2H), 7.22 (d, 1H). MS (M+H)+ m/z 204.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(O[N:34]1N=[N:41][C:36]2C=[CH:38][CH:39]=[CH:40][C:35]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.ClCl.[O:59]1CCCC1>ClCCl.C(O)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[NH:20][C:16]([CH:14]([NH:13][C:11](=[O:12])[C:9]3[CH:8]=[CH:7][C:3]([C:4]([N:34]4[CH2:38][CH2:39][CH2:40][C@@H:35]4[C:36]([NH2:41])=[O:59])=[O:6])=[C:2]([Cl:1])[CH:10]=3)[CH3:15])=[N:17][C:18]=2[CH:24]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CCOC1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCC[C@@H]2C(N)=O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 47 %

Procedure:
Prepared analogously to Example 1g from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and R-prolinamide in tetrahydrofuran. Yield: 47%; Rf value: 0.15 (silica gel; dichloromethane/ethanol=9:1); C22H21Cl2N5O3 (474.35); mass spectrum: (M+H)+=474/476/478 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[CH3:14][C:15]1[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][CH:30]=2)[CH:24]=1.CCN(C(C)C)C(C)C>ClCCCl.O1CCOCC1>[CH3:14][C:15]1[N:20]=[C:19]([NH:21][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])[CH:18]=[CH:17][C:16]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[CH:33][CH:34]=2)[CH:24]=1
Reactant: Cc1nc(N)ccc1Oc1ccnc(-c2ccc(N3CCN(C)CC3)cc2)c1
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(-c2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.1 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.040 g, 0.400 mmol) in DCE (2 mL) was treated with oxalyl chloride (0.035 mL, 0.400 mmol), stirred at RT for 5 min, then warmed to 80° C. for 0.5 h. The solution was cooled to RT, added to a mixture of 6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine (0.10 g, 0.266 mmol) and DIEA (0.2 mL, 1.145 mmol) in dioxane (4 mL) and stirred at RT for 3 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were washed with 1N NaOH, then brine, dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN, and the resulting solid was collected via filtration and dried to afford N-((6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (75 mg, 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.16 (br s, 1H), 10.40 (br s, 1H), 8.43 (d, J=5.6 Hz, 1H), 7.94-7.87 (m, 3H), 7.65 (d, J=8.8 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 6.65 (dd, J=5.6, 2.4 Hz, 1H), 3.21 (t, J=4.6 Hz, 4H), 2.44 (br s, 4H), 2.27 (s, 3H), 2.21 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 503.3 (M+H+).
Reaction SMILES: C1(=O)[C:10]2[C:5](=[CH:6]C=CC=2)[CH2:4]CC1.C[Si](C#N)(C)C.P(Cl)(Cl)(Cl)=O.[C:23]([C:25]1[C:34]2[CH:33]=[C:32]([C:35]([O:37]C)=[O:36])[CH:31]=[CH:30][C:29]=2[CH2:28][CH2:27][CH:26]=1)#[N:24].C1([C:49]([O-:51])=[O:50])C2C(=CC=CC=2)C=CC=1>N1C=CC=CC=1.[I-].[Zn+2].[I-]>[C:49]([NH:24][CH2:23][CH:25]1[C:34]2[CH:33]=[C:32]([C:35]([OH:37])=[O:36])[CH:31]=[CH:30][C:29]=2[CH2:28][CH2:27][CH2:26]1)([O:51][C:5]([CH3:4])([CH3:6])[CH3:10])=[O:50]
Reactant: O=C([O-])c1cccc2ccccc12
Reactant: COC(=O)c1ccc2c(c1)C(C#N)=CCC2
Reactant: O=C1CCCc2ccccc21
Agent: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC1CCCc2ccc(C(=O)O)cc21

Procedure:
As shown above in Scheme 7, the remaining tetralone was then converted to the methyl ester (9). Using a procedure from Gregory, G. B. and Johnson, A. L, JOC, 1990, 55, 1479, the tetralone methyl ester (9) was converted, first, to the cyanohydrin by treatment with trimethylsilylcyanide and zinc iodide and then, via the in situ dehydration with phosphorous oxychloride in pyridine, to the methyl 8-cyano-5,6-dihydro-2-naphthoate (11). This naphthoate was divided into two portions and some was subjected to hydrogenolysis, N-BOC-protection and saponification to give N-(BOC)-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoic acid (12) as an intermediate for incorporation into the cyclic peptide.