Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=C)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:30]CC1>CC(C)=O.O.O=[Os](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:17](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(c1ccccc1)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C(=O)c3ccccc3)cc21
Yield: 65 %

Procedure:
To a solution of 3,3-dimethyl-6-(1-phenyl-vinyl)-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (914 mg, 2.6 mmol) in THF (10 mL), acetone (5 mL) and water (5 mL) was added NaIO4 (2.8 g, 13.05 mmol), then OsO4 (2 mL of 4% solution in water, 0.3 mmol) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo, water (20 mL) was added and the product was extracted with EtOAc (2×20 mL). The organic phase was washed with brine, dried (MgSO4), filtered and the solvent evaporated. The crude product was purified by column chromatography on silica, eluted with petrol-EtOAc 0-40% to afford the title compound (654 mg, 65%). MS: [M+H]+=353.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([I:15])=[N:6][CH:7]=1
Reactant: Oc1cncc(Cl)c1
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1cc(Cl)cnc1I
Reaction time: 5 h
Yield: 95.8 %

Procedure:
To a solution of 5-chloropyridin-3-ol [CAS no 74115-12-1] (15 g, 116 mmol) in sodium carbonate (1 M in water, 232 ml, 232 mmol) at 23° C. was portionwise added iodine (29.4 g, 116 mmol) and the mixture was stirred for 5 h. Poured onto 1 M hydrochloric acid (300 ml), adjusted pH by additional hydrochloric acid to pH 1, the precipitate was filtered off, washed with water, dissolved in ethyl acetate, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left the 5-chloro-2-iodopyridin-3-ol (28.33 g, 111 mmol, 95.8% yield) as a light brown solid. MS (ISP): m/z=256.1 [(M+H)+] and 258.2 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH2:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=1)=[O:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C#CCOc1ccc(NCc2ccccc2)c(C(=O)c2ccc(C(C)C)cc2)c1

Procedure:
A solution of 100 mg (0.341 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone, 44.6 μl (0.375 mmol) benzyl bromide and 32 μl (0.375 mmol) N-ethyl-diisopropylamine in 2 ml dioxane is heated at 100° for 90 h. The reaction mixture is concentrated and the residue taken up in 0.1 M sodium hydroxide solution and extracted with dichloromethane. Preparative HPLC affords (2-benzylamino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone.
Reaction SMILES: [CH2:1]([CH:4]([CH2:14][CH2:15][CH3:16])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH2:10][NH:9]1)[CH2:2][CH3:3].[CH2:17]1[O:20][CH2:19][CH2:18]1>C(O)C>[CH2:14]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH2:10][N:9]1[CH2:17][CH2:18][CH2:19][OH:20])[CH2:15][CH3:16]
Reactant: C1COC1
Reactant: CCCC(CCC)CCCC1COCCN1
Solvent: CCO
Product: CCCC(CCC)CCCC1COCCN1CCCO
Yield: 86.2 %

Procedure:
A mixture of 22.7 grams (0.1 mole) of 3-(4-propyl-heptyl)morpholine, 6.4 grams (0.11 moles) trimethyleneoxide and 150 ml. 96% ethanol was kept at 150°-200° C. for 15 hours in an autoclave. Distillation of the reaction mixture gave 24.6 g (86%) of 3-(4-propyl-heptyl)-4-(3-hydroxypropyl)morpholine), boiling point 122°-124° C./0.01 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.Cl.[F:10][C:11]([F:22])([F:21])[C:12]1[N:16]2[CH2:17][CH2:18][NH:19][CH2:20][C:15]2=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:19]2[CH2:18][CH2:17][N:16]3[C:12]([C:11]([F:22])([F:10])[F:21])=[N:13][N:14]=[C:15]3[CH2:20]2)[CH:3]=1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: Fc1cc(Br)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nnc2n1CCN(c1cc(Br)ccn1)C2
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-fluoropyridine (0.216 mL, 2.1 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.399 g, 1.75 mmol) and potassium carbonate (0.482 g, 3.49 mmol) in anhydrous DMF (7.0 mL) was heated at 100° C. for 16 h. Reaction mixture was cooled, diluted with ethyl acetate, washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 50% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C11H10BrF3N5: 348.0. (M+H+); Found: 348.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]2[NH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[N+:1]([C:4]1[CH:28]=[CH:27][C:7]2[NH:8][C:9]([S:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:40])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Sc2nc3cc([N+](=O)[O-])ccc3[nH]2)c(-c2ccccn2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)c2nc3cc([N+](=O)[O-])ccc3[nH]2)c(-c2ccccn2)c1
Reaction time: 0.5 h

Procedure:
A solution of the sulphide of step (a) above (1.15 mmoles) in methanol (70 ml)/dichloromethane (50 ml) was stirred at 10°. Solid m-chloroperbenzoic acid (80%; 1.38 mmoles) was added portionwise over 5 minutes. The solution was stirred at 10° for a further 30 minutes and then concentrated to approximately 25 ml. Silica gel (approximately 10 g) was added and the remaining solvent removed. Flash chromatography using dichloromethane containing 20 % ethyl acetate as eluant gave a pale orange solid (0.20 g) which was slurried in dichloromethane (50 ml) and filtered to give the title compound as an off-white solid, mp 208°-9° (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].[C:22]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:23][C:24]([CH3:26])=O>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:13][CH2:12]2)[N:1]=[C:24]([CH3:26])[C:23]=1[C:22]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)C(=O)N1CCC(Oc2cccc(N)c2C#N)CC1
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCN(C(=O)C(C)C)CC3)c2c1N

Procedure:
Prepared as in Example Ba from 2-amino-6-((1-isobutyrylpiperidin-4-yl)oxy)benzonitrile (Example 10b) and ethyl acetoacetate as an off-white solid (82%). MS 400 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1>CO.C1(C)C=CC=CC=1.[Pt]=O>[O:1]=[C:2]1[CH2:11][CH:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COC(=O)Cc1cc(=O)[nH]c2ccccc12
Agent: O=[Pt]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CC1CC(=O)Nc2ccccc21
Yield: 73 %

Procedure:
50 g (0.23 mol) of methyl 2-oxo-1,2-dihydro-4-quinolinacetate dissolved in 1 l of methanol is subjected to hydrogenation in a Parr apparatus in the presence of 2 g of Adams' platinum oxide under 40 to 45 psi and at 60° C. for approximately 1 h. After the catalyst is filtered off and the solvent evaporated off, the oily residue is chromatographed on silica. Elution with a dichloromethane/acetone (95:5) mixture yields an oil, which is solubilized in 250 ml of boiling toluene. After being cooled, this solution is diluted with 250 ml of petroleum ether. The crystalline product thereby obtained is drained, washed and dried. 36.8 g (73%) of methyl (±)-2-oxo-1,2,3,4-tetrahydro-4-quinolineacetate, melting point 115°-116° C., are obtained.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH2:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[F:30][C:18]([F:17])([F:29])[C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:8]2[CH2:12][C@H:11]3[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]3[CH2:9]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@H]21

Procedure:
(3aS,4R,6aR)-2-(4-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine was prepared by following the procedures described in Example 252 Steps A-D substituting (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step E of Example 16 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in Step A of Example 252 and 4-(trifluoromethyl)benzene-1-sulfonyl chloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in the procedure described in Step C of Example 252: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.15 (d, J=8.2, 2H), 7.92 (d, J=8.3, 2H), 3.40 (dd, J=9.8, 2.9, 1H), 3.13 (dd, J=9.7, 3.2, 1H), 3.06-2.93 (m, 3H), 2.54 (s, 1H), 2.21-2.12 (m, 1H), 1.93-1.85 (m, 1H), 1.78-1.69 (m, 1H), 1.67-1.33 (m, 2H), 1.33-1.15 (m, 2H); MS (ESI+) m/z 335 (M+H)+.
Reaction SMILES: [CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>O1CCOCC1>[CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([SiH:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C[SiH](C)c1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Product: C[SiH](C)c1ccc(C(=O)Oc2ccc(-c3ccc(OC(=O)c4ccc([SiH](C)C)cc4)cc3)cc2)cc1

Procedure:
A solution of 49.7 g (0.250 mol) of p-dimethylsilylbenzoyl chloride and 18.6 g (0.100 mol) of 4,4'-dihydroxybiphenyl in 40 ml of dry dioxane was boiled for 15 hours. The completeness of the reaction was checked by thin-layer chromatography. After the solvent had been stripped off in vacuo on a rotary evaporator, the crude product was recrystallized from toluene, to give 4,4'-bis-(4-dimethylsilylbenzoyloxy)biphenyl, [-4 s 146 n 184 i].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[CH:3]=1.C[N:31](C=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:31])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[CH:3]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](O)CC3)c12
Reactant: CN(C)C=O
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](O)CC3)c12

Procedure:
Prepared analogously to example 1.4 from 7 g 4-[4-fluoro-2-(trans-4-hydroxycyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid in DMF.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[OH:30]>>[CH3:13][C:12]1[C:7]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]2[OH:30])=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NC1CCCCC1O
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2O)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 2-aminocyclohexanol instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (400 MHz, methanol-d6) δ ppm 1.16-1.22 (m, 1H), 1.30-1.41 (m, 3H), 1.50-162 (m, 3H), 1.68-1.74 (m, 1H), 1.91 (s, 3H), 2.20 (s, 3H), 3.72 (bs, 1H), 3.79 (bs, 1H), 4.61 (bs, 2H), 7.18-7.26 (m, 1H), 7.34-7.45 (m, 1H), 7.70-7.82 (m, 1H), 8.47 (bs, 1H); MS (ESI) m/z 328.8 (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:63]([O:67][C:68]([C:70]1[N:71]([CH3:76])[C:72]([NH2:75])=[CH:73][CH:74]=1)=[O:69])([CH3:66])([CH3:65])[CH3:64]>>[C:63]([O:67][C:68]([C:70]1[N:71]([CH3:76])[C:72]([NH:75][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:73][CH:74]=1)=[O:69])([CH3:66])([CH3:65])[CH3:64]
Reactant: Cn1c(N)ccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)OC(C)(C)C
Yield: 35.9 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.25 g, 1 mmol), then reacted with 5-amino-1-methyl-1H-pyrrole-2-carboxylic acid tert-butyl ester prepared in Example 193 (0.15 g, 0.78 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-1-methyl-1H-pyrrole-2-carboxylic acid tert-butyl ester as a yellow solid (Yield 0.12 g, 36%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C([Si](C)(C)[O:31][CH2:32][CH2:33][CH:34]=O)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:23][CH2:22][C@H:21]([NH:24][CH2:34][CH2:33][CH2:32][OH:31])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CC[C@H](N)C4)n3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CC[C@H](NCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out starting from (S)-1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]pyrrolidin-3-ylamine and 3-(tertbutyldimethylsilanyloxy)propionaldehyde. The protecting group is cleaved off as already described by means of a 1M TBAF/THF solution. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:15]([CH:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])(C)(C)C.ClCCl.Cl>O1CCOCC1>[NH2:7][C@@H:8]([C@@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH:39]([CH3:40])[CH3:41])=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)C1CC1c1ccccn1)c1ccc(-c2ccc(OC(C)C)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)CN(C(=O)[C@@H]1C[C@H]1c1ccccn1)c1ccc(-c2ccc(OC(C)C)cc2)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of ((1S,2S)-1-{[(4′-isopropoxy-biphenyl-4-yl)-(2-pyridin-2-yl-cyclopropanecarbonyl)-amino]-methyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (48 mg, 0.084 mmol) and dichloromethane (4 mL) was treated with a solution of HCl in dioxane (4 N, 0.5 mL) and the resulting reaction mixture was maintained at room temperature for 12 h. The reaction was then concentrated to dryness to afford (1R,2R)-2-pyridin-2-yl-cyclopropanecarboxylic acid ((2S,3S)-2-amino-3-methyl-pentyl)-(4′-isopropoxy-biphenyl-4-yl)-amide (38 mg, 95% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 8.34 (d, J=5.3 Hz, 1H), 7.95 (t, J=7.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 2H), 7.38-7.45 (m, 3H), 7.29-7.37 (m, 3H), 6.88 (d, J=8.6 Hz, 2H), 4.54 (dt, J=12.1, 6.1 Hz, 1H), 4.22 (dd, J=15.0, 9.0 Hz, 1H), 3.65 (dd, J=15.0, 2.7 Hz, 1H), 3.23-3.30 (m, 1H), 2.66-2.76 (m, 1H), 1.99-2.06 (m, 1H), 1.72-1.80 (m, 1H), 1.63-1.71 (m, 1H), 1.45-1.54 (m, 1H), 1.26-1.36 (m, 1H), 1.24 (d, J=6.1 Hz, 6H), 1.05-1.17 (m, 1H), 0.88 (d, J=6.8 Hz, 3H), 0.75 (t, 3H); LRMS (ESI) m/e 472.3 [(M+H)+, calcd for C30H38N3O2 472.3].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.Cl.[CH3:29][NH:30][CH3:31]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]([N:30]([CH3:31])[CH3:29])=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[N:3]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(C(=O)O)cc4C3)nc(N)n2)CC1
Reactant: CNC
Agent: Cl
Product: CN1CCN(c2cc(N3CCc4ccc(C(=O)N(C)C)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid and dimethylamine hydrochloride (Aldrich Cat. No. 391956).
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](Cl)=[O:16])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47].C(N(CC)CC)C>C(Cl)Cl>[CH2:49]([O:48][C:46](=[O:47])[CH2:45][CH2:44][NH:43][C:15](=[O:16])[C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C@@H:12]([C:10]([O:9][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Reactant: NCCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Pivaloyloxymethoxycarbonyl)-2,4-(R*,R*) -dibenzylbutyryl chloride (1.2 g) in 10 ml of methylene chloride is added slowly to a solution of 1.15 g of benzyl 3-aminopropionate p-toluenesulfonic acid salt and 0.46 ml of triethylamine in 20 ml of methylene chloride. The reaction is stirred overnight at room temperature. The solution is washed with 2N hydrochloric acid, then with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to give N-[4-pivaloyloxymethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid benzyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[C:13](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][C:18]=3[C:19]([OH:21])=[O:20])[O:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].CCN=C=NCCCN(C)C.Cl.O>CN(C1C=CN=CC=1)C.O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[C:13](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][C:18]=3[C:19]([O:21][C:30]3[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)=[O:20])[O:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)O)c23)C1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c23)C1

Procedure:
A solution of 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylic acid (from step 7) (0.352 g, 1.1 mmol), 4-nitrophenol (0.229 g, 1.65 mmol), EDCl (0.253 g, 1.32 mmol) and 4-(N,N-dimethyl)aminopyridine (0.027 g, 0.22 mmol) in tetrahydrofuran was stirred overnight. Water was added to RM, extracted with ethyl acetate and org layer was concentrated after drying on anhy. Sod. Sulphate. The solid was chromatographed on silica gel to yield 4-nitrophenyl 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1.[NH3:25]>C(O)C>[NH2:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: COc1ccc(-c2nc(Cl)c3cc(OC)ccc3c2[N+](=O)[O-])cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(-c2nc(N)c3cc(OC)ccc3c2[N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
In a 25-mL Schlenk flask, under argon, 1-chloro-7-methoxy-3-(4-methoxyphenyl)-4-nitroisoquinoline (100 mg, 0.43 mmol) is dissolved in 20 mL of a saturated solution of ammonia in ethanol. After stirring for 4 days at 80° C., the medium is concentrated under vacuum then purified by silica gel column chromatography with dichloromethane-ethanol (95/5) as eluent in order to produce the expected amine compound 71 (79 mg, 56%) in the form of a yellow solid. 1H NMR CDCl3 δ 7.81 (d, 1H), 7.60 (d, 2H), 7.45 (d, 1H), 7.07 (s, 1H), 6.99 (d, 2H), 5.44 (s, 2H), 3.99 (s, 3H), 3.87 (s, 3H); MS 326 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17]>C(O)C>[C:20]([O:19][C:15]([CH2:16][CH2:17][NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CCO
Product: CCO[Si](CCCNCCC(=O)OC(C)(C)C)(OCC)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
In dehydrated ethanol, 22.1 g (100 mmol) of 3-aminopropyltriethoxysilane was dissolved, and to the solution, was added 12.8 g (100 mmol) of t-butyl acrylate, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, 32.5 g of the objective compound was obtained by removing solvent.