Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27].Cl>CN(C)C=O.O>[CH3:27][O:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:6]2[N:7]=[C:3]([CH3:2])[S:4][CH:5]=2)[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: Cc1nc(-c2c[nH]c(=O)[nH]c2=O)cs1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2csc(C)n2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
5-(2-methyl-1,3-thiazol-4-yl)-2,4(1H,3H)-pyrimidinedione hydrochloride (Prep20, 287 mg, 1.110 mmol) was dissolved in N,N-Dimethylformamide (DMF) (4 ml). K2CO3(460 mg, 3.33 mmol) were added and the reaction mixture stirred at room temperature for 1 h. 3-bromo-1,1-bis(methyloxy)propane (0.185 ml, 1.221 mmol) was added. The obtained mixture was then stirred at room temperature. After 4 days it was diluted with water, neutralized with HCl, and extracted by EtOAc. The organic phase was washed with water (3 times), brine, dried over Na2SO4, filtered and the solvent evaporated. The obtained crude was purified by preparative LC-MS. 58.5 mg of the title compound were isolated as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]([CH2:10][C:11]([O:13]C)=[O:12])[CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO.CCOCC>[C:11]([CH2:10][CH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1)([OH:13])=[O:12]
Reactant: COC(=O)CC1COc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CC1COc2ccccc21
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of methyl [2,3-Dihydro-Benzofuran-3-yl]-acetate (reference example 10b, 6.18 g, 32 mmol) in THF (40 mL), methanol (40 mL) is added a solution of NaOH (40 mL, 1 M). The resulting solution is stirred for 2 hr then acidified with HCl (25 mL, 2M), diluted with ether, washed with brine, dried over MgSO4 and concentrated. The residue crystallized on standing to give the title compound (5.62 g) as a colorless solid. 1H NMR (CDCl3) d 2.69 (dd, J=16, 9 Hz, 1H), 2.89 (dd, J=16, 6 Hz, 1H), 3.88 (m, 1H), 4.30 (dd, J=8, 6 Hz, 1H), 4.77 (t, J=8 Hz, 1H), 6.86 (m, 2H), 7.18 (m, 2H). The racemic acid, prepared above, can be resolved into individual enantiomers by recrystallization of the salt of racemic 3-(carboxy-methyl)-2,3-dihydro-benzofuran (1 eq) with enantiomerically pure a-methylbenzyl amine (0.5 eq) from isopropanol. The free acid is generated from the salt by dissolving the salt in excess aq. HCl (1 M) and extracting the acid into ether. The ether extract is dried over MgSO4 and concentrated to give the enantiomerically pure title compound ad (CH2Cl2, C=10 mg/mL)=−8.4 (using D-(+) a-methyl benzyl amine.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][O:17]S(C)(=O)=O)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]=2[CH:28]=1.[CH2:29](O)[CH2:30][OH:31]>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][O:17][CH2:29][CH2:30][OH:31])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]=2[CH:28]=1
Reactant: CS(=O)(=O)OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: OCCO
Agent: [Na]
Product: OCCOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 6 h

Procedure:
A solution, prepared at 70°, of 2.83 g of sodium in 200 ml of ethylene glycol is treated with 24.8 g of 8-chloro-1-methylsulphonyloxymethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (c.f. German Offenlegungsschrift 2,201,210, Example 1) and the mixture is stirred for 6 hours at 70°. The reaction mixture is partitioned between ethyl acetate and water. The organic phase is separated off, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and evaporated. Crystallisation from ethyl acetate gives 8-chloro-1-(2-hydroxyethoxy-methyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, melting point 162°-164°.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:10])[CH2:6][CH:7]([CH3:9])[CH3:8].C[Si]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH3:21])(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:8][CH:7]([CH2:6][C:5](=[O:10])[C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:9]
Reactant: CCCCC#C[Si](C)(C)C
Reactant: CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC#CC(=O)CC(C)C
Temperature: 2 °C
Reaction time: 24 h
Yield: 100.2 %

Procedure:
21.6 g of AlCl3 (0.162 moles) in 65 mL of CCl4 are cooled to 2° C. and 19.7 mL of isovaleroyl chloride (0.162 moles) in 30 mL of CCl4 are added dropwise. 25 g of trimethylsilylhexyne (0.162 moles) in 30 mL of CCl4 are then added dropwise. The mixture is stirred for 1 h at 2° C. and for 24 h at ambient temperature. It is poured into 200 mL of 1:3 37% HCl/ice, stirred for 1 h, the phases are separated and the aqueous phase is extracted with CH2Cl2. The combined organic phases are washed to neutrality, dried with Na2SO4 and evaporated. 27 g of product are obtained, which are used in the subsequent step without further purification. Formula: C11H18O (m.w. 166.27). Quantitative yield. IR (film) 2956; 2209; 1670 cm−1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:21][N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH3:20][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:25]3[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=3)[CH:7]=2)=[C:14]([CH3:15])[N:13]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:11]=1
Reactant: CC(=O)Nc1cc(C)c(Oc2ccnc(Cl)c2)c(C)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cc(C)c(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of N-(5-((2-chloropyridin-4-yl)oxy)-4,6-dimethylpyridin-2-yl)acetamide (598 mg, 2.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (554 mg, 2.66 mmol), K2CO3 (850 mg, 6.15 mmol) and Pd(PPh3)4 (118 mg, 0.102 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar and heated at 80° C. overnight. The mixture was cooled to RT, diluted with EtOAc, washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford crude N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (100% yield assumed) which was used without further purification. MS (ESI) m/z: 338.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.COCCOCCOC.NN.[OH-].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCCC(=O)c1cccc(Br)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: CCCCc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
A mixture of 1-(3-bromophenyl)butan-1-one (1.0 g, 4.4 mmol) and diglyme (10 mL) was treated with hydrazine (1.49 g, 44 mmol), stirred at 100° C. for 2 h, treated with KOH (1.23 g, 22 mmol), stirred at 150° C. for 6 hours, cooled to room temperature, poured into water and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated under vacuum. Purification of the resultant residue on silica gel (ISCO) using hexanes as the eluting solvent gave 1-bromo-3-butylbenzene as a clear oil (0.81 g, 86% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH:24]([CH3:25])[CH:23]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)OC2=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C)C.C([O-])=O.[K+]>O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:24]([CH3:25])[CH2:23][C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1C(c2ccc(S(C)(=O)=O)cc2)OC(=O)N1CCCCN1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(Cc1ccc(S(C)(=O)=O)cc1)NCCCCN1CCN(C(=O)OC(C)(C)C)CCC1=O
Yield: 97.8 %

Procedure:
A mixture of 10 g 4-{4-[5-(4-methanesulfonyl-phenyl)-4-methyl-2-oxo-oxazolidin-3-yl]-butyl}-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester, 1 g of 20% palladium hydroxide on carbon, 10 ml water, and 90 ml isopropanol was stirred and heated to 50°–60° C. A solution of 3.5 g potassium formate in 5 ml water was slowly added. The mixture was stirred for 3 hours and was then cooled and filtered. The filtrate was stripped to yield ca. 9 g of 4-{4-[2-(4-methanesulfonyl-phenyl)-1-methyl-ethylamino]-butyl}-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:19]([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][C:30]3[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[C:21]2=[O:39])=[CH:18][C:12]2[N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:17][N:13]1[C:12]2[CH:18]=[C:19]3[C:20]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH2:29][C:30]5[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=5)[C:21]4=[O:39])[CH2:2][O:8][C:9]3=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1
Reactant: CN1CCOc2cc(O)c(C3C(=O)N(Cc4ccc(C(F)(F)F)o4)c4ccccc43)cc21
Reactant: O=C(O)C(F)(F)F
Agent: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: CN1CCOc2cc3c(cc21)C1(CO3)C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one trifluoroacetate salt to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one was obtained. To a suspension of 1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1H)-one (0.59 g, 1.3 mmol) in methanol (8.5 mL) was added 4 M hydrochloric acid in 1,4-dioxane (1.5 mL, 6.0 mmol) and the resulting solution was stirred at ambient temperature for 35 min. The solvent was removed and the residue was dried under reduced pressure. The residue was then precipitated by addition of hexanes, sonicated and the solvent was removed under reduced pressure. This process was repeated several times, until the solid formed a fine suspension in hexanes. The material was then collected by filtration and air-dried to afford 1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one hydrochloride (0.60 g, 94%) as a pale gray powder: mp 105° C. (dec.) (hexanes); 1H NMR (300 MHz, DMSO-d6) δ7.33 (ddd, J=7.8, 7.5, 0.9 Hz, 1H), 7.22-7.17 (m, 3H), 7.07 (dd, J=7.5, 7.5 Hz, 1H), 6.74 (d, J=3.3 Hz, 1H), 6.48 (s, 1H), 6.25-6.19 (m, 1H), 5.10 (d, J=16.2 Hz, 1H), 5.02 (d, J=16.2 Hz, 1H), 4.76 (d, J=9.3 Hz, 1H), 4.65 (d, J=9.3 Hz, 1H), 4.33-4.22 (m, 2H), 3.27-3.18 (m, 2H), 2.68 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.4, 157.2, 153.2, 147.9, 141.9, 139.6 (q, J=42.0 Hz), 131.3, 129.0, 123.9, 123.4, 121.5, 119.0 (q, J=267 Hz), 114.2 (q, J=2.8 Hz), 112.4, 109.9, 109.3, 98.8, 79.9, 62.7, 57.1, 48.8, 48.6, 41.5, 36.6; MS (ES+) m/z 457.1 (M+1); Anal. Calcd. for C24H19FN2O4.HCl: C, 58.49; H, 4.09; N, 5.68. Found: C, 58.85; H, 3.74; N, 5.37.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[CH3:9][C:3]1[C:4]([CH3:8])=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1cccc(N)c1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])cc(N)c1C
Temperature: 12 °C

Procedure:
363 g of 2,3-xylidine are run into 1.8 l of pure sulphuric acid while the temperature is kept at 40° C. To this solution, cooled to 12° C., a sulphonitric mixture (132 ml of nitric acid (d=1.52) and 180 ml of pure sulphuric acid) is added dropwise over 1 hour, the temperature not exceeding 15° C. After 15 minutes the mixture is poured onto 6 kg of ice with stirring.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.O.[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[F:19]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(-c2c(F)cnn2C)c(Cl)s1
Reaction time: 12 h
Yield: 24.3 %

Procedure:
To a solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg, 0.974 mmol) [prepared according to the procedure in Example 95] in acetonitrile (4.864 ml) and H2O (486 μl) was added selectfluor (449 mg, 1.27 mmol). The resulting solution was stirred at 70° C. in a sealed tube for 1 h after which additional selectfluor (449 mg, 1.266 mmol) was added in one portion. After stirring 12 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM-THF and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 10% EtOAc in hexanes) affording methyl 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (65 mg, 0.237 mmol, 24.30% yield) as a yellow solid; LCMS (ES) m/z 274, 276 (M, M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][C:34](=[O:43])[N:35]3[CH2:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:30][CH:29]=2)=[CH:9][CH:8]=1.Br[C:45]1[C:50]([O:51][CH3:52])=[CH:49][CH:48]=[CH:47][N:46]=1>>[CH3:42][O:41][CH2:40][CH2:39][CH2:38][N:35]1[C:36]2[C:31](=[CH:30][CH:29]=[C:28]([CH2:27][O:26][CH:14]3[CH:13]([C:10]4[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:45]5[C:50]([O:51][CH3:52])=[CH:49][CH:48]=[CH:47][N:46]=5)=[CH:8][CH:9]=4)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15]3)[CH:37]=2)[CH2:32][CH2:33][C:34]1=[O:43]
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCN)cc3)cc21
Reactant: COc1cccnc1Br
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCNc4ncccc4OC)cc3)cc21

Procedure:
Analogously to Example 125a, 0.200 g of tert-butyl 4-[4-(4-aminobutoxy)phenyl]-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 125b) and 0.076 g of 2-bromo-3-methoxypyridine are reacted. The title compound is obtained as a colourless oil. Rf=0.34 (3:1:0.04 EtOAc-heptane-triethylamine); Rt=4.65.
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:32]=4)[CH:27]4[CH2:29][CH2:28]4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:46](Cl)(=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48]>CC#N>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:26]([CH:27]2[CH2:28][CH2:29]2)[C:25]([C@H:23]2[CH2:22][C@@H:21]([NH:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:20][NH:19][CH2:24]2)=[O:44])=[CH:32][C:33]=1[O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43]
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1Cl
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)C(C)(C)C)C2)C2CC2)ccc1Cl

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{[4-chloro-3-(3-methoxy-propoxy)-benzyl]-cyclopropyl-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride and pivaloyl chloride. MS: 480.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.29 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C=O)C.O>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[CH:17][CH:18]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Reactant: NCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1ccc(C(=O)NCc2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.36 g of 4-diethoxyphosphinylmethylbenzoic acid and 0.54 g of benzylamine in 15 ml of dry DMF was added dropwise a solution of 1.00 g of diethyl phosphorocyanidate in 2 ml of dry DMF under ice-cooling with stirring. Then, a solution of 0.56 g of triethylamine in 3 ml of dry DMF was added dropwise thereto requiring 5 minutes. The mixture was stirred for 30 minutes under ice-cooling and one hour at room temperature. After adding 30 ml of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water two times. After drying over anhydrous sodium sulfate, the solvent was evaporated. The residue was subjected to silica gel column chromatography (eluent; chloroform:ethyl acetate=1:1), and 4-diethoxyphosphinylmethyl-N-benzylbenzamide was obtained. It was recrystallized from benzene-n-hexane to give 1.60 g of colorless needles.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[CH3:2].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1C=C>ClCCl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[F:15])[CH3:2]
Reactant: C=Cc1ccccc1F
Reactant: C=CCCCCCCCC(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCC=Cc1ccccc1F
Temperature: 40 °C
Yield: 56.8 %

Procedure:
To a solution of 9-decenoic acid ethyl ester (Tetrahedron 2003, 59, 7973; 500 mg, 2.53 mmol) and 2-fluorostyrene (617 mg, 5.05 mmol) in dichloromethane (12.5 mL) was added dichloro(1,3-dimesityl-4,5-dihydroimidazol-2-ylidene)(phenylmethylene) (tricyclohexylphosphine)ruthenium (107 mg, 0.13 mmol). The mixture was flushed with nitrogen and sealed in a pressure tube, then heated at 40° C. for 18 h. After cooling and evaporation of the solvent, the product was purified by chromatography (SiO2, heptane-dichloromethane 3:1), to afford 10-(2-fluoro-phenyl)-dec-9-enoic acid ethyl ester (420 mg, 57%).
Reaction SMILES: C1(C([NH:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[NH:26][N:25]([Sn](CCCC)(CCCC)CCCC)[NH:24][N:23]=3)=[C:17]([O:40]C(C3C=CC=CC=3)=O)[CH:16]=2)[C:11]([O:13]C)=[O:12])=O)C=CC=CC=1>Cl>[NH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[C:17]([OH:40])[CH:16]=1)[C:11]([OH:13])=[O:12]
Reactant: CCCC[Sn](CCCC)(CCCC)N1NN=C(Cc2ccc(C(NC(=O)c3ccccc3)C(=O)OC)cc2OC(=O)c2ccccc2)N1
Agent: Cl
Product: NC(C(=O)O)c1ccc(Cc2nnn[nH]2)c(O)c1
Temperature: 25 °C

Procedure:
A solution of methyl α-[(phenylcarbonyl)amino]-3-[(phenylcarbonyl)-oxy]-4-[[2-(tributylstannyl)-1H-tetrazol-5-yl]methyl]benzeneacetate from the Preparation 11 above in 6N HCl is heated at reflux until consumed. The reaction mixture is cooled to room temperature and extracted with 1:1 ether/toluene. The aqueous phase is concentrated to give the product of α-amino-3-hydroxy-4-(1H-tetrazol-5-ylmethyl)-benzeneacetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]#[N:43])[CH:33]=1)[C:10]([NH:12][C:13]1[N:18]=[CH:17][C:16]([N:19]([CH2:27][CH2:28][O:29][CH3:30])C(=O)OC(C)(C)C)=[CH:15][CH:14]=1)=[O:11])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:42]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[CH2:35][O:34][C:32]1[CH:31]=[C:9]([CH:8]=[C:7]([O:6][CH2:5][C:4]2[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=2[C:1]#[N:2])[CH:33]=1)[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH2:27][CH2:28][O:29][CH3:30])=[CH:17][N:18]=1)=[O:11])#[N:43]
Reactant: COCCN(C(=O)OC(C)(C)C)c1ccc(NC(=O)c2cc(OCc3ccccc3C#N)cc(OCc3ccccc3C#N)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNc1ccc(NC(=O)c2cc(OCc3ccccc3C#N)cc(OCc3ccccc3C#N)c2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a stirred solution of tert-butyl 6-({3,5-di(2-cyanobenzyloxy)benzoyl}amino)pyridin-3-yl(2-methoxyethyl)carbamate (237 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (3 ml). The solution was stirred at ambient temperature for three hours. Volatile material was removed by evaporation. The residue was diluted in DCM (100 ml), washed with 2M sodium Hydroxide (50 ml), brine (50 ml), dried over MgSO4. Volatile material was removed by evaporation to give the title compound (190 mg) as a foam, 1H NMR δ (d6-DMSO): 3.22 (t, 2H), 3.28 (2, 3H), 3.50 (t, 2H), 5.31 (s, 4H), 6.92 (s, 1H), 7.12 (dd, 1H), 7.34 (s, 2H), 7.57 (m, 2H), 7.75 (m, 5H), 7.82 (d, 1H), 7.91 (d, 2H), 10.49 (br s, 1H). MS ES+534.41 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]([N:11]([CH3:13])[CH3:12])[CH3:10])[CH:6]=[CH:7][CH:8]=1>Br>[CH3:13][N:11]([CH3:12])[CH:9]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)[CH3:10]
Reactant: COc1cccc(C(C)N(C)C)c1
Agent: Br
Product: CC(c1cccc(O)c1)N(C)C
Temperature: 25 °C

Procedure:
94 g of [1-(3-methoxyphenyl)ethyl]dimethylamine (V) are dissolved in 285 ml of azeotropic hydrobromic acid and the resulting solution is refluxed under stirring using a reflux condenser for 12 hours (bath temperature 145-150° C.). During boiling, the reaction mixture darkens. The solution is then left to cool down to room temperature. Excess hydrobromic acid is evaporated using a rotary vacuum evaporator and the evaporation residue is dissolved in 200 ml of water. The solution is extracted with 3×100 ml ethylacetate. The aqueous fraction is then gradually alkalized with the saturated solution of sodium carbonate with constant stirring (foam creation). The solution becomes milky turbid and it is extracted with 3×200 ml ethylacetate. The ethylacetate fraction is shaken out 1× with water, 1× with brine and dried with anhydrous magnesium sulfate. Activated carbon is added before filtering off the desiccant and the desiccant along with the carbon are filtered off. The ethylacetate solution of compound (IV) is used for the next step.