Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([Li])CCC.[C:12]([O:16][C:17](=[O:49])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:48])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[C:31]([O:46][CH3:47])[CH:30]=2)=[CH:22][CH:21]=1)([CH3:15])([CH3:14])[CH3:13].[H-].[Na+].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:12]([O:16][C:17](=[O:49])[CH2:18][CH:19]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:48])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[C:31]([O:46][CH3:47])[CH:30]=2)=[CH:22][CH:21]=1)[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([CH3:13])([CH3:15])[CH3:14]
Reactant: C1COCCN1
Reactant: COc1cc(CC(=O)Nc2ccc(C=CC(=O)OC(C)(C)C)cc2)ccc1NC(=O)Nc1ccccc1C
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CC(=O)Nc2ccc(C(CC(=O)OC(C)(C)C)N3CCOCC3)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
A solution of morpholine (87 mg) in anhydrous tetrahydrofuran (10 ml), cooled to −78° C. and under an atmosphere of nitrogen, was treated with a solution of n-butyl lithium in hexanes (0.4 ml, 2.5M). After stirring at −78° C. for 15 minutes the mixture was treated dropwise with a solution produced from treating a stirred suspension of 3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}phenyl)-propenoic acid tert-butyl ester (0.25 g, Reference Example 8) in anhydrous tetrahydrofuran (10 ml) with sodium hydride (58 mg of a 60% dispersion in mineral oil), under an atmosphere of nitrogen. The resulting mixture was stirred a further 30 minutes at −78° C. then poured into a mixture of ethyl acetate (50 ml) and saturated aqueous sodium chloride solution (50 ml). The organic layer was separated, then dried over magnesium sulphate and then evaporated. The residue was triturated with diethyl ether to give the title compound (165 mg) as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH2:13](O)[CH3:14].N1C=CC=CC=1>O1CCCC1>[CH3:12][Si:2]([CH3:1])([CH3:11])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:13][CH3:14])=[O:9]
Reactant: CCO
Reactant: C[Si](C)(C)C#CCCCC(=O)O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCC#C[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 5.3 gm of 1,1-carbonyldiimidazole in 80 ml of dry tetrahydrofuran under argon, was added a solution of 5.03 gm of 6-trimethylsilyl-5-hexynoic acid in 15 ml of dry tetrahydrofuran. The mixture was stirred for 1 hour. Absolute ethanol (80 ml) and pyridine (1 ml) were then added, and the resulting mixture was stirred at room temperature for 48 hours. The solvent was evaporated and the residual oil was extracted with ether and 1.5% hydrochloric acid. The ethereal layer, which was washed with water and then dried, was evaporated to an oil. This material was purified by distillation, b.p. 70°-75° C. (0.6 mm Hg); IR: 2170, 1735 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([S:15][CH3:16])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(B(CC)[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)C>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([S:15][CH3:16])[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: CSc1nncc(-c2ccc(F)c(Br)c2)n1
Reactant: CCB(CC)c1cccnc1
Product: CSc1nncc(-c2ccc(F)c(-c3cccnc3)c2)n1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-methylsulfanyl-[1,2,4]triazine was coupled to diethyl(3-pyridyl)borane by the method of Example 12 to give 5-[4-fluoro-3-(pyridin-3-yl)phenyl]-3-methylsulfanyl-[1,2,4]triazine as a yellow solid: δH (400 MHz, CDCl3) 2.74 (3H, s), 7.37-7.46 (2H, m), 7.91-7.95 (1H, m), 8.16-8.20 (1H, m), 8.30 (1H, dd, J 2.3, 7.4 Hz), 8.70 (1H, dd, J 1.4, 4.9 Hz), 8.86 (1H, s), 9.40 (1H, s); m/z (ES+) 299.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1C[CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([CH2:29][CH:30]4[CH2:34][CH2:33][N:32]([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[C:31]4=[O:41])=[C:24]([Cl:42])[CH:23]=3)=[CH:18][CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.Cl.[O-]C#[N:47].[K+]>O1CCOCC1>[Cl:28][C:26]1[CH:27]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:14]([N:10]3[CH2:9][CH2:8][N:7]([C:6]([NH2:47])=[O:5])[CH2:12][CH2:11]3)=[O:15])=[CH:21][CH:20]=2)[CH:23]=[C:24]([Cl:42])[C:25]=1[CH2:29][CH:30]1[CH2:34][CH2:33][N:32]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:31]1=[O:41]
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)C1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: NC(=O)N1CCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)CC1
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
Dissolve racemic 4-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.40, 0.65 mmol) in dioxane (20 mL), add 4N hydrochloric acid in dioxane (10 mL) and stir 30 min to obtain an orange residue in reaction vessel. Concentrate under vacuum, dilute residue with water (10 mL) and add potassium cyanate (0.55 g, 0.68 mmol). Stir the reaction at room temperature to obtain a white precipitate. Filter off solid and wash with water. Dissolve the solid in dichloromethane and concentrate under vacuum to yield a clear foam. Use resin bound solid phase acidic media (SCX) to remove residual starting material and obtain 0.168 g (46%) of product as a white solid: MS (m/z): 557 (M+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:46]2[CH:58]=[CH:57][C:49]([CH2:50][N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[CH:48][CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:46]3[CH:47]=[CH:48][C:49]([CH2:50][N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[CH:57][CH:58]=3)=[CH:21][CH:22]=2)[CH2:29][CH2:28][CH2:27]1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(CN5CCOCC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Yield: 44.1 %

Procedure:
A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.097 mmol), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (59 mg, 0.20 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7 mg, 0.1 mmol), and 2M Na2CO3 aq. (0.097 mL, 0.20 mmol) in DMF (1.5 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water (×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified twice by preparative thin-layer chromatography (CH2Cl2/MeOH=10:1×2) and (AcOEt/MeOH=10:1) to afford the desired product (28 mg, 44%) as a yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.17 (dd, J=8.0 Hz and 1.7 Hz, 1H), 8.00 (d, J=4.6 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.30 (td, J=8.0 Hz and 1.7 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.17-7.13 (m, 3H), 6.94 (d, J=8.0 Hz, 1H), 6.80 (d, J=6.9 Hz, 1H), 6.59 (dd, J=8.0 Hz and 5.2 Hz, 1H), 6.24 (s, 1H), 5.10 (br s, 1H), 3.70 (t, J=4.6 Hz, 4H), 3.47 (s, 2H), 2.57-2.50 (m, 2H), 2.45-2.42 (m, 4H), 2.19-2.10 (m, 2H), 1.93-1.85 (m, 2H), 1.39 (br s, 9H). LCMS: 655 [M+H].
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (55 mg, 104 μmol) in dichloromethane (3 mL) was added TFA (1.48 g, 1000 μL, 13.0 mmol25), the reaction mixture turned orange and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (added few drops MeOH and heating) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product suspended in dichloromethane and cyclohexane added to complete solid formation, solid was separated by decantation and dried under high vacuum to give N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (26 mg, 64.9 μmol, 62.7%) as a white solid. MS (M+H)+=401.1 (100% purity); 1H NMR (DMSO-d6) δ: 9.12 (s, 1H), 8.36 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.88 (s, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.35 (dd, J=9.1, 2.3 Hz, 1H), 7.17 (t, J=74.4 Hz, 1H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].Br[CH2:11][C:12](=O)[CH3:13]>C(#N)C>[Cl:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[N:3]([CH:11]=[C:12]([CH3:13])[N:1]=2)[N:4]=1
Reactant: Cc1cc(Cl)nnc1N
Reactant: CC(=O)CBr
Solvent: CC#N
Product: Cc1cn2nc(Cl)cc(C)c2n1

Procedure:
3-Amino-6-chloro-4-methylpyridazine (5.50 g, 38.3 mmol) and bromoacetone (6.90 g, 40.0 mmol) were heated in acetonitrile (50.0 ml) for 8 hours under reflux. The reaction solution was concentrated under reduced pressure, and water (100 ml) was added to the residues which were then adjusted to pH 9 with 20% aqueous sodium hydroxide and extracted twice with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate and concentrated, and the residues were purified by silica gel column chromatography (ethyl acetate:chloroform=1:2), to give the title compound as white crystals. The yield was 3.80 g (54.6%).
Reaction SMILES: C(C1C2C=C(C)C(CNC3C=CC(C(OCC)=O)=CC=3)=CC=2C(C)(C)CC=1)(C)C.[CH3:30][N:31]([C:43]1[C:52]([CH3:53])=[CH:51][C:50]2[C:49]([CH:54]([CH3:56])[CH3:55])=[CH:48][CH2:47][C:46]([CH3:58])([CH3:57])[C:45]=2[CH:44]=1)[C:32]1[CH:42]=[CH:41][C:35]([C:36]([O:38]CC)=[O:37])=[CH:34][CH:33]=1>>[CH3:30][N:31]([C:43]1[C:52]([CH3:53])=[CH:51][C:50]2[C:49]([CH:54]([CH3:55])[CH3:56])=[CH:48][CH2:47][C:46]([CH3:57])([CH3:58])[C:45]=2[CH:44]=1)[C:32]1[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:41][CH:42]=1
Reactant: CCOC(=O)c1ccc(N(C)c2cc3c(cc2C)C(C(C)C)=CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(NCc2cc3c(cc2C)C(C(C)C)=CCC3(C)C)cc1
Product: Cc1cc2c(cc1N(C)c1ccc(C(=O)O)cc1)C(C)(C)CC=C2C(C)C
Yield: 66 %

Procedure:
Following General Procedure E, ethyl 4-[(5-isopropyl-3,8,8-trimethyl-7,8-dihydronaphthalen-2-yl)methylamino]benzoate, AGN 196549, (Compound 49, 0.12 g, 0.31 mmol) was reacted to give 0.074 g (66%) of the title compound as a yellow solid. PNMR (300 MHz, CDCl3) δ13 1.24 (s, 6H), 1.25 (d, 6H, J=7.5 Hz), 2.12 (s, 3H), 2.22 (d, 2H, J=2.5 Hz), 3.02 (m, 1H), 3.32 (s, 1H), 5.82 (t, 1H, J=3.0 Hz), 6.52 (d, 2H, J=7.7 Hz), 7.08 (s, 1H), 7.28 (s, 1H), 7.94 (d, 2H, J=7.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13](Cl)(=O)[CH3:14]>C(O)C>[CH2:13]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([OH:12])[CH:4]=1)[CH3:14]
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of step (iii) (4 g) was added to a solution of acetyl chloride (10 ml) in ethanol (40 ml). The mixture was stirred for 1 h at RT then evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent 2:1 isohexane/EtOAc) to give the subtitle compound (4.4 g).
Reaction SMILES: Br[C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.C([O-])(=O)C.[K+].C(N(CC)CC)C>C(O)(C)C>[Cl:11][C:10]1[C:2]([NH:17][CH:14]2[CH2:16][CH2:15]2)=[C:3]([CH:7]=[C:8]([F:13])[C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: NC1CC1
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(F)c(F)c(Cl)c1NC1CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
In a sealed tube a mixture of 2-bromo-3-chloro-4,5-difluorobenzoic acid (Example 20, 7.96 g, 29.3 mmol), cyclopropyl amine (4.20 mL, 58.7 mmol), potassium acetate (5.77 g, 58.6 mmol), cupric acetate monohydrate (0.50 g, 2.5 mmol), and triethylamine (4.9 mL, 35.19 mmol) in isopropyl alcohol is stirred at 80° C. After 16 hours, the reaction mixture is concentrated under vacuum, and the resulting residue is dissolved in ethyl acetate. The organic layer is washed with 1.0 M hydrochloric acid, water, and brine. The organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under vacuum and purified via flash column chromatography (5% isopropyl alcohol/1% formic acid/94% dichloromethane) to afford the title compound (4.62 g). MS CI: m/z 248 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3([N:23]4[CH2:32][C@H:31]([OH:33])[CH2:30][C@H:24]4[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=4)[NH:12][C:11]3=[O:22])[C:4]=2[O:3][CH2:2]1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3([N:23]4[CH2:32][C@H:31]([OH:33])[CH2:30][C@H:24]4[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=4)[N:12]([S:42]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][C:38]=4[O:46][C:47]([F:48])([F:49])[F:50])(=[O:44])=[O:43])[C:11]3=[O:22])[C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C1(c2cccc3c2OCO3)C(=O)Nc2ccc([N+](=O)[O-])cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cccc4c3OCO4)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc([N+](=O)[O-])ccc32)c(OC(F)(F)F)c1
Yield: 37.5 %

Procedure:
With 279 mg of the compound obtained in Step 94-2 (Isomer B) and 214 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 163 mg of the title compound (pale yellow solid) was obtained by a similar method to Example 2.
Reaction SMILES: [C:1]([N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])(=[O:5])[CH2:2][CH2:3][CH3:4].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:29]([O:32][CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[C:36]([CH2:44]Br)[CH:35]=1)[CH2:30][CH3:31].[Cl-].[NH4+]>O1CCCC1>[CH2:3]([C@@H:2]([CH2:44][C:36]1[CH:35]=[C:34]([CH2:33][O:32][CH2:29][CH2:30][CH3:31])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[C:1]([N:6]1[C@H:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5])[CH3:4]
Reactant: CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CCCOCc1cc(CBr)cc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCOCc1cc(C[C@H](CC)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc2ccccc12
Temperature: -75 °C
Reaction time: 1 h

Procedure:
30 ml of tetrahydrofuran and a solution of 2.97 g of 3-butyroyl-4(R)-benzyl-oxazolidin-2-one in 15 ml of tetrahydrofuran are added dropwise in succession to a solution, stirred at -75° C., of 12 ml of 1M lithium hexamethyldisilazide solution. The reaction mixture is stirred for 1 hour at -75° C., a solution of 3.52 g of 4-propoxymethyl-2-bromomethyl-naphthalene in 15 ml of tetrahydrofuran is added dropwise thereto and the mixture is then stirred further for 1 hour at -30° C. and for 3 hours at 0° C. After the dropwise addition at 0° C. of 2.7 ml of saturated ammonium chloride solution, the reaction mixture is concentrated by evaporation and the residue is partitioned between diethyl ether and water. The organic extracts are concentrated by evaporation and the residue is purified by FC (1 kg of silica gel, eluant: dichloromethane/hexane=3:1), yielding the title compound: Rf (dichloromethane/hexane=3:1)=0.24; FAB-MS (M+Na)+ =482.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:27])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[CH3:27]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (LC/MS): 357.1 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][C@@H:6]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:27][C:28]([CH3:31])=[N:29][N:30]=3)=[CH:22][CH:21]=2)[CH:18]=1)[C:12]([O:14]C)=[O:13])[CH3:7]>O.CO>[CH3:3][O:4][CH2:5][C@@H:6]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:27][C:28]([CH3:31])=[N:29][N:30]=3)=[CH:22][CH:21]=2)[CH:18]=1)[C:12]([OH:14])=[O:13])[CH3:7]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triphenyl phosphine (21 g, 80 mmol, 2.8 equiv.) was added to a stirring solution of Methyl 3-hydroxy-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)benzoate (Intermediate 7) (9.3 g, 28.52 mmol, 1 equiv.) in toluene (100 mL) under nitrogen atmosphere at room temperature. The mixture was heated to 90° C. for 30 min. A mixture of Diisopropylazadicarboxylate (DIAD) (11.52 g, 57 mmol, 2 equiv.) and (R)-(−)-1-Methoxy-propan-2-ol (3.8 g, 42.8 mmol, 1.5 equiv.) in toluenene (50 mL) was added to the above reaction mixture at 90° C. and the reaction mixture was stirred for 3 h at 100° C. The completion of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under vacuum and purified by column chromatography to get (5)-Methyl 3-[(1-methoxypropan-2-yl)oxy]-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (Intermediate 8) as thick liquid (27 g). Sodium hydroxide (3.43 g, 85.92 mmol, 3 equiv.) in water (55 mL) was added to a stirring solution of (9-Methyl 3-[(1-methoxypropan-2-yl)oxy]-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (crude) (Intermediate 8) in methanol (110 mL) in round bottomed flask. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion, methanol was removed under vacuum and water was added. The reaction mixture was filtered. Filtrate was washed with ethyl acetate. The aqueous layer was acidified and extracted with DCM twice. The combined organic layer was washed with water, brine and dried over anhydrous sodium sulphate, filtered and concentrated in vacuum to furnish title acid as thick liquid (9.5 g).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:15][CH2:14]2)=[O:9])=[C:6]([O:30]C)[CH:5]=1.B(Br)(Br)Br.CO>ClCCl>[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:15][CH2:14]2)=[O:9])=[C:6]([OH:30])[CH:5]=1
Reactant: COc1cc(Cl)ccc1C(=O)NCCN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(NCCN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
A solution of the product of step (b) (3 g) in dichloromethane (50 ml) was cooled to −78° C. and a 1.0M solution of boron tribromide in dichloromethane (8.5 ml) added. After 1 hour the solution was allowed to warm to room temperature. After 3 hours, methanol (6 ml) was added and the solution concentrated. This process was repeated, the residue dissolved in methanol, treated with concentrated hydrochloric acid and stirred at room temperature for 3 hours. The solution was concentrated, sodium bicarbonate solution and ethyl acetate were added, the organic phase separated, dried and concentrated to a gum which was purified by chromatography (dichloromethane:methanol, 97:3) to give the product as a solid (2.0 g), m.p. 238-240° C.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:8]([OH:10])=[O:9])[CH:5]([CH3:7])[CH3:6].[NH:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=2)=[N:14][N:13]=[N:12]1.[BH4-].[Na+].Cl>O.CO>[CH3:6][CH:5]([CH3:7])[C@H:4]([NH:3][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[NH:11][N:12]=[N:13][N:14]=2)=[CH:23][CH:24]=1)[C:8]([OH:10])=[O:9]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)[C@H](NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)O
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Aqueous sodium hydroxide solution 10 M (approximately 41 ml; 410 mmol) is added to a stirred suspension of L-Valine (24.8 g; 210 mmol) and 2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde (50 g; 200 mmol) in water (200 ml) at room temperature, until pH 11 is reached. The resulting clear solution is evaporated at 60° C. in vacuo, and remaining water is azeotropically removed with 1-butanol. The residue (imine as a solid foam) is dissolved in methanol (600 ml), and sodium borohydride (3.13 g; 80 mmol) is added in portions to the solution at 0-5° C. The reaction mixture is stirred for 30 min at 0-5° C., and, if the reaction is complete (HPLC), quenched by addition of water (300 ml) and hydrochloric acid 2.0 M (160 ml; 320 mmol). The organic solvent (methanol) is stripped off from the clear solution (pH 7) at 50° C. in vacuo. The remaining aqueous concentrate is adjusted to pH 2 by slow addition of hydrochloric acid 2.0 M (approximately 90 ml) at 40° C. During the addition the desired product precipitates. It is collected by filtration, washed with water and dried in vacuo. The crude product is suspended in methanol at 50° C., and stirred for a few minutes. Then the slurry is cooled to room temperature. (S)-3-methyl-2-((2′-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl)-amino)-butyric acid is collected by filtration and then dried in vacuo.