Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH:3]1[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[C:13]1([N:19]2[C:23]([SH:24])=[N:22][N:21]=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].O>CCO>[O:10]1[C:6]2([CH2:11][CH2:12][CH:3]([CH2:2][S:24][C:23]3[N:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:20]=[N:21][N:22]=3)[CH2:4][CH2:5]2)[O:7][CH2:8][CH2:9]1
Reactant: ICC1CCC2(CC1)OCCO2
Reactant: Sc1nnnn1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(-n2nnnc2SCC2CCC3(CC2)OCCO3)cc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A solution of 8-iodomethyl-1,4-dioxa-spiro[4.5]decane (prepared according to WO 2003/095438, 26 g, 92 mmol) was dissolved in EtOH (200 ml), 1-phenyl-1H-tetrazole-5-thiol (18.9 g, 106 mmol) and KOH (6.7 g, 120 mmol) was added and the mixture stirred at 80° C. for 2.5 h. A little water was added and the mixture concentrated in vacuo. The residue was taken up in water and EA. The yield after work up was 30.9 g (100%; yellowish oil).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4]C[CH2:2]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Yield: 82 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 41, intermediate b)), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (82%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:8]([CH:26]=1)[C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)=[O:10])(=[O:3])[CH3:2].[Br-:35].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>O1CCCC1>[CH2:28]([O:27][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH2:2][Br:35])=[CH:26][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)=[O:10])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.7 %

Procedure:
5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (compound of Example 58(3); 4.81 g, 10 mmol) was dissolved in tetrahydrofuran (30 ml). Phenyltrimethylammonium tribromide (3.75 g, 10 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with aqueous sodium hydrogen sulfite, water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1), and recrystallized (ethyl acetate/n-hexane) to give the title compound (2.39 g, 42.7%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16](O)[CH:15]=[CH:14][C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5].FC1C=C([N+:26]([O-:28])=[O:27])C=CC=1C.[O-][Mn](=O)(=O)=O.[K+]>>[F:1][C:2]1[CH:17]=[C:16]([N+:26]([O-:28])=[O:27])[CH:15]=[CH:14][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1F
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc([N+](=O)[O-])cc1F

Procedure:
This was prepared as described above in Example 33 except that benzyl 2-fluoro-4-hydroxybenzoate (prepared from 2-fluoro-4-nitrotoluene by oxidation with KMnO4 to give 2-fluoro-4-nitrobenzoic acid, followed by catalytic reduction to give 4-amino-2-fluorobenzoic acid, followed by diazotization/hydrolysis to give 4-hydroxy-2-fluorobenzoic acid which was converted to benzyl 2-fluoro-4-hydroxybenzoate in a fashion analogous to that described in Example 23) was used as starting material in place of benzyl 2-chloro-4-hydroxybenzoate.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([N+:16]([O-])=[O:17])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[Al]>O1CCCC1>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[N:16][OH:17])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(C=C(C)[N+](=O)[O-])cc1
Agent: [Al]
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(CC(C)=NO)cc1
Yield: 91.3 %

Procedure:
1-(4-Carbomethoxymethoxyphenyl)-2-nitroprop-1-ene (8.7 g) in tetrahydrofuran (100 ml) was stirred with aluminium amalgam, made in the normal way from aluminium (6 g) and mercuric chloride (3 g). The mixture was cooled in ice and stirring was continued until reaction was complete. The slurry was filtered through celite and the filtrate was evaporated to give a cream solid (7.5 g). τ(CDCl3) 8.24 (3H, s), 6.36 (2H, s), 6.24 (3H, s), 5.43 (2H, s), 3.20 (2H, d, J=8 Hz), 2.83 (2H, d, J=8 Hz), 2.5-3.4 (1H, broad, disappears with D2O).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.[ClH:15].Br[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:15].[ClH:15].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([O:14][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2ncccc2O)n1
Reactant: BrCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1csc(Nc2ncccc2OCc2cccnc2)n1
Yield: 99.7 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (prepared according to Example 3, Step A; 75 mg, 0.362 mmol), 3-(bromomethyl)pyridine hydrochloride (75.4 mg, 0.362 mmol) and potassium carbonate (175 mg, 1.27 mmol) were reacted according to Example 3, Step B, to provide N-(4-methylthiazol-2-yl)-3-(pyridin-3-ylmethoxy)pyridin-2-amine dihydrochloride (67 mg, 49.9% yield) as a tan solid. 1H NMR (d6-DMSO) δ 10.15 (bs, 1H), 8.82 (s, 1H), 8.57 (d, 1H), 8.07 (m, 1H), 7.88 (dd, 1H), 7.46 (m, 2H), 6.92 (dd, 1H), 6.58 (s, 1H), 5.29 (s, 2H), 2.24 (s, 3H). Mass spectrum (apci) m/z=299 (M+H-2HCl).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:12]=[CH:11][C:10](=[O:13])[C:9]([O:14]CC2C=CC=CC=2)=[C:8]1[CH2:22][CH:23](OC(=O)C)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26]C=1)(=[O:3])[CH3:2]>O1CCCC1.[Pd]>[CH2:22]([C:8]1[N:7]([CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:12]=[CH:11][C:10](=[O:13])[C:9]=1[OH:14])[C:23]1[CH:24]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)OCCn1ccc(=O)c(OCc2ccccc2)c1CC(OC(C)=O)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)OCCn1ccc(=O)c(O)c1Cc1ccccc1

Procedure:
2.2 g of acetic acid [1-(2-acetoxy-ethyl)-3-benzyloxy-4-oxo-1,4-dihydropyridin-2-yl-methyl]-phenyl-methyl ester are hydrogenareal in 50 ml of tetrahydrofuran over 0.5 g of palladium on carbon (5%) under normal pressure and at a temperature of 50° C. until 2 mol of H2 per mol of starting material have been taken up. The catalyst is removed by filtration and the flitrate is concentrated by evaporation using a rotary evaporator. Recrystallisation from tetrahydrofuran yields 2-benzyl-3-hydroxy-1-(2-acetoxy-ethyl)-1H-pyridin-4-one, Colourless crystals, m.p.: 139.7°-140.7° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-amino-6-chloro-2-(3-chlorobenzoyl)-1H-indole (step 2) and ethyl chloroformate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[CH:26][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[S:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])=[CH:26][N:27]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1-c1cnc(CBr)s1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2ncc(-c3ccccc3Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
70 mg (0.23 mmol) of the compound from Example 5A were reacted with 66 mg (0.23 mmol) of the compound from Example 88A analogously to the preparation of the compound in Example 77. This gave 65 mg (55% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[CH:25]([C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)O)[CH:8]=2)[N:3]=1>CC(O)C.Cl>[CH3:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:25][C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)[C:18]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:10]2
Reactant: Cc1cccc(C(O)c2cnccn2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cccc(Cc2cnccn2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1

Procedure:
A solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrazin-2-yl)methanol (0.040 g, 0.094 mmol, prepared as Example 36 above) in i-PrOH and 5N HCl (15 mL) was refluxed for 15 h, or until starting material was consumed. The mixture was brought to RT, carefully washed with 5N NaOH and extracted with DCM. The combined organics were dried over Na2SO4, filtered, concentrated and purified by HPLC to afford a light brown solid as 6-(2-methyl-6-(pyrazin-2-ylmethyl)phenyl)-3-morpholinoquinolin-2-amine. MS (ESI, pos. ion) m/z: 412 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17](O)=[O:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].C1COCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[CH2:31]([N:33]([CH2:34][CH3:35])[C:17]([C:14]1([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][N:5]2[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4]2)[CH2:12][CH2:13]1)=[O:18])[CH3:32]
Reactant: CCNCC
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCN(CC)C(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 50 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid (0.11 mmol, 1.0 equiv), 65 μL of 2.0 M diethylamine/THF (0.13 mmol, 1.2 equiv), 60 μL TEA (0.43 mmol, 4.00 equiv), 71 mg BOP (0.16 mmol, 1.5 equiv), and 500 μL of NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield the desired 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid diethylamide:.MS (ES) M+H expected=477.3, found=477.4.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[O:27][N:26]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:38][C:32]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=1[CH2:30][C:28]1[O:27][N:26]=[C:25]([C:23]([NH:22][CH2:21][CH2:20][C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:12]=3)[NH:16][CH:15]=2)=[O:24])[CH:29]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Br)cc12)c1cc(Cc2cc(F)ccc2F)on1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(-c3ccccc3)cc12)c1cc(Cc2cc(F)ccc2F)on1
Yield: 6 %

Procedure:
A mixture of benzene boronic acid (0.023 g; 0.191 mmol), N-(2-(5-bromo-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide (0.080 g; 0.174 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020; 0.017 mmol) and sodium carbonate (0.037 g; 0.347 mmol) in DME (3 mL) and water (1 mL) was irradiated in the microwave oven at 130° C. for 20 minutes, the resulting solution was partitioned between water and EA, the organic layer was concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.0048 g (6%) of 5-(2,5-difluorobenzyl)-N-(2-(5-phenyl-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[O:7][C:8]=1[CH2:9]O.C(N(CC)CC)C.CS([Cl:32])(=O)=O>ClCCl>[Cl:32][CH2:9][C:8]1[O:7][C:6]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:5][C:4]=1[CH2:3][O:2][CH3:1]
Reactant: COCc1nc(C=Cc2ccc(OC)cc2)oc1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1nc(C=Cc2ccc(OC)cc2)oc1CCl
Temperature: 25 °C

Procedure:
420 mg {4-Methoxymethyl-2-[2-(4-methoxy-phenyl)-vinyl]-oxazol-5-yl}-methanol were dissolved in 5 ml dichloromethane and cooled in an ice bath. 0.32 ml triethylamine were added, followed by the addition of 141 μl methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. 50 ml dichloromethane were added and the reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 491 mg 5-chloromethyl-4-methoxymethyl-2-[2-(4-methoxy-phenyl)-vinyl]-oxazole as an oil which was used without further purification.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:39]=[CH:38][C:15]2[N:16]([CH:26]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:27]([O:29]CC)=[O:28])[C:17]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[N:18][C:14]=2[CH:13]=1>C(O)C.[OH-].[Na+]>[F:25][C:19]([F:24])([C:17]1[N:16]([CH:26]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:27]([OH:29])=[O:28])[C:15]2[CH:38]=[CH:39][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]3[N:1]=[N:2][NH:3][N:4]=3)=[CH:13][C:14]=2[N:18]=1)[C:20]([F:21])([F:23])[F:22]
Reactant: CCCCCCC(C(=O)OCC)n1c(C(F)(F)C(F)(F)F)nc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C(=O)O)n1c(C(F)(F)C(F)(F)F)nc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Yield: 91.9 %

Procedure:
Ethyl 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-2-pentafluoroethyl-1H-benzimidazol-1-yl]octanoate (0.25 mmoles, 0.14 g) was dissolved in 25 ml ethanol and 1 ml 5N NaOH. The solution heated on a steam bath for 1 hour. The solvent was removed in vacuo. The residue was dissolved in water. The pH was adjusted to 3.0 using 5N HCl. The precipitate was collected and dried to yield 0.12 g of 2-[2-pentafluoroethyl-5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid. (MS)
Reaction SMILES: [ClH:1].[CH2:2]([O:6][CH:7]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])[C@H:8]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:31])[NH2:30])[NH:9][C:10](=[O:24])[C@H:11]([CH3:23])[NH:12]C(OCC1C=CC=CC=1)=O)[CH2:3][CH2:4][CH3:5].[H][H]>CO.[Pd]>[ClH:1].[CH2:2]([O:6][CH:7]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])[C@H:8]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:30])[NH2:31])[NH:9][C:10](=[O:24])[C@H:11]([CH3:23])[NH2:12])[CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](C)N
Yield: 98 %

Procedure:
After N-benzyloxycarbonyl-L-alanyl-L-argininal dibutylacetal hydrochloride (0.45 g, 0.85 mmol) was dissolved in methanol (25 ml), palladium black (1 g) was added to the solution. The mixture was stirred at room temperature for 2 hours in a hydrogen flow. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to give 0.33 g (97%) of L-alanyl-L-argininal dibutylacetal hydrochloride as oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([CH3:16])[C:7]=1[C:8]1[C:9](=[O:15])[CH2:10][CH2:11][C:12]=1[O:13][CH3:14].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:33]1[CH2:37][CH2:36][CH:35]([CH:38]=[O:39])[CH2:34]1>O1CCCC1>[CH3:16][C:6]1[CH:5]=[C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[C:8]1[C:9](=[O:15])[CH:10]([CH:38]([OH:39])[CH:35]2[CH2:36][CH2:37][O:33][CH2:34]2)[CH2:11][C:12]=1[O:13][CH3:14]
Reactant: O=CC1CCOC1
Reactant: COC1=C(c2c(C)cc(-c3ccccc3)cc2C)C(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(-c3ccccc3)cc2C)C(=O)C(C(O)C2CCOC2)C1
Temperature: -75 °C
Reaction time: 0.67 h
Yield: 136.7 %

Procedure:
To a solution of 2-(3,5-Dimethylbiphenyl-4-yl)-3-methoxy cyclopent-2-enone (0.6 g, 2.05 mmol) in tetrahydrofuran (12 ml) is added 1 molar solution of lithium bis(trimethylsilyl)amide in THF (2.5 ml, 2.5 mmol) under nitrogen atmosphere at −75° C. The resulting solution is stirred at −75° C. for 40 minutes and to this mixture, a solution of 3-tetrahydrofurancarboxaldehyde (0.42 g, 4.1 mmol) in THF is added over 20 minutes. The resulting solution is stirred at −75° C. for 2 hours. The cooling bath is removed and the mixture is allowed to reach room temperature, then stirred for 2 hours. The reaction mixture is quenched with ice cold water (100 ml) and extracted with ethyl acetate (3×75 ml, dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated in vacuo to give a residue (1.1 g) which is used as such for the next step.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31][C:32]1[N:37]=[C:36]([CH:38](O)[CH2:39][C:40]2[CH:48]=[C:47]([CH3:49])[C:46]3[C:42](=[CH:43][N:44]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:45]=3)[CH:41]=2)[CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.CCCCCC>[Br:31][C:32]1[N:37]=[C:36]([CH:38]([N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:39][C:40]2[CH:48]=[C:47]([CH3:49])[C:46]3[C:42](=[CH:43][N:44]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:45]=3)[CH:41]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(CC(O)c2cccc(Br)n2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cc(CC(c2cccc(Br)n2)N2C(=O)c3ccccc3C2=O)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 118.3 %

Procedure:
A solution of phthalimide (294 mg, 2 mmol) and triphenylphosphine (525 mg, 2 mmol) in anhydrous methylene chloride (10 mL) was added via syringe to (±)-1-(6-bromopyridin-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethanol (460 mg, 1 mmol). To the resulting suspension was then added diisopropylazidodicarboxylate (0.3 mL, 1.5 mmol) under nitrogen at room temperature via syringe. The resulting mixture was stirred at room temperature overnight (17 h). The mixture was diluted with hexane and purified by flash column chromatography to give a light yellow oil (700 mg, 100%). MS (ESI) [M+H]+=592. HPLC tR=2.05 min.
Reaction SMILES: [CH3:1][O:2][C:3]([O:13][CH3:14])([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.C[C:16](C)(C)[CH2:17][C:18]([CH2:23]O)([CH2:21]O)[CH2:19]O>Cl>[CH3:23][C:18]([CH3:19])([CH3:21])[CH2:17][C:16]12[CH2:14][O:13][C:3]([C:4]3[CH:9]=[CH:8][C:7]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:5]=3)([O:11][CH2:12]1)[O:2][CH2:1]2
Reactant: CC(C)(C)CC(CO)(CO)CO
Reactant: COC(OC)(OC)c1ccc(Br)cc1
Agent: Cl
Product: COCCCc1ccc(C23OCC(CC(C)(C)C)(CO2)CO3)cc1

Procedure:
Trimethyl 4-bromo-orthobenzoate (1.5 g.) (McElvain and Venerable, J. Amer.Chem.Soc., 1950,72,1661) was added to 2-(2,2-dimethylpropyl)-2-hydroxymethyl-propan-1,3-diol (1.0 g.). One drop of concentrated hydrochloric acid was added and the mixture was maintained at 140° for one hour, under a current of nitrogen. The volatile components were removed in vacuo (1.0 mm), at 140° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[C:5]([CH3:14])=[N:4][N:3]=1.B(Br)(Br)Br>ClCCl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[C:5]([CH3:14])=[N:4][N:3]=1
Reactant: COc1ccc2c(C)nnc(Cl)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnc(Cl)c2cc(O)ccc12
Temperature: 25 °C
Yield: 33.4 %

Procedure:
A solution of 4-chloro-6-methoxy-1-methylphthalazine (4) (2.08 g, 9.99 mmol), 1.0 M boron tribromide (17.00 mmol) in dichloromethane (17 mL), and dichloromethane (50 mL) is stirred under argon at −78° C. for 10 min, room temperature for 38 h, and at reflux for 3 h. The mixture is cooled to room temperature, diluted with sat. NaHCO3 (130 mL), and extracted with ethyl acetate (150 mL and 4×60 mL). The extract is washed (water and brine) and dried. After solvent removal at reduced pressure, the remaining solid is washed with dichloromethane to give 650 mg (70%) of 5 as a yellow solid, mp >260° C. IR 3351, 2938, 1610, 1223 cm−1; 1H NMR (DMSO-d6) δ 2.84 (s, 3H, CH3), 7.44 (d, J=8.7 Hz, 1H, 8-PhthH), 7.59 (dd, J=9.0, 2.4 Hz, 1H, 6-PhthH), 8.19 (d, J=9.0 Hz, 1H, 5-PhthH), 11.27 ppm (s, 1H, OH).