Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1>>[C:10]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1
Reactant: O=C(O)c1cccnc1
Reactant: CCCCC(CC)CO
Product: CCCCC(CC)COC(=O)c1cccnc1
Temperature: 200 °C
Reaction time: 6 h

Procedure:
2-Ethylhexyl alcohol (215.5 g, 1.65 mol) was charged to a 500 ml resin kettle and equipped with mechanical stir, a Dean-Stark trap and a thermocouple. The mixture was stirred at 300 rpm and nicotinic acid (61.5 g, 0.5 mol) was added in portions through a powder funnel. The mixture was heated to 200° C. with sub-surface nitrogen flow and held for 6 hours. The mixture was then cooled to 150° C. and vacuum was applied to −15 in Hg and held for 45 min. 22.9 g process oil was added and the mixture was then allowed to cool to room temperature under nitrogen atmosphere. The resulting mixture was then filtered twice through Celite Hyflow and Whatman #1 filter paper to yield desired product.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:35]([F:38])([F:36])[F:37])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.6 %

Procedure:
To a cooled and stirred solution of 3′-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.45 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield the title compound as a white solid (0.34 g, 72%). MS (ISN) 522.2 [(M−H)−]; mp 241° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]5[CH:31]=[C:32]([O:36][CH3:37])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[CH:29]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Product: COc1cc(-c2ccc3c(c2)ncn3-c2ccnc(N[C@@H](C)c3ccccc3)n2)cc(OC)c1OC

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 3,4,5-trimethoxyphenyl boronic acid. Mass spectrum (ESI) 415.4 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:27][CH2:28][CH:29]([CH3:35])[C:30]([O:32]CC)=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:14]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:27][CH2:28][CH:29]([CH3:35])[C:30]([OH:32])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)CSC(CCc1ccccc1C(C)=O)c1cccc(COC2CCCCO2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1ccccc1CCC(SCC(C)C(=O)O)c1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the ester of Step 7 (6.67 mmol) and 1.0N NaOH (13 mL) in 55 mL of MeOH:THF 3:2 was stirred at r.t. for 24 hours. 25% Aq NH4OAc was then added and the mixture was acidified with HOAC. The title acid was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica with acetone:toluene:HOAc.
Reaction SMILES: BrBr.Br[CH2:4][CH2:5][O:6][C:7]1[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K].[I-].[K+]>CN(C)C=O>[O:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH2:4][N:21]3[C:17](=[O:27])[C:18]4[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:20]3=[O:22])[C:16]=2[O:15][CH2:14][CH2:13]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCOc1cccc2c1OCCO2
Agent: BrBr
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc2c1OCCO2

Procedure:
Replacement of the bromine of the compound obtained in Step A is carried out in dimethylformamide (10 ml) under an argon atmosphere in the presence of potassium phthalimide (1.5 eq.) catalysed by potassium iodide (0.07 eq.). The reaction mixture is stirred and heated at reflux for 3 hours. The residual and resulting salts are removed by filtration; the product is then precipitated in the cold by the addition of water to the filtrate. The solid formed is filtered and then dried in vacuo in the presence of phosphorus pentoxide.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CC(=O)CC>[Cl:19][CH2:18][CH2:17][CH2:16][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: ClCCCOc1ccc(I)cc1
Temperature: 25 °C

Procedure:
A mixture of p-iodophenol (20 g, 91 mmol), potassium carbonate (25.2 g, 182 mmol) and 1-bromo-3-chloropropane (commercially available, for example, from Aldrich) (18 g, 114 mmol) in anhydrous 2-butanone (300 ml) was heated at reflux for 72 h, cooled to room temperature, filtered and evaporated to dryness. The resulting residue was purified by SPE filtration (70 g silica cartridge, eluting with 20:1 cyclohexane-ethyl acetate) to afford the title compound (24.9 g); 1H NMR (CDCl3) δ 7.5 (2H, d), 6.7 (2H, d), 4.1 (2H, t), 3.8 (2H, t), 2.2 (2H, q).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]([NH:23][NH2:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39](Cl)=[O:40])=[CH:34][CH:33]=1>O1CCCC1>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([NH:24][NH:23][C:21]([C:10]2[N:11]=[C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:22])=[O:40])=[CH:34][CH:33]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: Cc1ccc2nc(C(=O)NN)c(OCc3ccccc3)c(=O)n2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2nc(C(=O)NNC(=O)Cc3ccc(F)cc3)c(OCc3ccccc3)c(=O)n2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The product from Example 9.1 (160 mg, 0.524 mmol) and sodium carbonate (106 mg, 1 mmol) were mixed with anhydrous tetrahydrofuran (25 mL) and then cooled in ice bath. To this stirred solution was added 4-fluorophenylacetyl chloride (90 mg, 0.55 mmol) dropwise. The mixture was stirred at room temperature for 2 h then concentrated in vacuo. The residue was portioned between ethyl acetate and water and the organic phase washed with water, dried (Na2SO4) and concentrated in vacuo. Short column chromatography afforded the desired compound (210 mg, yield 86%)
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:11]([CH2:36][CH:37]([CH3:39])[CH3:38])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:15][CH:14]=2)=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][CH2:9][C:10]1[C:11]([CH2:36][CH:37]([CH3:38])[CH3:39])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[CH:17][C:16]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:15][CH:14]=2
Reactant: CCOC(=O)CCCOc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccc2nc(CC(C)C)c(CN)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
To a solution of ethyl 4-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}butanoate (0.2 g, 0.37 mmol) in ethyl acetate (10 ml) was added 4N solution of hydrogen chloride in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate was added to neutralize the residue. The obtained mixture was extracted with ethyl acetate and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give ethyl 4-{[3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-6-quinolinyl]oxy}butanoate (0.12 g) as an oil. The oil and p-toluenesulfonic acid monohydrate (57 mg, 0.25 mmol) were dissolved in ethanol (10 ml) and the mixture was concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound (0.11 g, yield 50%) as colorless crystals.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH:33]2[CH2:35][CH:34]2[C:36]([O:38]CC)=[O:37])[CH:28]=[C:29]([F:32])[C:30]=1O>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:30]3[C:29]([F:32])=[CH:28][C:27]([CH:33]4[CH2:35][CH:34]4[C:36]([OH:38])=[O:37])=[CH:26][C:25]=3[F:24])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(C3CC3C(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 5 and 6 by coupling [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate and ethyl 2-(3,5-difluoro-4-hydroxyphenyl)cyclopropane-1-carboxylate followed by hydrolysis to afford the desired product as an off-white solid. 1HNMR (300 MHz, CDCl3) δ 7.75 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 6.63-6.71 (m, 2H), 5.16 (s, 2H), 2.69-2.77 (m, 2H), 2.49-2.55 (m, 2H), 1.64-1.89 (m, 2H), 1.29-1.37 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H18F5NO3S, 482.1[M−H]. found 482.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>C(OCC)(=O)C>[F:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: Nc1ccc(Br)cn1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(Br)cn1
Reaction time: 72 h

Procedure:
A 2 g. portion of 5-bromo-2-aminopyridine was reacted with 2.5 g. of 2,6-difluorobenzoyl isocyanate under nitrogen in 50 ml. of ethyl acetate. The reaction mixture was stirred for 3 days, and was then filtered. The solids were washed with dichloromethane, ethyl acetate and diethyl ether and dried under vacuum to obtain the desired product, m.p. 232°-235° C. The elemental analysis showed:
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)C.[OH-].[K+].O>C(O)C>[CH3:28][O:27][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)OCC)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1OC
Yield: 68 %

Procedure:
The title compound is prepared by the procedure of Example 64 using 60 g of product from Example 66, 24.84 g Of potassium hydroxide, 45 ml of water and 650 ml of ethyl alcohol. The reaction is heated at reflux temperature for 41 hours. The residue is recrystallized from methylene chloride/hexane to give 38 g of the desired product as cream needles.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1.Cl>O1CCOCC1>[CH3:1][NH:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: CNc1n[nH]c2cc(C(=O)OC)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: CNc1n[nH]c2cc(C(=O)O)ccc12
Temperature: 100 °C
Yield: 115.1 %

Procedure:
To a solution of methyl 3-(methylamino)-1H-indazole-6-carboxylate (30.0 mg, 0.15 mmol) in 1,4-dioxane (0.2 mL) was added 3 N aqueous hydrochloric acid (0.2 mL, 0.6 mmol). The mixture was heated to 100° C. for 2 hours. The reaction was concentrated and dried under vacuum to give the title compound (33 mg, 99%) as a tan solid. +ESI (M+H) 192.1; 1H NMR (400 MHz, CD3OD, δ): 8.09 (s, 1H), 7.98 (dd, J=8.58, 0.78 Hz, 1H), 7.85 (dd, J=8.58, 1.37 Hz, 1H), 3.12 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1.O1CCOCC1>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.O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
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: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CS1)c1cc(-c3cncc(F)c3)ccc1Oc1ncc(Br)cc12
Temperature: 100 °C
Yield: 46 %

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (300 mg, 0.63 mmol, prepared as described in Method BB26), potassium carbonate (437 mg, 3.16 mmol), 5-fluoropyridin-3-ylboronic acid (178 mg, 1.27 mmol), tetrakis(triphenylphosphine)palladium(0) (73.1 mg, 0.063 mmol), dioxane (4.22 mL) and water (2.12 mL). The reaction was stirred and heated at 100° C. for 1 h. After cooling for rt, the organic layer was separated with a separatory funnel, dried over sodium sulfate, filtered, and concentrated to afford a yellow oil which was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (24 g), 0-50% EtOAc in hexanes to provide a white solid, (S)-3-bromo-7-(5-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (130 mg, 0.29 mmol, 46%). MS m/z=443.0 [M+H]+. Calc'd for C19H12BrFN4OS: 441.99.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[N:17]=[CH:16][C:15]2[CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[NH:20][C:14]=2[CH:13]=1.Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CN(C=O)C.O.CCOC(C)=O>[Br:11][C:12]1[N:17]=[CH:16][C:15]2[CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:20]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:14]=2[CH:13]=1
Reactant: BrCC1CC1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2CC2CC2)cn1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
NaHMDS (173 mL, 0.173 mmol) was added to a solution of 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 40 mg, 0.144 mmol) in DMF (630 mL). The reaction mixture was stirred for 15 minutes at 60° C. before the addition of (bromomethyl)cyclopropane (21 mL, 0.217 mmol). The reaction was then stirred for 24 hours at 60° C. before being diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was purified via Biotage silica gel column chromatography eluting with DCM/EtOAc (99/1 to 80/20) to afford a colourless oil as the title compound. (29 mg, 61%). 1H NMR (500 MHz, CDCl3) d 0.21-0.24 (m, 2H), 0.52-0.56 (m, 2H), 1.08-1.15 (m, 1H), 4.02 (s, 3H), 4.06 (d, J=6.3 Hz, 2H), 6.54 (d, J=0.9 Hz, 1H), 7.45 (t, J=0.9 Hz, 1H), 7.61 (d, J=0.8 Hz, 1H), 7.70 (d, J=0.8 Hz, 1H), 8.60 (d, J=0.9 Hz, 1H). LC (Method B)-MS (ESI, m/z) tR 2.64 min, 331 [(M+H+), 100%].
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4S[C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:29][N:30]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=[O:55])=CC=2)=CC=1.C1(C2OC(C(OCC)=O)=NC=2)C=CC=CC=1>>[CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[O:55][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:29][N:30]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: CCOC(=O)c1ncc(-c2ccccc2)o1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)o4)cc3)cc2C1=O

Procedure:
The compound of example 613 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with ethyl 5-phenyloxazole-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:6]=1[CH3:21])=[O:4].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[C:6]=1[CH2:21][Br:22])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n([C@@H](C)c2ccccc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n([C@@H](C)c2ccccc2)c1CBr
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture of (S)-5-bromo-2-methyl-6-oxo-1-(1-phenyl-ethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.34 g, 6.69 mmol), N-bromosuccinimide (1.31 g, 7.35 mmol), and benzoyl peroxide (0.16 g, 0.669 mmol) in CCl4 (70 mL) was refluxed for 16 h. After cooling the mixture to r.t., the precipitate was removed by filtration. The filtrate was evaporated in vacuo, and the residue was chromatographed (0-25% EtOAc/hexanes) to give 2.67 g of the title compound as a white solid. MS: (+) m/z 452.06 (M+Na).
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1N.P(OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO)(O)(O)=O>>[CH2:11]([OH:12])[C@H:9]1[O:10][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Product: OC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
D-mannitol was obtained commercially (Pfanstiehl Laboratories, Waukegan, IL). 2,5-anhydro-D-mannitol was prepared by deamination and reduction of D-glucosamine according to a known procedure of Bera, D. C., Foster, A. B. and Stacey, N., J. Chem. Soc. (1956) p. 4531-4541. The fructose 6-phosphate site of phosphofructokinase. J. Biol. Chem. (1974) 249:5749-5754.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[C:29]1(C2C=CC=CC=2)C=CC(C[C@@H](NC(OC(C)(C)C)=O)C[C@H](C)C(O)=O)=C[CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(I)C.C(OC(C)C)(=O)C>O.CN(C)C=O>[CH2:29]([O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)[CH3:30]
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) and (2S,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H), ratio of diastereomers of 80:20 ratio, respectively, prepared according to Example 3 in WO/2008/031567, is added to 2.55 g caesium carbonate. Dimethylformamide (4 ml) is then added. Ethyl iodide (0.55 ml) is then added and the mixture is stirred for 16 h at room temperature. Water (10 ml) and isopropyl acetate (10 ml) are added. The phases are separated. The aqueous phase is washed with isopropyl acetate (2×10 ml). The combined organic phases are washed with 20% aqueous sodium chloride solution (15 ml) and then dried (MgSO4). The mixture is concentrated under reduced pressure to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-a, R1=Boc, R2=H, R3=CO2Et) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-a, R1=Boc, R2=H, R3=CO2Et) as an 80:20 mixture of diastereomers, respectively. 1H NMR (CDCl3): 1.16-1.20, 1.25-1.29, 1.42, 1.47-1.52, 1.56-1.62, 1.76-1.84, 1.92-1.98, 2.48-2.57, 2.58-2.67, 2.77-2.88, 3.77-4.01, 4.10-4.18, 4.32-4.41, 7.26-7.28, 7.33-7.37, 7.43-7.47, 7.53-7.55, 7.59-7.60. Ratio of diastereomers 80:20 (1-a, R1=Boc, R2=H, R3=CO2Et:1-b, R1=Boc, R2=H, R3=CO2Et) by integration of signals at 1.76-1.84 (1-b, R1=Boc, R2=H, R3=CO2Et) and 1.92-1.98 (1-a, R1=Boc, R2=H, R3=CO2Et).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[OH-].[Na+].[CH:14](=[O:16])[CH3:15]>C(O)(C)C.O>[N:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:15][CH:14]=[O:16])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C=O)cc1
Reactant: CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C=CC=O)cc1
Yield: 27.8 %

Procedure:
4-Azidobenzaldehyde (14.71 g, 0.1 mol) was dissolved in a solvent mixture of isopropyl alcohol (50 g) and pure water (15 g). Under cooling in an ice bath, sodium hydroxide (1 g) dissolved in pure water (10 g) was added to the solution, and the resultant mixture was stirred for ten minutes. Acetaldehyde (4.41 g, 0.1 mol) was added to the mixture, and the resultant mixture was stirred for two hours at the same temperature. Subsequently, acetaldehyde (4.41 g, 0.1 mol) was again added to the mixture, and the resultant mixture was stirred for a further three hours. The formed precipitates were collected through filtration and dried, to thereby yield 4.82 g of p-azido-cinnamaldehyde as brown solid (yield: 28%) as a mixture containing acetaldehyde (2.7%).