Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]([Br:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:18]O>>[Br:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]([Br:17])=[CH:12][C:8]=1[C:9]([O:11][CH3:18])=[O:10]
Reactant: CO
Reactant: Cc1cc(Br)c(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(C)cc1Br

Procedure:
Molecules of the present invention can be synthesized using well-known organic synthesis methods. FIG. 8 shows a method for synthesizing a molecule belonging to the subclass shown in FIG. 6 according to one embodiment of the present invention. A detailed description of the organic synthesis is described below in an experimental subsection called “Synthesis of 1,4-bis[3′,5′-di-tert-butylphenylethynyl]-5-methyl-2-methoxycarbonylbenzene.” The organic synthesis includes adding nitric acid and water to a solution of 2,5-dibromo-p-xylene 802, which is refluxed to obtain in solution 2,5-dibromo-4-methylbenzoic acid 804. Methanol and concentrated sulfuric acid are added to the solution of 2,5-dibromo-4-methylbenzoic acid 804, which is refluxed to obtain a solution of methyl 2,5-dibromo-4-methylbenzoate 806. In a separate part of the synthesis, trifluoromethanesulfonic anhydride and pyridine are added to a solution of 3,5-di-tert-butylphenol 808 and the solution is warmed to room temperature to obtain 3,5-di-tert-butylphenyl triflate 810. A solution of 3,5-di-tert-butylphenyl triflate 810, PdCl2, (PPH3)2, CuI, tetrabutylammonium iodide, and trimethylsilylacetylene are stirred to obtain 1-[3′,5′-di-tert-butylphenyl-2-trimethylsilylacetylene 812. Combining 1-[3′,5′-di-tert-butylphenyl-2-trimethylsilylacetylene 812, methyl 2,5-dibromo-4-methylbenzoate 806, PdCl2, (PPH3)2, CuI, triethylamine, tetrahydrofuran, and tetrabutylammonium fluoride and stirring at room temperature yields the desired molecule 1,4-bis[3′,5′-di-tert-butylphenylethynyl]-5-methyl-2-methoxycarbonylbenzene 814.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[C:6]([OH:23])[N:5]=[C:4]([CH3:24])[N:3]=1.CC(O)C.[ClH:29]>C1COCC1>[ClH:29].[ClH:29].[NH2:1][C:2]1[N:3]=[C:4]([CH3:24])[N:5]=[C:6]([OH:23])[C:7]=1[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1nc(N)c(CCC2CCN(C(=O)OC(C)(C)C)CC2)c(O)n1
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1nc(N)c(CCC2CCNCC2)c(O)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
Combine tert-butyl 4-[2-(4-amino-6-hydroxy-2-methyl-pyrimidin-5-yl)ethyl]piperidine-1-carboxylate (3.73 kg, 11.09 mol) and IPA in a 50 L reactor under a nitrogen atmosphere. Add 12 N hydrochloric acid (3.05 L, 36.6 mol) with stiffing over 3 h. Heat the mixture at 50° C. for 16 h, forming a thick slurry. At that time NMR analysis shows no BOC group remaining. Cool the reaction mixture to 20-25° C., diluting with THF (12 L). Collect the solids by filtration. The filtration is slow and may take over 24 h to complete. Wash with IPA (2×10 L). Dry the material in a vacuum oven at 50° C. to provide the title compound (3.117 kg, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH3:16])=[N:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[C:17]([OH:21])(=O)[CH2:18]O>>[OH:21][CH2:17][C:18]1[N:15]([CH3:16])[C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[C:5]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[N:4]=2
Reactant: O=C(O)CO
Reactant: CNc1nc(Sc2ccccc2)ccc1N
Product: Cn1c(CO)nc2ccc(Sc3ccccc3)nc21

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 2.62. g of 3-amino-2-methylamino-6-phenylthiopyridine (prepared as described in Preparation 89) and 2.58 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 50:1 to 10:1 by volume as the eluent, to give 1.80 g of the title compound, melting at 119-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CCN(CC)CC.Br[CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20])=[CH:4][CH:3]=1
Reactant: COC(CBr)OC
Reactant: Sc1ccc(Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(CSc1ccc(Cl)cc1)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chlorobenzenethiol (13 mmol) and Et3N (1.4 g, 13 mmol) in THF (25 mL) at room temperature was added 2-bromo-1,1-dimethoxyethane (2.36 g, 13 mmol) in THF (5 mL). After stirring at room temperature for 30 minutes, the reaction mixture was poured into water (200 mL) and extracted with diethyl ether (3×150 mL). The combined organic layer was dried over Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound.
Reaction SMILES: [CH:1]([C:3]1([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[CH2:2].C[N+]1([O-])CC[O:29]CC1.S([O-])(O)(=O)=O.[Na+].[OH2:39]>O1CCCC1.[Os](=O)(=O)(=O)=O>[OH:39][CH:1]([C:3]1([CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:5][CH2:4]1)[CH2:2][OH:29]
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2ccccc2)(C(O)CO)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
Osmium tetroxide (2.5 wt % solution in tert-butanol, 240 mL) was added to a mixture of 1,1-dimethylethyl 4-ethenyl-4-(phenylmethoxymethyl)-1-piperidinecarboxylate (Description 96, 1.01 g, 3 mmol) and N-methylmorpholine-N-oxide (460 mg, 4 mmol) in water (4 mL) and tetrahydrofuran (12 mL). The mixture was stirred at room temperature for 24 hours then saturated aqueous sodium hydrogen sulphate (5 mL) was added. The mixture was extracted with ethyl acetate (2×15 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (1.05 g, 96%). m/z (ES+) 366 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:18]1[C:27]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.CC(C)([O-])C.[Na+].C[N:40]1C(=O)[CH2:43][CH2:42][CH2:41]1>>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([O:16][C:18]2[C:27]([C:28]3[S:29][C:30]4[CH:31]=[CH:32][CH:43]=[CH:42][C:41]=4[N:40]=3)=[N:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN1CCCC1=O
Reactant: Clc1nc2ccccc2nc1-c1cccs1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2nc3ccccc3nc2-c2nc3ccccc3s2)C[C@H]1C(=O)O

Procedure:
(2S,4R)—N-Boc-4-hydroxyproline can be reacted with 2-chloro-3-(thiophen-2-yl)quinoxaline in NMP, in the presence of sodium t-butoxide, to produce (2S,4R)-1-(tert-butoxycarbonyl)-4-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)pyrrolidine-2-carboxylic acid. Methyl tertiary butyl ether (MTBE) and water can then be added. The aqueous layer is separated, washed, and then HCl is added, followed by extraction with MTBE. The extracted product can be mixed with diisopropylethylamine (DIPEA) and HATU (CAS #148893-10-1), and then reacted with (1R,2S)-ethyl-1-amino-2-vinylcyclopropanecarboxylate tosylate salt in dimethylformide (DMF) and toluene. The reaction produces (2S,4R)-tert-butyl 2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)pyrrolidine-1-carboxylate, which can be extracted with MTBE and washed with HCl, further extracted, washed, dried, and dissolved in 2-propanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]([C:23]#[N:24])([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[BH4-].[Na+]>O.O.O.O.O.O.[Co](Cl)Cl.CO>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:24][CH2:23]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)c(OC)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC1(c2ccc(OC)c(OC)c2)CNC(=O)C1
Temperature: 25 °C

Procedure:
Combined 3-cyano-3-(3,4-dimethoxy-phenyl)-pentanedioic acid diethyl ester (16.8 g, 48.0 mmol), methanol (300 mL) and cobalt (II) chloride hexahydrate (22.8 g, 96.0 mmol). Cooled until the internal temperature reached 10° C. Added portionwise so as to maintain the reaction temperature below 20° C., sodium borohydride (44.2 g, 1.17 mol). After addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirred over the weekend. Concentrated in vacuo to obtain a residue. Partitioned between 1N HCl (800 mL) and dichloromethane (800 mL). The organic layer was extracted with 1N HCl (2×200 mL). The combined aqueous layers were extracted with dichloromethane (3×100 mL). The organic layers were combined, dried over Na2 SO4, filtered, and concentrated in vacuo to obtain a residue. The residue was chromatographed on silica gel eluting with ethyl acetate/methanol (20:1) to obtain the title compound: Rf =0.27 (silica gel, 20:1 ethyl acetate/methanol), mp=116°-118° C. Analysis: calculated for C16H21NO5C 62.53; H 6.89; N 4.56; Found C 62.52; H 6.85; N 4.50.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([N:6]1[CH2:7][C@H:2]([CH3:1])[N:3]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:4][C@H:5]1[CH3:8])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1
Product: CC(=O)N1C[C@H](C)N(c2ccc([N+](=O)[O-])cc2)C[C@H]1C
Reaction time: 8 h

Procedure:
The title compound was prepared from (2S,5R)-2,5-dimethyl-1-(4-nitrophenyl)piperazine (Method 28, 8.22 g, 34.95 mmol) and acetyl chloride (4.5 ml, 62.91) by the procedure of Method 26. It was obtained as an oil which solidified on standing overnight (11.39 g, >100%, contaminated with solvent) NMR (400 MHz) 1.13 (m, 6H), 3.07 (m, 1H), 3.33 (m, 1H), 3.68 (m, 1H), 4.25 (m, 2H), 4.69 (m, 1H), 7.00 (d, 2H), 8.05 (d, 2H); m/z 278.
Reaction SMILES: C1COCC1.[CH:6]1([C:9](=[O:12])[CH2:10][CH3:11])[CH2:8][CH2:7]1.[C:13]([O:20][CH2:21][CH3:22])(=[O:19])[C:14]([O:16]CC)=O>C(OCC)C>[CH:6]1([C:9](=[O:12])[CH:10]([CH3:11])[C:14](=[O:16])[C:13]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][CH2:7]1
Reactant: CCC(=O)C1CC1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=O)C1CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
165 mL of an 1 M solution of bis(trimethylsilyl)lithiumamid in THF (166 mmol, 1.10 eq.) were brought forward in 500 mL of diethyl ether and cooled down to −78° C. 14.8 g of 1-cyclopropylpropan-1-one 1-12-1 was dissolved in 100 mL of diethyl ether and added dropwise at −78° C. The mixture was stirred for one hour at −78° C. and then 24.5 mL of diethyl oxalate was added dropwise. The cooling bath was removed and the mixture was stirred for 24 hours at rt. 500 mL of aqueous 1M hydrogen chloride solution was added and the mixture was extracted with DCM, dried over a silicone filter sulfate and concentrated in vacuo to provide 27.2 g (137 mmol, 91%) of the target compound as crude product. The crude product was used for the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10]C=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])OCC.[N+]([O-])([O-])=O.[NH4+].[CH2:28](O)C>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:13]([O:17][CH2:18][CH3:19])([O:20][CH2:21][CH3:22])[CH3:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCO
Reactant: O=CC=Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(OCC)OCC
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Product: CCOC(C)(/C=C/c1ccc(Cl)c(Cl)c1)OCC

Procedure:
The above aldehyde (0.66 g) was stirred in ethanol (5 ml) with triethyl orthoformate (0.6 ml) (ex Aldrich) and ammonium nitrate (ex Aldrich) (0.01 g) for 3.5 hours at 25°. Concentration in vacuo and work up in the usual manner gave E-1-(3,4-dichlorophenyl)-3,3-diethoxy but-1-ene (0.97g). NMR 1H: 7.32(3H,m), 6.79(1H,d), 6.19(1H,dd), 5.08(1H,d), 3.69(4H,m), 1.29(6H,m).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23](O)[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>O1CCCC1>[C:35]([C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[CH:19]([CH2:18][CH2:17][C@@H:16]3[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:27])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24]1)(=[O:37])[CH3:36]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)[C@@H]1CC[C@@]2(C)C(CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
To tetrahydrofuran was added 0.1 mole of lithocholic acid and 0.1 mole of triethylamine, and the resulting solution was maintained at a temperature below 4° C. in an ice bath. 0.12 mole of acetyl chloride was slowly added thereto, and the resulting solution was reacted for 8 hours. Thereafter, residual solvent was removed by using a vacuum distillator. A compound was extracted by using ethyl acetate, and washed with water a few times, to obtain 3α-acetylcholanic acid. To tetrahydrofuran was added 0.2 mole of 3α-acetylcholanic acid thus obtained and a slight amount of p-toluensulfonic acid. 0.21 mole of ethylvinylether was added to the resulting solution. Then, the resulting solution was reacted for 12 hours, to obtain 3α-acetylethoxyethyl lithocholate of formula 3 (yield: 70%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:24])[N:3]=1.B([C:28]1[CH:39]=[CH:38][C:31]([CH2:32][C@@H:33]([C:35]([OH:37])=[O:36])[NH2:34])=[CH:30][CH:29]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:34][CH:33]([CH2:32][C:31]1[CH:38]=[CH:39][C:28]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:24])[N:3]=2)=[CH:29][CH:30]=1)[C:35]([OH:37])=[O:36]
Reactant: Nc1nc(Cl)cc(OC(c2ccccc2C(F)(F)F)C(F)(F)F)n1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Nc1nc(OC(c2ccccc2C(F)(F)F)C(F)(F)F)cc(-c2ccc(CC(N)C(=O)O)cc2)n1
Temperature: 150 °C
Yield: 11.2 %

Procedure:
In a microwave vial, 4-chloro-2-amino-6-[1-(2-trifluoromethylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 ml of acetonitrile, 0.7 ml of water. 0.3 ml of 1N aqueous sodium carbonate was added to above solution followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 5.6 mg of 2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-trifluoromethylphenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ 7.96 (m, 3H), 7.80 (d, J=8.06 Hz, 1H), 7.74 (t, J=7.91 Hz 1H), 7.63 (t, J=8.06 Hz, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.21 (m, 1H), 6.69 (s, 1H), 3.87 (m, 1H), 3.34 (m, 1H), 3.08 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C@@H:6]([N:10]1[C:14]2=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=[C:13]2[NH:12][C:11]1=[O:20])[CH2:7][CH2:8][CH3:9])[CH3:2].C([O-])([O-])=O.[K+].[K+].[I-].[CH3:29][N:30]1[C:38]2[C:33](=[C:34]([CH3:39])[CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:40][N+](C)(C)C)=[CH:31]1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C@@H:6]([N:10]1[C:14]2=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=[C:13]2[N:12]([CH2:40][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])[N:30]([CH3:29])[CH:31]=2)[C:11]1=[O:20])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)[nH]c2ccc(C)nc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccc(C)nc21
Temperature: 60 °C
Yield: 44.6 %

Procedure:
To a solution of (S)-3-(5-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-hexanoic acid ethyl ester (247 mg, 0.85 mmol) in DMF (5 mL) were added K2CO3 (234 mg, 1.7 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (438 mg, 1.27 mmol). The reaction mixture was heated to 60° C. for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 170 mg (45%) of the title compound. LCMS, M++1, m/z: 449.47.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1([OH:28])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[C:9]([CH3:13])([CH3:12])[CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CS(OS(C)(=O)=O)(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:9]([CH3:13])([CH3:10])[CH2:12][O:28][C:15]2([CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:19][CH2:20]2)[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN(Cc2ccccc2)C(C)(C)CO)CC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)C(C)(C)CO2
Temperature: 65 °C
Yield: 28.3 %

Procedure:
To a solution of tert-butyl 4-[[benzyl-(2-hydroxy-1,1-dimethyl-ethyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (330 mg, 0.841 mmol) in tetrahydrofuran was added N,N-diisopropylethylamine (439 μL, 2.52 mmol) and methanesulfonic anhydride (439 mg, 2.52 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 65° C. for 18 h. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-80% of ethyl acetate/hexanes) to provide tert-butyl 8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (89 mg, 28%) as white solid. ESI-MS m/z calc. 374.5. Found 375.3 (M+1)+; Retention time: 1.30 minutes (3 min run).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:17][CH2:18][C:19]2[CH:33]=[CH:32][C:22]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=2)=[N:14][CH:15]=1)(=O)[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C(O)(C)(C)C>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:44])[F:43])=[CH:37][CH:36]=2)[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:32][CH:33]=2)=[N:14][CH:15]=1)([CH3:1])=[CH2:8]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(C(C)=O)cn2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C=C(C)c1ccc(N(CCc2ccc(OC(C)(C)C(=O)OCC)cc2)Cc2ccc(C(F)(F)F)cc2)nc1
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A solution of methyltriphenylphosphonium bromide (101 mg; 0.28 mmol) in 0.76 ml of THF was treated under nitrogen with potassium tert-butoxide (0.28 ml of a 1M solution in tert-butanol). After 10 minutes, ethyl 2-[4-(2-{(5-acetylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (100 mg; 0.19 mmol) was added. After 2 hours the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate and concentrated. Purification by flash chromatography using 10% ethyl acetate-hexane mixtures afforded ethyl 2-[4-(2-{(5-isopropenylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (30 mg; 30% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])[CH:7]=1.O.NN.ClCCl>CO.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:21])=[C:6]([CH2:8][NH:9][CH2:10][C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH:7]=1
Reactant: COc1cccc(OC)c1CNCc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1cccc(OC)c1CNCc1cc(Cl)ccc1N
Temperature: 64 °C

Procedure:
1-(5-Chloro-2-nitrophenyl)-N-(2,6-dimethoxybenzyl)methanamine (19.2 g, 57.0 mmol) was dissolved in 400 mL methanol in the heat. Activated carbon (20.0 g) and catalytic amounts of sublimed iron trichloride (0.24 g, 1.48 mmol) were added at room temperature. Finally, hydrazine hydrate (11.10 mL, 228.0 mmol) was added slowly by drops at 64° C. In doing so, it foamed up somewhat. After heating for 2 hours at 64° C., the reaction was concluded. After cooling the reaction mixture to room temperature, the batch was filtered through Hyflo Super Cel and the solid constituents were separated out. The solvent was removed in vacuo. The colorless oil was again dissolved in dichloromethane and extracted with water (3×) and with 2N hydrochloric acid (3×). The hydrochloric two-phase mixture was adjusted to a pH of 11 with 2N sodium hydroxide solution, at which point a bulky colorless precipitate was formed. When dichloromethane was added, the solids dissolved again in the organic phase which was dried over sodium sulfate after separating the aqueous phase, then filtered and freed of the solvent in vacuo. By storing into petroleum ether, a colorless precipitate was obtained from the oily yellow crude product, then filtered with suction and dried. By fractional crystallization of the mother liquor, the yield was further increased. Yield: 11.5 g (37.5 mmol, 66%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@H:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=C(C4C=CC(C(F)(F)F)=CC=4)C=CC=3)=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])=[N:5][N:4]=[N:3]1.[CH3:36]COC(C)=O>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:7]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH2:8][C:9]([O:11][CH3:36])=[O:10])=[CH:13][CH:14]=1
Reactant: CCOC(C)=O
Reactant: Cn1nnnc1[C@@H](CC(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Product: COC(=O)C[C@@H](c1ccc(O)cc1)c1nnnn1C
Reaction time: 8 h

Procedure:
Methyltetrazole M14.2 (413 mg, 0.833 mmol) was dissolved in 5 mL of EtOAc and nitrogen was bubbled through the solution for 5 minutes. Palladium on carbon (200 mg, 5 wt. %, wet contains 50% water) was added, and a hydrogen balloon was attached. After 8 hours, the mixture was filtered through a plug of silica with 10% MeOH in EtOAc. The organic layer was concentrated under reduced pressure and partitioned between ACN (10 mL) and hexane (5 mL). The ACN layer was washed with hexane (4×5 mL). The ACN layer was concentrated under reduced pressure to afford (S)-methyl 3-(4-hydroxyphenyl)-3 -(1-methyl-1H-tetrazol-5-yl)propanoate (M 14) (203 mg, 0.775 mmol) as a colorless oil.