Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1([CH2:11][O:12][CH3:13])[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.[N:18]([O-])=O.[Na+]>O.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1([CH2:11][O:12][CH3:13])[CH2:10][CH2:9][CH2:8][N:7]([NH2:18])[CH2:6]1
Reactant: O=N[O-]
Reactant: COCC1(Cc2ccccc2F)CCCNC1
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COCC1(Cc2ccccc2F)CCCN(N)C1
Temperature: 25 °C

Procedure:
In an argon purged flask, 3-(2-fluorobenzyl)-3-(methoxymethyl)piperidine (337 mg, 1.23 mmol) was dissolved in water (0.8 mL) and acetic acid (2 mL). A solution of sodium nitrite (170 mg, 2.46 mmol) and water (1 mL) was drop wise added to the reaction flask. The reaction was stirred for an hour at room temperature. Water (5 mL) was added to the reaction mixture. The reaction mixture then was extracted 3 times with ethyl acetate (20 mL). The organic layers were combined, dried with sodium sulfate, and concentrated. The oil was dissolved in acetic acid (5 mL). The solution was drop-wise added to a suspension of Zn (321 mg, 4.92 mmol) in acetic acid (1 mL) and water (1 mL) solution. The reaction was stirred for 1.5 hour at room temperature. Upon completion, the reaction was filtered through celite. The Zn and salt was rinsed with 1N HCl in water. The filtrate was concentrated to yield crude hydrogen chloride salt of the amine. The crude product was progressed to the next step without further purification.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[O:9][N:8]=1)(=O)=O.[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C=O)C>[N:16]([CH2:6][C:7]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[O:9][N:8]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1cc(C(F)(F)F)on1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of 8.7 g (5-(trifluoromethyl)isoxazol-3-yl)methyl methanesulfonate in 87 mL DMF was added 9.23 g sodium azide. The reaction mixture was stirred 3 h at RT. 80 mL water was added under cooling. The mixture was extracted with diethyl ether (3×100 mL) and the organic layers were washed with water (3×100 mL) and then with sat. NaCl solution (1×100 mL). The combined organic layer was dried over Na2SO4, filtered off and concentrated in vacuo to yield 6.26 g of the title compound as a brown oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])C(O)=O.CN(C)C=O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:1]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]([F:20])([F:21])[F:22])[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCC(F)(F)F)c(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
Oxalyl chloride (0.053 ml, 0.6 mmol) was added to a stirred solution of the 3-chloro-4-[(2,2,2-trifluoroethyl)oxy]benzoic acid (D20; 76 mg, 0.30 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at 0° under nitrogen and the mixture was allowed to warm to room temperature with stirring overnight. The solvent was evaporated to give the title compound as a yellow solid (ca 90 mg) which was used crude in the next reaction (D48).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][CH:22]=2)=[CH:12][CH:11]=1)(=O)=O.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:25]1(/[CH:24]=[CH:23]/[C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][CH:14]=3)[N:19]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl methanesulfonate (430 mg), ethyl 2-imidazolecarboxylate (155 mg), potassium carbonate (305 mg) and N,N-dimethylformamide (10 ml) was stirred for two hours at temperatures ranging from 80 to 90° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. The crystalline product obtained from the fraction eluted with ethyl acetate-hexane (2:1, v/v) was recrystallized from ethyl acetate-hexane to give ethyl 1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]-2-imidazolecarboxylate (280 mg, 60%) as colorless prisms, mp 96-97° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:21])([F:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[NH:64]1[CH:68]=[N:67][C:66]([NH2:69])=[N:65]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:4]1[N:3]=[C:2]([NH:69][C:66]2[N:67]=[CH:68][NH:64][N:65]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Nc1nc[nH]n1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccccc3n2)nc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Fc1ccc(C(F)(F)c2nc(Nc3nc[nH]n3)c3ccccc3n2)nc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a mixture of 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline from Example 4 Step A (100 mg, 0.32 mmol), Pd2(dibenzylideneacetone)3 (12 mg, 0.013 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol), SEM protected 1,2,4-triazol-3-amine (97 mg, 0.45 mmol), and Na2CO3 (48 mg, 0.45 mmol) was added toluene (3 mL), and the mixture was evacuated and flushed with argon three times. The mixture was heated at 110° C. for 2 h, and then diluted with DCM and filtered. To the filtrate was added TFA (3 mL) and the mixture was stirred at rt for 2 h and then concentrated under reduced pressured. To the residue was added MeOH and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex C-18 reverse phase column eluting with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O). The obtained material was triturated with diethyl ether to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(1H-1,2,4-triazol-3-yl)quinazolin-4-amine (16 mg, 14%). 1H NMR (300 MHz, methanol-d4) δ 8.68 (br s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.90-8.15 (m, 4H), 7.71-7.88 (m, 2H). LCMS (ESI) m/z 358 (M+H)+.
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])CCC.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH2:21][NH2:22]>O1CCCC1>[C:11]([NH:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:22][CH2:21][C:20]1[CH:19]=[C:18]([Cl:17])[CH:25]=[C:24]([Cl:26])[CH:23]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: NCc1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(C)Nc1c(NCc2cc(Cl)cc(Cl)c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A mixture of 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5 mmol, Example 1), 3.5-dichlorobenzylamine (0.88 g, 5 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature overnight, and then was processed as in Example 2, Step 4. Recrystallization (twice) of the crude product from methanol gave 1.095 g of the title compound as a whte solid: mp 281°-283° C. (dec). MS (m/z) 326/328/330 (M+). HPLC indicates a major component (99.2%).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[C:29]1([CH:35]([CH3:38])[CH2:36][OH:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:26][C:23]1[C:22]([CH2:27][O:37][CH2:36][CH:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:38])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CC(CO)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COCC(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 17, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenyl-propan-1-ol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:23])[C:11]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2F)=[S:12])=[CH:6][CH:5]=1.CN(C=O)C>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:11]2[S:12][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:22])[N:13]=2)[CH3:23])=[CH:6][CH:5]=1
Reactant: CN(C(=S)NC(=O)c1ccncc1F)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(c1ccc(Cl)cc1)c1nc(=O)c2ccncc2s1
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
In an atmosphere of argon, a suspension of 167 mg of sodium hydride (60% oil suspension) in 1 ml of THF was added to a mixture of 1.230 g (3.80 mmol) of 1-(4-chlorophenyl)-3-(3-fluoroisonicotinoyl)-1-methylthiourea and 10 ml of DMF while being cooled over a water bath. The mixture was stirred for 10 minutes, and then stirred over a 110° C. oil bath for 5 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure. The resulting residue was then poured into ice-water. The resulting precipitate was collected by filtration, washed with water, and then dried under reduced pressure. The resulting crude product was then recrystallized from ethanol to obtain 802 mg of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[4,3-e]-1,3-thiazin-4-one.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@:10]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][C@H:12]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@:10]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][C@H:12]2[S:24]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: N[C@@H]1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Yield: 48.8 %

Procedure:
(1R*,2R*,5S*,6R*)-2-benzylamino-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane (Description 4; 8.34 g, 16 mmol) was dissolved in methanol (150 mL) and acetic acid (150 mL), then treated with 10% palladium on activated charcoal (2 g). The suspension was then hydrogenated at 50 psi hydrogen for 16 hours, then filtered. The filtrate was concentrated in vacuo, and the oil remaining suspended in saturated aqueous sodium hydrogen carbonate solution (250 mL). This was extracted with ethyl acetate (2×250 mL) and the extracts were dried (MgSO4), then concentrated. Purification by silica chromatography yielded the title compound as a gum (3.37 g, 7.8 mmol).
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[CH2:12][NH:13][CH2:14][C:15]#[N:16])([O-:9])=[O:8].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[N+:7]([C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[CH2:12][N:13]([CH2:14][C:15]#[N:16])[C:22](=[O:23])[O:24][CH2:25][CH3:26])([O-:9])=[O:8]
Reactant: CCOC(=O)Cl
Reactant: N#CCNCc1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N(CC#N)Cc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Pyridine (151 mg, 1.91 mmol) was added to a CH2Cl2 solution (20 mL) containing 2-(2-nitrobenzylamino)acetonitrile (1) (122 mg, 0.638 mmol). The reaction mixture was cooled to 0° C. under a nitrogen atmosphere, and ethyl chloroformate (0.182 mL, 1.914) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, and then washed with 1N HCl (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting oil was purified by column chromatography (Biotage 40 m, 100% CH2Cl2) to provide 97 mg (0.37 mmol, 58% yield) of ethyl 2-nitrobenzyl(cyanomethyl)carbamate (2) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([C:11]1[CH:77]=[CH:76][C:14]([CH2:15][O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:68]C(OC(C)(C)C)=O)[C:24]([O:26][C@H:27]2[C@@H:31]([OH:32])[C@H:30]([N:33]3[CH:41]=[N:40][C:39]4[C:34]3=[N:35][CH:36]=[N:37][C:38]=4[NH2:42])[O:29][C@H:28]2[CH2:43][O:44][P:45]([O:48][C@H:49]2[CH2:53][C@H:52]([N:54]3[CH:59]=[CH:58][C:57]([NH2:60])=[N:56][C:55]3=[O:61])[O:51][C@@H:50]2[CH2:62][O:63][P:64]([OH:67])([OH:66])=[O:65])([OH:47])=[O:46])=[O:25])=[O:18])=[CH:13][CH:12]=1)=[N+:9]=[N-:10]>ClCCl>[NH2:68][C@H:23]([CH2:22][CH2:21][CH2:20][NH:19][C:17]([O:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([N:8]=[N+:9]=[N-:10])=[CH:77][CH:76]=1)=[O:18])[C:24]([O:26][C@H:27]1[C@@H:31]([OH:32])[C@H:30]([N:33]2[CH:41]=[N:40][C:39]3[C:34]2=[N:35][CH:36]=[N:37][C:38]=3[NH2:42])[O:29][C@H:28]1[CH2:43][O:44][P:45]([O:48][C@H:49]1[CH2:53][C@H:52]([N:54]2[CH:59]=[CH:58][C:57]([NH2:60])=[N:56][C:55]2=[O:61])[O:51][C@@H:50]1[CH2:62][O:63][P:64]([OH:67])([OH:66])=[O:65])([OH:47])=[O:46])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=Nc1ccc(COC(=O)NCCC[C@@H](N)C(=O)O[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@H]2COP(=O)(O)O[C@H]2C[C@H](n3ccc(N)nc3=O)O[C@@H]2COP(=O)(O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21.1 %

Procedure:
A 10% solution of trifluoroacetic acid in dichloromethane (0.4 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy) (hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk59) (22.7 mg, 0.022 mmol) in dichloromethane (0.4 mL), and the mixture was stirred at room temperature for 20 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-5-((((4-azidobenzyl)oxy)carbonyl)amino)pentanoate (Orn(Acbz)-pdCpA) (Compound tk60) (4.3 mg, 21%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)O1>>[CH3:8][C:6]1[CH:7]=[C:2]([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)[CH:3]=[C:4]([CH3:24])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1
Reactant: CC1(C)OB(c2cncc(C(F)(F)F)c2)OC1(C)C
Product: Cc1cc(-c2cncc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone (example 22) was reacted with 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-pyridine (intermediate 6) to give the title compound as light yellow oil. MS: 462.2 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[Li+].[OH-].Cl>O1CCCC1.CO>[CH3:20][O:19][CH2:18][CH2:17][CH2:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1oc2cccc(CCCOC)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCCc1cccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 0.1 %

Procedure:
To a solution of 4-(3-methoxy-propyl)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (2.213 g, 8.018 mol) in tetrahydrofuran (25 mL) and methanol (9 mL) at room temperature was added 1N LiOH (16.838 mL). The resulting yellow solution was stirred at room temperature for 2.5 hours, neutralized with 1N HCl and was then partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and reduced to dryness furnishing 1.98 g (98%) of 4-(3-methoxy-propyl)-3-methyl-benzofuran-2-carboxylic acid as a white solid. MS (ES) m/z: 249.11214 (M+H)+, 497.21700 (2M+H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].ClC(Cl)C.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[N:4]1[CH:16]=[CH:20][CH:19]=[CH:18]1
Reactant: Nc1c(Br)cccc1Br
Reactant: COC1CCC(OC)O1
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Brc1cccc(Br)c1-n1cccc1

Procedure:
To a 200 mL round bottom flask was added 2,6-dibromoaniline (8.63 g, 34.7 mmol, 1.0 equiv.), dichloroethane (35.0 mL, 1.0 M), acetic acid (35.0 mL, 1.0 M), and 2,5-dimethoxytetrahydrofuran (10.5 mL, 3.3 M). A reflux condenser was fitted to the flask and the mixture was heated to reflux for 2 hours. During this time the solution slowly changes colors from clear to yellow. An aliquot was removed and the reaction was judged complete by NMR. The mixture was diluted with CH2Cl2, rinsed with H2O, and then rinsed with saturated aqueous K2CO3. The organic layer was dried over MgSO4 and filtered through a pad of SiO2 with CH2Cl2 as eluent. The oil was place under high vacuum overnight to remove the excess 2,5-dimethoxytetrahydrofuran. During this time 1-(2,6-dibromophenyl)-1H-pyrrole, 2, changes to a white solid (8.72 g, 29.1 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ7.68 (d, J=8.0 Hz, 2H), 7.18 (t, J=8.4 Hz, 2H), 6.72 (t, J=2.0 Hz, 2H), 6.42 (t, J=2.0 Hz, 2H).
Reaction SMILES: C([Li])CCC.C([Si](C)(C)[O:11][CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(C)(C)C.Cl[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>C1COCC1.C1(C)C=CC=CC=1>[OH:11][CH2:12][CH2:13][C:14]1[S:15][C:16]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccs1
Reactant: CC(C)OC(=O)Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1ccc(CCO)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of n-butyllithium (37 mL of a 1.6 M solution in hexanes, 59.2 mmol) was added slowly to a solution of tert-butyldimethyl(2-(thiophen-2-yl)ethoxy)silane (see U.S. Pat. No. 5,739,141; 9.5 g, 39.0 mmol) in THF (100 mL) at −78° C. After 1 h at −78° C., isopropyl chloroformate (60 mL of a 1.0 M solution in toluene, 60 mmol) was added slowly. After 1 h at −78° C., the reaction was quenched by addition of saturated aqueous NH4Cl (150 mL) and was allowed to warm to room temperature. The phases were separated and the organic phase was dried (Na2SO4), filtered (washing with excess THF) and concentrated in vacuo. The crude residue was dissolved in THF (100 mL), cooled to 0° C. and treated with tetrabutylammonium fluoride (43 mL of a 1.0 M solution in THF, 43 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was concentrated in vacuo, saturated aqueous NH4Cl (100 mL) was added and the mixture was extracted with EtOAc (3×150 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified on 330 g silica (40% EtOAc/hexanes→60% EtOAc/hexanes, gradient) to afford 6.6 g (71%) of isopropyl 5-(2-hydroxyethyl)thiophene-2-carboxylate.
Reaction SMILES: [OH:1][C@@H:2]([CH3:21])[CH2:3][C@@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)C>[C:22]([O:1][C@@H:2]([CH3:21])[CH2:3][C@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(=O)O[C@@H](C)C[C@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 47.4 %

Procedure:
0.50 g of the (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile obtained in the above Example 1 was mixed with 0.12 g of acetic anhydride, 0.51 g of triphenylphosphine and 5 ml of ethyl ether. To the obtained mixture, was added dropwise 0.34 g of diethyl azodicarboxylate under stirring. The obtained mixture was stirred at room temperature for three hours. The triphenylphosphine oxide thus precipitated was filtered and desolvated to thereby give a crude product which was purified by silica gel column chromatography with the use of a mixture of ethyl acetate and n-hexane (1:3) as a developing solvent. Thus 0.18 g of the title compound as obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12][OH:13])=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].I(O)(=O)(=O)=[O:15]>CC#N.CCOC(C)=O.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:15])=[O:13])=[CH:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: COC(=O)c1sc(CO)cc1C#N
Reactant: [O-][I+3]([O-])([O-])O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1sc(C(=O)O)cc1C#N
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of 3-Cyano-5-hydroxymethyl-thiophene-2-carboxylic acid methyl ester (0.1342 g, 0.68 mmol) and Periodic Acid (0.34 g, 1.50 mmol) in MeCN (9.5 ml) was stirred for 30 min. A solution of PCC (0.010 g, 0.015 mmol) in MeCN (0.5 ml) was added. After 1 h, the reaction mixture was diluted with EtOAc (50 ml), washed with sodium sulfite, brine, dried over sodium sulfate, filtered and evaporated. Isolate 0.13 g (90%) of beige solid.