Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.Br.[Br:50][CH2:51][C:52]([CH3:56])([CH3:55])[CH2:53][NH2:54].C(N(CC)CC)C>CN(C=O)C>[Br:50][CH2:51][C:52]([CH3:56])([CH3:55])[CH2:53][NH:54][C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:26]
Reactant: CC(C)(CN)CBr
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCC(C)(C)CBr)c2n1
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To a solution of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B; 150 mg, 0.420 mmol), EDCI (88.5 mg, 0.462 mmol), and HOBT-H2O (70.7 mg, 0.462 mmol) in DMF (10 mL) was added 3-bromo-2,2-dimethylpropan-1-amine hydrobromide (124 mg, 0.504 mmol) followed by triethylamine (55.2 mg, 0.546 mmol). The reaction was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 50% EtOAc/Hexanes to provide (R)-N-(3-bromo-2,2-dimethylpropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (180 mg), to which was added HCl (5 mL, 4M in dioxane). The reaction was sealed and heated to 90° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 20% Hexanes/EtOAc to provide the desired product (130 mg, 63% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:21](=[O:24])(=[O:23])[NH2:22])[C:12]=1[NH:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([OH:9])=[O:8])([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:21](=[O:24])(=[O:23])[NH2:22])[C:12]=1[NH:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccccc1Nc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Cc1ccccc1Nc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
By substituting 3-nitro-5-sulphamyl-4-(o-toluidino)-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15]C(OC(C)(C)C)=O)[CH:6]=1.OS(O)(=O)=O>CO.O1CCOCC1>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: Cc1cn(CCc2ccccc2NC(=O)OC(C)(C)C)cn1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cn(CCc2ccccc2N)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
2-(4-Methyl-1H-imidazol-1-yl)-1-[2-[(tert-butoxycarbonyl)amino]-phenyl]ethane (2.555 g) from Step B above was dissolved in methanol (20 mL) and 10% conc. H2SO4 in dioxane (v/v) (40 mL) was added. The solution was stirred at 25° C. for 4 h. The solution was diluted with methanol and BioRad AG® 1-X8 (OH−) resin was added until the pH was basic. The resin was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on silica gel using 4% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (1.605 g, 94%): ESMS: m/z 202.0 (MH+); δH (CDCl3) 2.20 (3H, s, 4-CH3), 2.90 (2H, dd, 1-CH2), 3.33 (2H, bs, NH2), 4.09 (2H, dd, 2-CH2), 6.60 (1H, s, Im-H5), 6.68 (1H, d, Ar—H6), 6.74 (1H, dd, Ar—H4), 6.92 (1H, d, Ar—H3), 7.08 (1H, dd, Ar—H5) and 7.22 ppm (1H, s, Im-H2); δC (CDCl3) CH3: 13.8; CH2: 33.7, 46.7; CH: 115.2, 116.3, 119.4, 128.2, 130.1, 136.3; C, 122.3, 138.7, 144.5.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].C([Li])CCC.CCCCCC.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24]>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][C:23](=[O:24])[C:22]([F:29])([F:28])[F:21])[CH3:2]
Reactant: C#CC(OCC)OCC
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(C#CC(=O)C(F)(F)F)OCC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
3,3-Diethoxy-1-propyne (10 mL, 70 mmol) was dissolved under argon in THF (200 mL) and cooled to −70° C. Then a 1.6 M solution of n-butyllithium in hexane (48 mL, 77 mmol) was added slowly at −70° C., then allowed to warm to −30° C. and stirred at −30° C. for 30 min, then cooled again to −70° C. Ethyl trifluoroacetate (9.2 mL, 77 mmol) was added in one portion at −70° C. (the temperature rose to −50°) then stirred without cooling until −30° C. was reached, then quenched with sat. NH4Cl solution (20 mL). Extraction: 2×AcOEt, 1× sat. NH4Cl sat., 1× sat. NaCl. Chromatography on silica gel in heptane/ethyl acetate 5:1 afforded 4.94 g (31%) of an orange oil. GC/MS: m/z=223 (M−H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:9][N:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNc1ccccc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(CCCCCCO)c1ccccc1
Yield: 51.8 %

Procedure:
6-Chlorohexyl alcohol (1.4 g), N-methylaniline (1.1 g) and sodium carbonate (1.1 g) were heated at 120° C. for 9 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.1 g of 6-(N-methy-N-phenylamino)hexyl alcohol.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH2:7][N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[C:9]2[C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=2[CH3:29])=[N:4][N:3]=[N:2]1.[OH-:30].[Na+].OO>CS(C)=O.O>[NH:4]1[C:5]([CH2:6][CH2:7][N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[C:9]2[C:21]2[CH:28]=[CH:27][C:24]([C:25]([NH2:26])=[O:30])=[CH:23][C:22]=2[CH3:29])=[N:1][N:2]=[N:3]1
Reactant: COc1ccc(-c2ccn(CCc3nnn[nH]3)c2-c2ccc(C#N)cc2C)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2ccn(CCc3nnn[nH]3)c2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.2 %

Procedure:
To a solution of 4-(1-(2-(1H-tetrazol-5-yl)ethyl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzonitrile (9J, R=2-(1H-tetrazol-5-yl) ethyl) (250 mg, 0.65 mmol) in DMSO (5 mL) was added a solution of NaOH (52 mg, 1.3 mmol) in a mixture of water (0.5 mL) and H2O2 (74 mg, 0.65 mmol). After being stirred at room temperature for 4 hours, the mixture was purified by preparative HPLC to give 24 mg of 4-(1-(2-(1H-tetrazol-5-yl)ethyl)-3-(4-methoxyphenyl)-1H-pyrrol-2-yl)-3-methylbenzamide (9K, R=2-(1H-tetrazol-5-yl) ethyl) (yield 9% in two steps) as a grey solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([OH:11])[CH2:8][C@H:7]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:8][C@H:7]1[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O)C[C@H]1COc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)C[C@H]1COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 96.6 %

Procedure:
To a cold (ice bath) solution of (1R,2R)-2-(4-Chloro-phenoxymethyl)-4-hydroxy-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, 312 mg) and triethylamine (528 mg) in dichloromethane (6 mL) was added methanesulfonyl chloride (580 mg). The reaction mixture was stirred 36 h at room temperature then hydrochloric acid (1N) was added. The reaction mixture was extracted with dichloromethane. The combined organic layers were washed with an aqueous half-saturated solution of sodium carbonate and half saturated brine then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethylacetate (3:1 to 3:1 v/v) as eluant to afford the title compound (0.380 g, 97%) as a light yellow oil. MS (EI): 377.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:15]3[N:10]([N:11]=[C:12]([OH:27])[CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:31]([F:33])[F:32].O>CN(C)C=O>[F:32][CH:31]([F:33])[O:27][C:12]1[CH:13]=[CH:14][C:15]2[N:10]([N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)[N:11]=1
Reactant: FC(F)Br
Reactant: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3nc(O)ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3nc(OC(F)F)ccc23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazin-6-ol (0.2 g) in anhydrous dimethyl formamide (5 ml) was treated with sodium hydride ( 0.046 g, 60% dispersion in mineral oil), after effervescence ceased a stream of bromodifluoromethane gas was passed through the mixture at ambient temperature for 30 minutes. The reaction mixture was then poured into water (50 ml) and extracted with ethyl acetate (50 ml), the organic extract was washed with water (3×50 ml), dried and concentrated in vacuo. The residue was purified by chromatography to give the title compound as a white solid (0.17 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)CCO.[Cl-].[Na+].O.[Cu]>[CH3:18][N:17]([CH3:19])[C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:3][N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]3=[N:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CN(C)c1ccc(-c2cnc3c(c2)c(Br)cn3COCC[Si](C)(C)C)cc1
Reactant: C1COCCN1
Agent: [Cu]
Agent: CN(C)CCO
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: CN(C)c1ccc(-c2cnc3c(c2)c(N2CCOCC2)cn3COCC[Si](C)(C)C)cc1
Temperature: 120 °C
Yield: 17.7 %

Procedure:
A mixture of 60 (0.055 g, 0.12 mmol), morpholine (0.021 mL, 0.24 mmol), tri-potassium phosphate monohydrate (0.057 g, 0.25 mmol), and copper (powder) (0.00078 g, 0.012 mmol) in N,N-dimethylethanolamine (1 mL) was heated at 120° C. for 2 days. The mixture was cooled and poured into brine and extracted with AcOEt. The organic layer was washed with brine twice, dried (MgSO4), concentrated, and purified by means of preparative TLC with hexane:AcOEt as eluent to afford 61 (0.0096 g, 17%) as a tan syrup. 1H NMR (400 MHz, CDCl3) δ 0.00 (s, 9H), 0.88-0.95 (m, 2H), 3.01 (s, 6H), 3.07-3.14 (m, 4H), 3.51-3.57 (m, 2H), 3.91-3.97 (m, 4H), 5.63 (s, 2H), 6.82-6.88 (m, 3H), 7.48-7.53 (m, 2H), 8.00 (d, J=0.21 Hz, 1H), 8.52 (d, J=0.21 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([Cl:18])=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:19])=[C:4]([F:22])[CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([Cl:18])=[CH:13][CH:14]=3)[N:9]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:8]2=[O:19])=[C:4]([F:22])[CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)n1Cc1ccc(Br)cc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Cl)cc21
Yield: 89.8 %

Procedure:
A solution of 3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (500 mg), ethyl bromoacetate (218 mg) and potassium carbonate (360 mg) in N,N-dimethylformamide (5 ml) was stirred at 30° C. for 30 minutes. The solution was evaporated and the residue was dissolved in ethyl acetate. The solution was washed in turn with 0.5N aqueous hydrochloric acid and water, and then dried over magnesium sulfate. The solvent was removed in vacuo to give a crystalline residue, which was crystallized from a mixture of ethyl acetate and n-hexane to give ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (550 mg).
Reaction SMILES: C1COCC1.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:17]=[C:18]([Br:22])[CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)([O-])=O.[BH4-].[K+]>CO>[NH2:6][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:17]=[C:18]([Br:22])[CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Sc2cccc(Br)c2)cc1
Agent: [BH4-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Sc2cccc(Br)c2)cc1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
To a THF (15 mL) solution of 3-(p-nitrobenzenethioxy)bromobenzene (2.0 g, 6.4 mmol), prepared as in step 1, was added methanol (50 mL) and CuC1 (0.89 g, 99%, 9.0 mmol). The solution was cooled to ~10° C. in an icebath and solid potassium borohydride (1.13 g, 21 mmol) was added in small portions while maintaining the reaction temperature below 20° C. After complete addition of potassium borohydride the icebath was removed. The reaction was judged to be complete after 20 min and was quenched by adding water (40mL) while maintaining the reaction temperature under 20° C. The quenched reaction mixture was filtered through celite and partitioned between ether and water. After separating the layers the aqueous layer was extracted three times with ether. The combined organic layers were washed twice with brine and concentrated to 1/2 the original volume. The solution was treated with decolorizing carbon while drying over MgSO4, filtered through a celite pad, and concentrated in vacuo to give 3-(p-aminobenzenethioxy)bromobenzene (1.81 g, 101%) as a waxy red solid which was carried on without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:9])=[N:6][C:7]=1[CH3:8].[CH3:11][CH:12]1[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH2:15][CH2:14][NH:13]1>CN(C)C=O>[CH3:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][C:16]3[CH:20]=[CH:19][S:18][C:17]=3[CH:12]2[CH3:11])=[N:4][C:5]([Cl:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Cl)nc(Cl)c1C
Reactant: CC1NCCc2ccsc21
Solvent: CN(C)C=O
Product: Cc1nc(Cl)nc(N2CCc3ccsc3C2C)c1C
Yield: 39.4 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that N,N-dimethylformamide(20 ml), 5,6-dimethyl-2,4-dichloropyrimidine(2.8 g, 16 mmol) prepared in Step 1 of Example 12 and 7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2.7 g, 17.6 mmol) in Preparation 2 were used as starting materials, 1.85 g of the titled compound was prepared. (Yield: 39.4%)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([OH:20])(=[O:19])[CH2:9][C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1>O>[C:1]([O:16][C:15]1[CH:17]=[CH:18][C:10]([CH2:9][C:8]([OH:20])=[O:19])=[CH:11][C:12]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc(CC(=O)O)ccc1OC(C)=O
Reaction time: 8 h

Procedure:
Specifically, acetic anhydride (120 mL) was added to 30.0 g (165 mmol) homovanillic acid and the mixture was allowed to reflux for 6 hours. The solvent was evaporated, leaving an oil which was poured into 1L H2O and allowed to stir overnight. The solid was collected and dried in vacuo to give 33.1 g of 4-acetoxy-3-methoxyphenylacetic acid.
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([Br:13])[CH:12]=1)[C:8]#[N:9]>CN1C(=O)N(C)CCC1.O>[Br:13][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([O:2][CH3:1])[CH:12]=1)[C:8]#[N:9]
Reactant: C[O-]
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: COc1cc(Br)cc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Sodium methoxide (2.02 g) was added to a stirred solution of 3-fluoro-5-bromobenzonitrile (5.0 g) in DMPU (20 ml) and stirred at RT for 2 h. The reaction was diluted with water and the resulting solid formed was filtered and washed with water, then dried in vacuo to give the subtitle compound (5.10 g).
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:29][C:30]1[CH:31]=[C:32]([CH:44]=[CH:45][CH:46]=1)[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:32]3[CH:44]=[CH:45][CH:46]=[C:30]([F:29])[CH:31]=3)=[CH:40][CH:39]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reactant: OB(O)c1ccc(OCc2cccc(F)c2)cc1
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: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3cccc(F)c3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 2 h
Yield: 64.9 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0443 g, 0.097 mmol), (4-((3-fluorobenzyl)oxy)phenyl)boronic acid (0.036 g, 0.146 mmol) and 2M Na2CO3 (0.122 ml, 0.243 mmol) in DMF 92 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.011 g, 9.73 μmol) was added, degassed for 5 min and placed in a oil bath pre-heated to 110 C. After 2 h, cooled and purified by pre-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((3-fluorobenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0361 g, 0.063 mmol, 64.3% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.39 (dt, J=5.8, 7.9 Hz, 1H), 7.24-7.27 (m, 1H), 7.22 (dd, J=2.1, 9.5 Hz, 1H), 7.17-7.20 (m, 1H), 7.02-7.10 (m, 4H), 6.03 (br. s., 1H), 5.12-5.20 (m, 2H), 4.23-4.31 (m, 1H), 4.19 (qd, J=7.1, 10.7 Hz, 1H), 3.06-3.28 (m, 1H), 2.85 (br. s., 1H), 2.65 (br. s., 3H), 2.26 (br. s., 3H), 1.96-2.11 (m, 1H), 1.27 (t, J=7.1 Hz, 4H), 1.20 (s, 9H), 0.90 (br.s., 3H), 0.66 (br. s., 3H). 5H of piperidine were not resolved. LCMS (M+H)=577.4.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH:4]([O:12][CH:13]1[CH2:16][NH:15][CH2:14]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH:4]([O:12][CH:13]1[CH2:14][N:15]([C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:16]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1
Reactant: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2Cl)cc1
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a stirred solution of 3-(2,4,4′-trichlorobenzhydryloxy)azetidine (4) (3 mmol) in dichloromethane (10 mL) was added tert-butyl isocyanate (3 mmol) and triethylamine (catalytic amount) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was eluted through a pre-wetted (CH2Cl2) SCX-2 (2 g) cartridge with dichloromethane to yield the desired product as a white foam (424 mg, 33%).
Reaction SMILES: [CH2:1]([C@H:4]([C@H:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3].Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:18][C@@H:11]([C@@H:4]([CH2:1]/[CH:2]=[CH:3]/[C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=1)[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13]
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: C=CC[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Product: CC(C)OC(=O)[C@@H](O)[C@@H](C/C=C/c1ccc(OC(F)(F)F)cc1)C(=O)OC(C)C
Temperature: 80 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a solution of diisopropyl (2R,3S)-2-allyl-3-hydroxybutanedioate (Intermediate 2a, 5.0 g; 19.4 mmol; 1.0 eq.), TEA (6.23 mL; 46.5 mmol; 2.4 eq.) in CH3CN (50.0 mL) was added 1-bromo-4-(trifluoromethoxy)benzene (5.13 g; 21.3 mmol; 1.1 eq.). To this solution was added a sonicated mixture of tri-o-tolylphosphine (0.59 g; 1.94 mmol; 0.10 eq.) and palladium(II) acetate (43.46 mg; 0.19 mmol; 0.01 eq.) in CH3CN (4 mL). The reaction was stirred at 80° C. for 14 h, cooled to RT and the solvents were evaporated (rotavap). The residue was taken up in EtOAc and washed with an aqueous saturated solution of NH4Cl, an aqueous saturated solution of NaHCO3 and then with an aqueous saturated solution of NaCl and dried over MgSO4. Evaporation of the solvent gave an oil. Purification by chromatography (SiO2, gradient from 10/90 EtOAc/c-hex to 100/0 EtOAc/c-hex in 30 min.) gave a colorless oil (6.98 g, 86.2%). M+(ESI): 419.2; M−(ESI): 417.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[Na].[CH3:10][NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>CO>[CH3:10][N:11]1[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:2][C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12]1
Reactant: N#Cc1ccncc1
Reactant: CNNC(=O)c1cccnc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(-c2cccnc2)nc1-c1ccncc1
Reaction time: 0.5 h

Procedure:
To 4-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.). The solution is allowed to stand 0.5 hours at ambient temperature and is then added to a solution of 1-methyl-2-nicotinoyl-hydrazine (3 g.) in methanol (30 ml.). The reaction mixture is heated 5 hours at reflux and is concentrated to an oil which solidifies. After chromatography on silica gel and recrystallization from acetonitrile 0.8 g. of 1-methyl-3-(3-pyridyl)-5-(4-pyridyl)-1,2,4-triazole melting 132°-133° C is obtained.