Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])O[CH2:5]2.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[CH:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][NH:40][NH2:41])=[CH:36][CH:37]=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.C(O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[N:40]([CH2:39][CH2:38][C:35]1[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=1)[N:41]=[CH:5]2
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: NNCCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCO
Product: O=c1c2ccc(Br)cc2cnn1CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 5-bromophthalide (1.0 g, 4.7 mmol, 1.0 equiv) and NBS (850 mg, 4.7 mmol, 1.0 equiv) in carbon tetrachloride (15 mL) was treated with AIBN (50 mg, cat.) and heated to reflux overnight. The hot reaction mixture was filtered and the filtrate concentrated to a yellowish solid (1.38 g, quant.). Crude 1H NMR indicated this material contained ca. 80% of the desired 3,5-dibromophthalide, and it was carried on without further purification. An aliquot of this crude material (250 mg, 0.69 mmol, 1.0 equiv) in 95% ethanol (6 mL) was treated with phenelzine sulfate (175 mg, 0.75 mmol, 1.1 equiv) and NaHCO3 (250 mg, 2.8 mmol, 4.0 equiv). After stirring overnight at ambient temperature, the reaction mixture was diluted with diethyl ether, washed with dilute NaOH, dilute HCl, and saturated NaHCO3, then dried over Na2SO4 and concentrated. Purification of the residue using flash silica gel chromatography (gradient of 3-12% ethyl acetate/hexanes) provided 6-bromo-2-phenethyl-1-phthalazinone (147 mg, 0.45 mmol, 65%) as a white solid. This crude phthalazinone (147 mg, 0.45 mmol) was converted, via Methods 1 and 2, to compound 13 (81 mg, 62%) which was isolated as a white solid. [M-H]-=293.1 m/z. Activity: A
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].Br[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:18]/[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:34])[CH:22]=2)=[CH:13][CH:12]=1>C(N(CC)CC)C.C1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:41][C:38]1[CH:37]=[CH:36][C:35](/[C:17](/[C:14]2[CH:13]=[CH:12][C:11]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:16][CH:15]=2)=[CH:18]\[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:34])[CH:22]=2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)C(C)c1ccc(OC/C=C(\c2ccc(Cl)cc2)c2ccc(Br)cc2)cc1C
Reactant: C#CCN1CCOCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C(C)c1ccc(OC/C=C(\c2ccc(Cl)cc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C

Procedure:
Under nitrogen atmosphere, 4-propargylmorpholine (550 mg, 4.4 mmol) bis(triphenylphosphine)palladium(II) dichloride (40 mg, 0.057 mmol) and copper(II) acetate (7 mg, 0.038 mmol) were added to a degassed solution of the above ester (280 mg, 0.55 mmol) in triethylamine (30 mL). The reaction mixture was refluxed for 8 h, diluted with benzene (100 mL), filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform/methanol 9:1) yielding ethyl (Z)-[4-[3-(4-chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]propionate.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:12]([C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[O:15])[NH2:13].C(OC(OCC)OCC)C>O>[O:15]1[CH:1]=[N:13][N:12]=[C:14]1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1
Reactant: NNC(=O)c1ccc(C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: O
Product: O=C(O)c1ccc(-c2nnco2)cc1
Temperature: 100 °C
Yield: 379.7 %

Procedure:
Hydrazine hydrate was added to a solution of terephthalic acid monomethyl ester (1 g, 5.5 mmol) in MeOH (10 mL) and stirring was continued for 1 hr. The reaction mixture was concentrated to afford 900 mg (90.09% Yield) of 4-hydrazinocarbonyl-benzoic acid. p-Toluene sulfonic acid (48 mg, 0.277 mmol) was added to a solution of 4-hydrazinocarbonyl-benzoic acid (500 mg, 2.77 mmol) in triethylorthoformate (7.5 mL, 44.0 mmol) and stirring was continued with heating at 100° C. for 3 hrs. The reaction mixture was diluted with water, the solid was collected to afford 200 mg (37.9% Yield) of 4-[1,3,4]oxadiazol-2-yl-benzoic acid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([CH:6]1[S:11][C:10]2[S:12][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:14][C:9]=2[C:8](=[O:19])[CH2:7]1)[CH2:4][CH3:5].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[OH:19][CH:8]1[CH2:7][CH:6]([CH2:3][CH2:4][CH3:5])[S:11][C:10]2[S:12][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:14][C:9]1=2
Reactant: CCCC1CC(=O)c2cc(S(N)(=O)=O)sc2S1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Product: CCCC1CC(O)c2cc(S(N)(=O)=O)sc2S1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
Sodium borohydride (9.46 g, 0.25 mol) was added over 10 minutes to a stirred suspension of 4 (56.0 g, 0.19 mol) in absolute ethanol (1900 ml) under nitrogen. The mixture was refluxed for 2 hours and stirred at ambient temperature for 20 hours. After acidification with 1N hydrochloric acid (270 ml), followed by addition of saturated sodium bicarbonate solution (200 ml), the mixture was concentrated in vacuo. The residue was distributed between ethyl acetate (1000 ml) and water (600 ml), the aqueous layer was separated and extracted with ethyl acetate (2×600 ml), the combined ethyl acetate extracts were washed with saturated sodium bicarbonate, twice with water and dried over sodium sulfate. Evaporation in vacuo afforded 55.73 g (99%) of homogeneous product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](OCC2C=CC=CC=2)=[O:17])=[C:11]([Cl:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[C:11]([Cl:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1Cl)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCCc1ccc(OCc2ccccc2)cc1Cl
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of benzyl [4-(benzyloxy)-2-chlorophenyl]acetate (4.39 g) in tetrahydrofuran (80.0 mL) was added a 1 M solution of diisobutylaluminum hydride in toluene (37.0 mL) under ice-cooling under an argon atmosphere, followed by stirring for 1 hour under ice-cooling. To the reaction mixture was added a saturated aqueous Rochelle salt solution under ice-cooling. After stirring at room temperature for 2 hours, water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-[4-(benzyloxy)-2-chlorophenyl]ethanol (3.01 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=2[Cl:28])[CH:14]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=3[CH3:9])=[CH:23][C:22]=2[Cl:28])[CH:14]=1
Reactant: COC(=O)c1ccc(C)c(C(=O)c2ccc(N)cc2Cl)c1
Reactant: Cc1c(F)cccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(C(=O)c2ccc(Nc3cccc(F)c3C)cc2Cl)c1
Temperature: 120 °C
Reaction time: 60 h

Procedure:
1-Bromo-3-fluoro-2-methyl-benzene (189 mg, 1.0 mmol) was dissolved in 4 mL dry 1,4-dioxane under an argon atmosphere. Compound 402 (304 mg, 1.00 mmol) was added and dissolved in the solvent. Dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (19 mg, 0.04 mmol), Pd(OAc)2 (5 mg, 0.02 mmol) and Cs2CO3 (407 mg, 1.25 mmol) were added, and the reaction mixture was stirred under an argon atmosphere at 120° C. for 60 h. The reaction mixture was filtered and then purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:4 as the eluent to afford the title compound as a solid. 13C NMR (CDCl3) δ
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]1[C:15](=[O:16])[N:14]2[CH:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:19][CH2:20][N:13]2[C:12](=[O:28])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.C(Cl)Cl>CCOC(C)=O>[C:1]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]2[C@H:17]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:18][CH2:19][CH2:20][N:13]2[C:12](=[O:28])[CH2:11][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)C1CCCN2C(=O)CCC(N)C(=O)N12
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)OC(C)(C)C)N2C1=O
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Acetic anhydride (307 mg, 3.01 mmol) was added to a stirred mixture of t-butyl 9-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (GB 2,128,984; 813.7 mg, 2.74 mmol), diisopropylethylamine (884 mg, 6.84 mmol) and CH2Cl2 (20 ml). The mixture was kept for 1 h then diluted with EtOAc, washed with NaHCO3 solution then brine, dried (MgSO4) and concentrated to yield a colourless oil. The product was purified by flash chromatography (0.5-8% MeOH/CH2Cl2) to afford 211c (804 mg, 71%) of colourless powder: mp 162-3° C.; [α]D23 −109 (c 1.03, CH2Cl2); IR(KBr) 3358, 2974, 1733, 1693, 1668, 1528, 1462, 1431, 1406, 1371, 1278, 1271, 1250, 1233, 1217, 1154, 1124; 6 1H NMR (CDCl3) d 6.32 (1H, d), 5.29-5.25 (1H, m), 4.98-4.85 (1H, m), 4.68-4.58 (1H, m), 3.55-3.39 (1H, m), 2.91-2.66 (2H, m), 2.39-2.18 (2H, m), 2.03 (3H, s), 1.88-1.64 (4H, m), 1.47 (9H, s); Anal. Calcd for C16H25N3O5: C, 56.62; H, 7.43; N, 12.38. Found: C, 56.62; H, 7.43; N, 12.36; MS (+FAB) 340 (M++1, 40%), 284 (100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1COCC1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=2)[CH2:27][CH2:26]1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Reactant: CN1CCNCC1
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
Tris(dibenzilideneacetone)dipalladium (1.1 g, 1.2 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (0.94 g, 2.4 mmol), 4-bromo-2-trifluoromethoxy-phenylamine (30.7 g, 120 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1M in THF, 288 mL) and N-methylpiperazine (26.7 mL, 194 mmol) were added and the reaction refluxed for 1 h. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated, the residue dissolved in DCM (200 ml) and washed with water (1×100 ml). The organic phases were dried over anhydrous Na2SO4, the solvent evaporated in vacuo and the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 23 g of 4-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (70% yield) as a light brown powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[N:9]=[CH:8][C:7]3[N:13]=[N:14][N:15]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:6]=3[C:5]=2[N:4]=1.[OH:22][C@H:23]([CH3:27])[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[N:9]=[CH:8][C:7]3[N:13]=[N:14][N:15]([CH:16]4[CH2:21][CH2:20][N:19]([C:24](=[O:25])[C@H:23]([OH:22])[CH3:27])[CH2:18][CH2:17]4)[C:6]=3[C:5]=2[N:4]=1
Reactant: C[C@@H](O)C(=O)O
Reactant: Clc1ccc2ncc3nnn(C4CCNCC4)c3c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)N1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of 8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine hydrochloride (600 mg, 1.85 mmol) in DMF (15 mL) was added (R)-2-hydroxypropanoic acid (540 mg, 1.85 mmol), HATU (850 mg, 2.21 mmol) and DIEA (0.8 mL, 3.70 mmol). The mixture was stirred at room temperature overnight. Another 3 eq of HATU and 2 eq of DIEA were added because the reaction did not go to completion as shown by HPLC-MS. The mixture was stirred for another 30 min, and was then diluted with water. The resulting mixture was extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous Na2SO4, and concentrated to give the crude product, which was subsequently purified by chromatography on silica gel using EtOAc:PE as eluent to afford (R)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one as a yellow solid (136 mg, yield 20.4%). MS (m/z): 361 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:40][CH:26]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37]CC)=[O:36])=[CH:31][CH:30]=1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[CH:31][CH:30]=1)[CH2:40][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(OCC2CO2)cc1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COc2ccc(C(=O)O)cc2)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(2-ethoxycarbonyl)-phenoxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 13 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted to pH 7 with 5N hydrochloric acid and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:7][CH2:6]1)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[S:27])[NH2:26])=[CH:20][CH:19]=1>C(O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][C:25]2[S:27][CH:2]=[C:3]([CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:7][CH2:6]3)[N:26]=2)=[CH:22][CH:23]=1
Reactant: C=CCOC(=O)N1CCC(C(=O)CBr)CC1
Reactant: NC(=S)Cc1ccc(Cl)cc1
Solvent: CCO
Product: C=CCOC(=O)N1CCC(c2csc(Cc3ccc(Cl)cc3)n2)CC1

Procedure:
A mixture of allyl 4-(bromoacetyl)piperidine-1-carboxylate (547 mg) and 2-(4-chlorophenyl)ethanethioamide (366 mg) in ethanol (15 ml) was refluxed for 5 hours. The reaction mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with methanol/dichloromethane (2:98) to give allyl 4-[2-(4-chlorobenzyl)-1,3-thiazol-4-yl]piperidine-1-carboxylate. Yield 698 mg. NMR (CDCl3): 1.65 (m, 2H), 2.25 (m, 2H), 2.95 (m, 2H), 3.2 (m, 1H), 4.3 (m, 2H), 4.55 (m, 4H), 5.3 (m, 2H), 6.0 (m, 1H), 6.95 (s, 1H), 7.35 (m, 4H).
Reaction SMILES: [OH-:1].[Na+].OO.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C@H:13]([C:15]2[N:16]([CH3:32])[C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[C:28]([F:31])([F:30])[F:29])=[N:18][N:19]=2)[CH3:14])=[N:10][CH:11]=1.O>C(O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C@H:13]([C:15]2[N:16]([CH3:32])[C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:1])=[CH:22][C:21]=3[C:28]([F:31])([F:29])[F:30])=[N:18][N:19]=2)[CH3:14])=[N:10][CH:11]=1
Reactant: [OH-]
Reactant: C[C@H](Oc1ccc(Br)cn1)c1nnc(-c2ccc(C#N)cc2C(F)(F)F)n1C
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H](Oc1ccc(Br)cn1)c1nnc(-c2ccc(C(N)=O)cc2C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1M aqueous sodium hydroxide solution (0.73 ml) and a 30% hydrogen peroxide solution (0.1 ml) were added to a solution of 4-(5-{(1S)-1-[(5-bromopyridin-2-yl)oxy]ethyl}-4-methyl-4H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)benzonitrile (50 mg) in ethanol (3 ml) in an ice bath, followed by stirring at room temperature for 3 hours, and a 1M aqueous sodium hydroxide solution (0.42 ml) was added thereto, followed by stirring overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate (1 ml) was added to the residue and the precipitated solid was washed with ethyl acetate and then diethylether to obtain, as a white solid 4-(5-{(1S)-1-[(5-bromopyridin-2-yl)oxy]ethyl}-4-methyl-4H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)benzamide (29.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[CH:15][C:3]=1[C:4]([O:6]CC1C=CC=C(Cl)C=1)=[O:5].[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[CH:15][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(OCc1cccc(Cl)c1)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A solution of (3-chlorophenyl)methyl 2-chloro-5-{[(3-chlorophenyl)methyl]oxy}benzoate (970 mg, 2.3 mmol) in dioxane (30 ml) and water (15 ml) was treated with lithium hydroxide (monohydrate) (145 mg, 3.5 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 2 hours. The solvent was then evaporated in vacuo, the residue take up into water (50 ml) and washed with ether (100 ml). The aqueous layer was then acidified with 2M HCl the extracted with ether (2×150 ml). Organic layers combined, washed with brine, dried and evaporated in vacuo to afford the title product as a white solid (600 mg). MS (ES−) m/z 295 [M−H]− (C14H1035Cl2O3). 1H-NMR (400 MHz, d6-DMSO) δ 5.17 (2H, s), 7.17-7.20 (1H, m), 7.38-7.53 (6H, m), 13.4 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[ClH:13].[CH3:14][CH2:15]O>>[ClH:13].[CH2:14]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:9][C:10]([OH:12])=[O:11])[CH3:15]
Reactant: O=C(O)CNc1ccc(O)cc1
Reactant: CCO
Agent: Cl
Product: CCN(CC(=O)O)c1ccc(O)cc1
Yield: 70 %

Procedure:
To a suspension of 4-hydroxyphenylglycine (18.00 g, 0.11 mol) in EtOH (100 mL) was added 20% ethanolic HCl (30 mL). The mixture was heated at reflux for 14 h, then was allowed to cool and was concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc, and the organic extract was concentrated in vacuo to afford the tide compound (15.00 g, 70%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[O:11][C@H:10]1[N:23]1[CH:38]=[C:37](I)[C:27]([NH:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])=[N:26][C:24]1=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:40][Si:41]([C:44]#[CH:45])([CH3:43])[CH3:42]>C(Cl)Cl.CCN(CC)CC.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>[Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[O:11][C@H:10]1[N:23]1[CH:38]=[C:37]([C:45]#[C:44][Si:41]([CH3:43])([CH3:42])[CH3:40])[C:27]([NH:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])=[N:26][C:24]1=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-iodo-N4 -(n-pentyloxycarbonyl)cytidine (130 mg, 0.18 mmol) in CH2Cl2 (2 ml) and Et3N(2 ml) Cul (10.7 mg, 0.1056 mmol), Pd(PPh3)2Cl2 (2.6 mg, 0.0036 mmol), and trimethylsilyl-acetylene (58.6 μl, 0.40 mmol) were added and stirred for 2 hours at room temperature under Ar in the dark. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc(25 ml×3), washed with 2% aq. EDTA.2Na(10 ml×2), water and brine, dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography on SiO2 (eluent: 10% EtOAc/n-hexane) to give 2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-[(trimethylsilyl)ethynyl]-N4 -(n-pentyloxycarbonyl)-cytidine as a colorless amorphous solid. (30.2 mg, 26% yield)
Reaction SMILES: Cl[C:2]1(Cl)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:11].C(O)(=O)C.O>CCOCC.[Zn]>[CH2:4]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:2][C:3]1=[O:11]
Reactant: O=C1CC2(CCOCC2)C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: O=C1CC2(CCOCC2)C1
Reaction time: 24 h

Procedure:
The impure 1,1-dichloro-7-oxaspiro[3.5]nonan-2-one from Step B was stirred with zinc (150 mg; 2.30 mmol) and 5 mL of acetic acid/water (1:1) for 4 hours. The mixture was stored at −20° C. for 1 day, diluted with ether (20 mL) and filtered through a pad of Celite®. The solution was neutralized with aqueous sodium bicarbonate solution and extracted into ether (5×20 mL). The combined ether extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The material was purified by chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane to give the product as a colorless oil (61 mg).