Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]2([CH2:20][O:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([Mg]Br)[CH:37]=[CH:38][CH:39]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C:13]2([CH2:20][O:21][S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:24])=[O:23])[CH2:18][CH2:17][C:16]([OH:19])([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([O:33][CH3:32])[CH:39]=3)[CH2:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCC(=O)CC2)cc1
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCC(COS(=O)(=O)c3ccc(C)cc3)(COS(=O)(=O)c3ccc(C)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of (4-oxocyclohexane-1,1-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (417 mg, 0.894 mmol) in THF (5 mL) at 0° C. was added 3-methoxyphenylmagnesium bromide (1.073 mL, 1.073 mmol) dropwise over a period of 5 min. The reaction was stirred at 0° C. for 2 h and quenched with sat′d aqueous NH4Cl (1 mL). The mixture was diluted with EtOAc (10 mL) and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residual crude oil was purified by flash chromatography on SiO2 (0-50% EtOAc:hexanes) to afford the title compound (372 mg, 72% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.76 (dd, J=10.9, 8.3 Hz, 4H), 7.37 (d, J=7.7 Hz, 4H), 7.23 (t, J=8.0 Hz, 1H), 6.93-6.88 (m, 1H), 6.88-6.82 (m, 1H), 6.78 (dd, J=8.1, 2.3 Hz, 1H), 4.00 (s, 2H), 3.81-3.78 (m, 5H), 2.47 (s, 3H), 2.43 (s, 3H), 1.79 (s, 1H), 1.73-1.60 (m, 2H), 1.61-1.53 (m, 4H), 1.53-1.45 (m, 2H).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:44][C:45]1([C:52]([O:54][CH3:55])=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.Cl>CN(C=O)C.O.C(Cl)CCl>[CH3:55][O:54][C:52]([C:45]1([NH:44][C:15]([C:13]2[CH:12]=[CH:11][C:10]3[N:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[C:7]([CH2:18][C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[N:8][C:9]=3[CH:14]=2)=[O:16])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:53]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Reactant: COC(=O)C1(N)CCCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)NC3(C(=O)OC)CCCCCC3)ccc21
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To a solution of 160 mg of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid (The preparation of intermediates is described below) in 3 ml of dry DMF 73 mg of HOAT, 131 mg of EDC and 0.16 ml of DIPEA were added at 0° C. After 15 min 100 mg of methyl 1-amino-cycloheptanecarboxylate-hydrochloride and 0.16 ml of DIPEA were added and the reaction was stirred at it for 16 h. The reaction was then poured into water and the pH was adjusted to 3 by the addition of 2 M aqueous hydrochloric acid. The reaction was extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. The crude product was purified by HPLC to yield 200 mg (85%) of 1-{[1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzimidazole-5-carbonyl]-amino}-cycloheptanecarboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:31])[C@H:16]([N:18]2[CH2:23][CH2:22][C:21]([OH:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:31])[C@@H:16]([N:18]2[CH2:23][CH2:22][C:21]([OH:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](C(=O)c1ccc(OCc2ccccc2)cc1)N1CCC(O)(c2ccccc2)CC1
Solvent: CO
Product: C[C@@H](C(=O)c1ccc(OCc2ccccc2)cc1)N1CCC(O)(c2ccccc2)CC1

Procedure:
Under a nitrogen atmosphere, (2S)-1-(4-benzyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanone dibenzoyl D-tartrate salt (150.0 g, 0.19 mol) was suspended in ethyl acetate (0.45 L, 3.0 mL/g of tartrate salt) and water (0.75 L, 50 mL/g of tartrate salt) containing NaHCO3 (51.0 g, 0.61 mol). The mixture was stirred for 2 hours at 20 to 25° C. while CO2 was liberated (pHf=8.1). Stirring was stopped and the clear layers were allowed to separate. The lower aqueous layer was separated and then the ethyl acetate layer was concentrated to 0.1 L at 25 to 30° C. under reduced pressure. The concentrate was slowly added over 2 hours to hexanes (0.5 L) cooled to 15 to 20° C., The slurry was concentrated to 0.4 L, the solids were granulated for 1 hour at 15 to 20° C., filtered, and then washed with additional hexanes (80 mL). (2S)-1-(4-benzyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanone was dried in vacuo for 12 hours at 40 to 45° C. to give 77.8 g of white free base in 96.7% yield. M.p. 102.5-103.8; [α]D25+18.9 (c 8.9, CH3OH). 1H NMR (CDCl3) δ 8.13 (d, J=8.7 Hz, 2H) 7.2-7.4 (m, 10H), 7.00 (d, J=8.7 Hz, 2H), 5.13 (s, 2H), 4.11 (g, J=6.8 Hz, 1H), 2.6-2.9 (m, 4H), 2.0-2.2 (m, 2H), 1.7-1.8 (m, 2H), 1.31 (d, J=6.8 Hz, 3H). 13C NMR (CDCl3) δ 199.69, 162.75, 136.47, 131.49, 129.72, 128.96, 128.55, 128.50, 127.77, 127.23, 124.80, 114.58, 71.44, 70.34, 64.78, 47.83, 44.62, 39.14, 38.79, and 12.28. Chiral HPLC showed that the (−) enantiomer, (2R)-1-(4-benzyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanone was present at 1.2%.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:7][CH2:8][C:9]([O:11]C)=[O:10])[C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CO.C1COCC1.O>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:1])([CH3:13])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: COC(=O)CCC(C)(C)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CCC(=O)O
Temperature: 25 °C
Reaction time: 68 h

Procedure:
To a solution of dimethyl 2,2-dimethylpentanedioate from Step A (25.4 g, 135 mol) in MeOH (150 mL), THF (100 mL) and water (100 mL), was added potassium carbonate (36.2 g, 262 mmol). This biphasic solution was allowed to stir for 68 h, at ambient temperature, after which time the reaction was about 50% complete. Solvents were carefully removed in vacuo such that the starting materials did not vaporize. The aqueous layer was diluted with water (266 mL) and then extracted with diethyl ether until no additional SM was detected in the aqueous layer. The aqueous layer was made acidic by the addition of 6 M HCl (95 mL), and was then saturated with NaCl. This aqueous layer was extracted once with diethyl ether (250 mL). This ethereal layer was washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound. MS: m/z=175 (M+1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:35]1([C:40](O)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:35]1([C:40]([NH:2][C@@H:3]2[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)[CH2:5][CH2:4]2)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)C1CCCC1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C3CCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 98.6 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by cyclopentanecarboxylic acid (32 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-[cis-4-(cyclopentanecarbonyl-amino)-cyclohexyl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (113 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>C1COCC1>[F:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2nc(F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C(=O)OC(C)(C)C)c3ccc(F)nc32)cc1
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 6-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (29.55 g, 125 mmol) in THF (300 mL) cooled in an ice bath was added KOtBu (13.98 g, 125 mmol) at such a rate as to maintain the temperature between 5-10° C., and then 4-methoxybenzyl bromide (18.2 mL, 125 mmol) was added. The resulting mixture was stirred in an ice bath for 1 hour and then stirred at room temperature for 18 hours. The resulting suspension was quenched with saturated aqueous NH4Cl (200 mL) and then extracted with EtOAc (2×300 mL). The combined organic extracts were washed with brine, dried with MgSO4 and the solvent removed in vacuo. The resulting residue was purified on a silica gel (1000 g) column (0-11% EtOAc/hexanes) to give the title compound. LRMS (M+1)=380.1
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(OO)(=[O:16])C.O>C(Cl)Cl>[C:8]1([CH2:7][CH:1]2[CH2:6][CH2:5][CH:4]3[CH:3]([O:16]3)[CH2:2]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OO
Reactant: C1=CCC(Cc2ccccc2)CC1
Solvent: O
Solvent: ClCCl
Product: c1ccc(CC2CCC3OC3C2)cc1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 9.55 g (0.056 mol) of (3-cyclohexen-1-ylmethyl)benzene, and 90 mL of methylene choride. Peracetic acid (17.5 g, 35 wt. % in acetic acid; 0.073 mol) in methylene chloride (70 mL) was added dropwise to the above mixture over 25 min. in an ice bath. After the above mixture was reacted at room temperature for 7 hrs., 200 mL of water was added to the above reaction mixture, the water layer was extracted with chloroform (2×150 mL). The organic layer was combined, washed with saturated sodium carbonate solution (2×150 mL), then with water (2×150 mL), and dried with sodium sulfate. The solvent was evaporated and the residue was vacuum distilled to give pure product.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([CH2:23][C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:22]=[C:17]4N=N3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-:30].[NH4+]>O>[N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH:14][C:18]3[C:17]([OH:30])=[CH:22][C:21]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][N:19]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: c1cncc(Cc2cnc3c(c2)nnn3CCCC2CCCc3cccnc32)c1
Agent: [NH4+]
Solvent: O
Product: Oc1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Reaction time: 0.83 h

Procedure:
A mixture of 3-[3-(5,6,7,8-tetrahydroquinol-8-yl)-propyl]-6-(pyrid-3-ylmethyl)-3H-1,2,3-triazolo[5,4-b]-pyridine (3.56 g) and polyphosphoric acid (17.5 g) were heated with stirring at 188°-197° C. for 50 minutes. Water (30 ml) was added to the hot residue and, after slight cooling, the solution was basified with aqueous ammonium hydroxide to pH 10 and then extracted with chloroform. The combined chloroform extracts were dried over magnesium sulphate, concentrated in vacuo and the residue was chromatographed on silica eluted with 5% v/v methanol in chloroform to give the title compound as a brown gum (0.68 g). The aqueous portion after extraction, was concentrated to dryness, to give a paste, water (100 ml) was then added, the mixture was refluxed for 1 hour and a brown oil which formed was extracted with chloroform (3 x 100 ml). The extracts were dried, combined and concentrated to give a further quantity of the title compound as an oil (0.31 g). The two portions of the product were combined, converted to the trihydrochloride with ethanolic HCl and then recrystallised, first from isopropanol and then from isopropanol/methanol to give the title compound as a buff solid (0.5 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][N:7]1[CH2:10][CH:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8]1)[CH2:3][OH:4].C1([O:25][C:26](=O)[NH:27][C:28]2[N:29]([CH3:35])[N:30]=[C:31]([CH2:33][CH3:34])[CH:32]=2)C=CC=CC=1>CS(C)=O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH:9]2[CH2:10][N:7]([CH2:6][CH2:5][C@H:2]([NH:1][C:26]([NH:27][C:28]3[N:29]([CH3:35])[N:30]=[C:31]([CH2:33][CH3:34])[CH:32]=3)=[O:25])[CH2:3][OH:4])[CH2:8]2)=[CH:17][CH:16]=1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)n(C)n1
Solvent: CS(C)=O
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1

Procedure:
A solution of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol (0.45 g, 2 mmol) and (5-Ethyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester (0.49 g, 1.66 mmol) in DMSO (5 ml) is stirred at ambient temperature for 1 hour, then partitioned between water and ethylacetate. The organic phase is dried over MgSO4 and evaporated. The crude product is purified by recrystallisation from hot ethylacetate to afford 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea.
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[Cl:16][CH2:17][CH2:18][O:19][CH:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:21]([OH:23])=O.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[NH:32][NH2:33].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:16][CH2:17][CH2:18][O:19][CH:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:21]([NH:33][NH:32][C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:23]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)C(OCCCl)c1ccc(F)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=O)C(OCCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride (4.38 g) was added to a solution of (2-chloroethoxy)-(4-fluorophenyl)acetic acid (2 g), tert-butyl carbazate (2.27 g) and triethylamine (3.58 mL) in tetrahydrofuran (20 mL), and the reaction solution was stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex, elution solvent: heptane/ethyl acetate) to obtain the title compound (2.8 g). The property values of the compound are as follows.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](=[O:22])[CH:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[N+:2]=[N-:3].[H-].[K+].[CH2:25]([N:27]([CH2:30][CH2:31]Cl)[CH2:28][CH3:29])[CH3:26]>CN(C)C=O.C(OCC)(=O)C>[N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([O:22][CH2:26][CH2:25][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[N+:2]=[N-:3]
Reactant: CCN(CC)CCCl
Reactant: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOC1=C(C(=O)OCc2ccccc2)N2C(=O)C(N=[N+]=[N-])C2C1
Temperature: 0 °C

Procedure:
An ice-cold solution of benzyl 6-azido-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (1 mmol) in anhydrous dimethylformamide (1 ml) is added dropwise to an ice-cold mixture of potassium hydride (1 mmol) in anhydrous dimethylformamide (4 ml). After stirring for several minutes in the cold and under nitrogen, the mixture is treated with diethylaminoethyl chloride and stirred in the cold for 2 hr. The mixture is diluted with ethyl acetate, washed thoroughly with water and brine, dried over magnesium sulfate, and filtered. Evaporation of the solvent in vacuo gives benzyl 6-azido-3-(2-diethylaminoethyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]#[N:25]>C(O)C.N1CCCCC1>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[CH:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=1)[C:24]#[N:25]
Reactant: N#CCc1ccccn1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1cc(C=C(C#N)c2ccccn2)cc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2.0 g (9.17 mmole) 3,5-di-tertbutylbenzaldehyde in 75 ml absolute ethanol are added 1.19 g (10.1 mmole) 2-pyridylacetonitrile and 12 drops piperidine. The reaction flask is equipped with a condenser and a drying tube (using anhydrous CaSO4), and the reaction is stirred and heated. After refluxing for 8 hours, the reaction is allowed to cool to room temperature and stirred overnight for 16 hours. The solvent is removed by rotary evaporation, and the residue purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate, 98:2. The colorless solid is washed with cold ether-hexane to give 2-(2-pyridyl)-3-(3,5-di-tert-butylphenyl)-2-propenenitrile, m.p. 90°-93° C.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:10]=3[O:9]C2=O)=[C:4]([F:23])[CH:3]=1.[OH-].[K+].Cl>C(O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:12](=[O:13])[C:11]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:10]=2[OH:9])=[C:4]([F:23])[CH:3]=1
Reactant: COc1ccc2c(=O)n(Cc3ccc(Br)cc3F)c(=O)oc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)NCc2ccc(Br)cc2F)c(O)c1
Reaction time: 3 h
Yield: 70.6 %

Procedure:
A solution of 3-(4-bromo-2-fluoro-benzyl)-7-methoxy benzo[e] [1,3] oxazine-2,4-dione (1.67 g, 4.4 mmol) in ethanol (80 mL, 0.06 M) was cooled to 0° C. and treated with aq KOH (0.673 g, 11.9 mmol, 1.2 M). After 3 h, the reaction was acidified to pH 1–2 with 2 N HCl and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated. The crude solid was recrystallized from heptane and ethyl acetate to give N-(4-bromo-2-fluoro-benzyl)-2-hydroxy-4-methoxy-benzamide as a white crystalline solid (1.10 g, 71%): mp 128–129.5° C.; Rf 0.28 (25% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 12.70 (br s, 1 H), 9.14 (br t, J=5.2 Hz, 1 H), 7.80 (d, J=8.5 Hz, 1 H), 7.50 (d, J=8.5 Hz, 1 H), 7.40–7.25 (m, 2 H), 6.50–6.48 (m, 2 H), 4.45 (d, J=5.2 Hz, 2 H), 3.75 (s, 3 H). ESI-LC/MS m/z calcd for C15H13BrFNO2: 353.0; found 352.0 (M−1)−. Anal. calcd for C15H13BrFNO2: C, 50.87; H, 3.70; N, 3.95. Found C, 50.70; H, 3.73; N, 3.91.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[CH:13][N:12]3[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)=O.C(N(CC)CC)C.Cl.Cl.[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40]1[NH:44][N:43]=[C:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[N:41]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)(Cl)Cl>[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40]1[NH:41][C:42]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:1][C:3]3[CH:4]=[CH:5][C:6]([C:9]4[N:10]=[C:11]5[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[CH:13][N:12]5[C:19]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:7][CH:8]=3)[CH2:47][CH2:46]2)=[N:43][N:44]=1
Reactant: N#Cc1cccn2c(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Reactant: c1coc(-c2nc(C3CCNCC3)n[nH]2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccn2c(-c3ccccc3)c(-c3ccc(CN4CCC(c5nnc(-c6ccco6)[nH]5)CC4)cc3)nc12
Reaction time: 0.08 h

Procedure:
To a solution of 0.180 g (0.557 mM) 2-(4-formylphenyl)-3-phenylimidazo[1,2-a]pyridine-8-carbonitrile in 5 mL of THF is added triethylamine (2 eq). The reaction mixture is stirred for 5 minutes. To this solution is added 4-[5-(furan-2-yl)-1H-1,2,4-triazol-3-yl]piperidine dihydrochloride (Intermediate H) (1.5 eq) followed by acetic acid (2.5 eq). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH(OAc)3 (6 eq) over a period of 60 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained is taken up in chloroform and washed with water, dried and concentrated. The crude is purified on a flash column chromatography to obtain the desired compound.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH:3]=[CH:4][CH2:5][OH:6].[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>O1CCCC1.C(OCC)C.C([O-])(=O)C.[Na+]>[C:12]([O:6][CH2:5]/[CH:4]=[CH:3]/[C:2]([F:8])([F:7])[F:1])(=[O:13])[CH2:11][C:10]([CH3:9])=[O:14]
Reactant: C=C1CC(=O)O1
Reactant: OCC=CC(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)CC(=O)OC/C=C/C(F)(F)F
Temperature: 25 °C
Yield: 154.6 %

Procedure:
To a refluxing solution of 4,4,4-trifluoro-2-buten-1-ol (10 g, 79 mmol) and sodium acetate (0.51 g, 6.2 mmol) in anhydrous tetrahydrofuran (27 mL) under nitrogen, a solution of diketene (6.7 mL, 43.1 mmol) in anhydrous tetrahydrofuran (14 mL) was added dropwise over a period of 1 hour. The reaction mixture was heated at reflux for an additional 30 min upon completion of the addition. Then, the reaction mixture mixture was cooled to room temperature and diluted with diethyl ether (100 mL). The resulting solution was washed with a saturated aqueous sodium chloride solution (2×20 mL) and the organic layer was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The brown residue was purified by column chromatography using a mixture 4:1 of hexane and ethyl acetate as eluent to afford 14.0 g (84% yield) of trans-4,4,4-trifluoro-2-buten-1-yl acetoacetate as a colorless liquid.