Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.Cl>O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of methyl 4,5-diphenyl-2-oxazoleoctanoate (7.00 g, 18.5 mmol), 5N sodium hydroxide solution (7.42 mL), water (100 mL) and methanol (20 mL) was heated on a steam bath for 45 minutes. After stirring at room temperature for 75 minutes, the mixture was diluted with water (150 mL), heated on a steam bath for 10 minutes and then allowed to stir overnight at room temperature. The mixture was heated to reflux for 1 hour, cooled, acidified with 2N hydrochloric acid solution and extracted with CH2Cl2. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give an oil that crystallized. Recrystallization from a mixture of diethyl ether, CH2Cl2 and hexanes furnished 4,5-diphenyl-2-ozazoleoctanoic acid (5.25 g, 77%), m.p. 70°-73° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: BrCCCOc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1)Oc1ccccc1
Yield: 24.5 %

Procedure:
A mixture of 3-(4-hydroxyphenyl)-2-phenoxypropanoic acid methyl ester (0.055 g, 0.18 mmol) with 1-(3-bromopropoxy)-4-phenoxybenzene (Step A) (0.055 g, 0.18 mmol) and potassium tert-butoxide (0.020 g, 0.18 mmol) were stirred in DMF (5 mL) overnight. The mixture reaction concentrated in vacuo with toluene (2 times), reconstituted in Ethyl acetate and washed with water (3 times) and brine, dryed (Na2SO4) and concentrated to afford a crude product that was purified by chromatographied in silicagel (hexanes/Ethyl acetate, 3:1) to give 0.022 g of the title compound (23%). 1H-NMR (200.15 MHz, CDCl3): δ 7.34–7.15 (m, 6H), 7.07–6.71 (m, 12H), 4.80–4.68 (m, 1H), 4.13 (t, 4H, J=15.1), 3.71 (s, 3H), 3.20–3.15 (m, 2H), 2.30–2.18 (q, 2H).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11](I)=[CH:12][CH:13]=3)[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C2C(=CC([O:28][C@H:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:30]([NH2:32])[CH3:31])=CC=2)C=N1)(C)C>>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([O:28][C@H:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@@H:30]([NH2:32])[CH3:31])=[CH:12][CH:13]=3)[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)n1ncc2cc(O[C@H](c3ccccc3)[C@H](C)N)ccc21
Reactant: Ic1ccc2c(cnn2C2CCCC2)c1
Product: C[C@H](N)[C@H](Oc1ccc2c(cnn2C2CCCC2)c1)c1ccccc1

Procedure:
Prepared from 1-cyclopentyl-5-iodo-1H-indazole (130c, 158 mg, 500 μmol) as described for 129b. Yield 34 mg (20%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a solution of 4-bromopyridine-2-carboxylic acid (0.5 g, 2.5 mmol, Apollo Scientific) in a mixture of ethyl acetate (15 mL) and methanol (1.5 mL), was added dropwise a solution of trimethylsilyldiazomethane (3.7 mL, 2 M in diethyl ether, 7.4 mmol), at about 0° C. After the addition was complete the temperature was raised to rt and the mixture stirred for about another 1.5 h at rt. The resulting mixture was concentrated in vacuo and diethyl ether (25 mL) was added to the residue. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:1) to give methyl 4-bromopyridine-2-carboxylate (0.39 g, 1.8 mmol, 73%) as a pale yellow solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 4.03 (3H, s), 7.67 (1H, dd, J=5.0, 1.6 Hz), 8.31 (1H, d, J=1.6 Hz), 8.57 (1H, d, J=5.0 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:18]1=[O:19]
Reactant: COCCNc1ccccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
The residue 109B (422 mg, 2.54 mmol) was dissolved in THF (7.5 mL). CDI (494 mg, 3.05 mmol) in THF (7.6 mL) was added slowly via addition funnel. After addition the mixture was stirred overnight at room temperature, solvent was removed under vacuum. The residue was purified by column chromatography (5% MeOH/DCM) to give the product 1-(2-methoxyethyl)-1H-benzo[d]imidazol-2(3H)-one (109C) as an orange solid (449 mg, 92%). ESI-MS:m/z 193.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH:4]=[CH2:5])[CH3:3].C(N(CC)CC)C.[C:14](OC(=O)C)(=[O:16])[CH3:15].O>C(Cl)Cl>[C:14]([O:6][C:2]([CH3:3])([CH:4]=[CH2:5])[CH3:1])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(C)(C)O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(C)(C)OC(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-methyl-3-buten-2-ol (86.13 g, 1.0 mole), triethylamine (101.19 g, 1.3 mole), and 4-dimethylaminopropyridine (25.0 g, 0.2 mole) at 0° C. is added dropwise acetic anhydride (102.09 g, 1.15 mole) in CH2Cl2 (700 ml). The mixture is stirred at 0° C. for 5 hours and at room temperature overnight. Water is then added and the CH2CL2 layer separated. The aqueous layer is extracted with CH2Cl2 (3×300 ml) and the combined CH2Cl2 solution is washed with cold 1N HCl (300 ml), water (330 ml) and dried over anhydrous MgSO4. Distillation of the CH2Cl2 solution gives 2-methyl-3-buten-2-yl acetate (113.07 g), 88 percent, boiling point 59° C. (80 mm Hg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:11])([F:10])[C:7](Cl)=[O:8].[C:12]([Cl:15])([Cl:14])=[CH2:13]>ClCCl.O>[Cl:14][C:12]([Cl:15])=[CH:13][C:7](=[O:8])[C:6]([F:11])([F:10])[F:5]
Reactant: C=C(Cl)Cl
Reactant: O=C(Cl)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)C(F)(F)F
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
To a solution of aluminum chloride (3.0 g, 22.5 mmol) in dichloromethane (100 mL) was added dropwise a solution of trifluoroacetyl chloride (3 g, 22.6 mmol) in dichloro-methane (5 mL) while keeping the temperature of the reaction mixture below −30° C. The reaction mixture was stirred for 15 minutes at −50° C. Then a solution of vinylidene chloride (2.2 g, 22.7 mmol) in dichloromethane (10 mL) was added dropwise over 2 h to the reaction mixture. The reaction mixture was stirred an additional 2 h at −50° C. and then warmed gradually to room temperature. The reaction mixture was diluted with water, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried (MgSO4), and concentrated under reduced pressure to give 4,4-dichloro-1,1,1-trifluoro-3-buten-2-one as an oil which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([Cl:11])=[CH:6][C:5]=1[N:12]([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)CCCBr
Reactant: COC(=O)c1cc(Br)c(Cl)cc1NC(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCCN(C(=O)OC(C)C)c1cc(Cl)c(Br)cc1C(=O)OC
Temperature: 60 °C
Yield: 85.8 %

Procedure:
To a mixture of 5-Bromo-4-chloro-2-isopropoxycarbonylamino-benzoic acid methyl ester (2.52 g, 7.19 mmol) and cesium carbonate (4.68 g, 14.4 mmol) in DMF (35 ml) under nitrogen was added methyl 4-bromobutyrate (2.60 g, 14.4 mmol) dropwise. The reaction mixture was heated to 60° C. for 4 hours and then cooled to room temperature. The mixture was diluted with ethyl acetate (100 ml), and then washed with 0.1N HCl(aq) (100 ml) and brine (3×100 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (gradient eluent, 0-20% ethyl acetate in hexane) provided 5-Bromo-4-chloro-2-[isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-benzoic acid methyl ester (2.78 g, 86%) as oil. MS (ES+): 450, 452 (M+H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:46]=O)=[C:28]([CH:45]=1)[O:29][CH:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH3:44])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1>[CH3:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH:30]([O:29][C:28]1[CH:45]=[C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:25]=[CH:26][C:27]=1/[CH:46]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C=O)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1/C=C/C(=O)OC)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred suspension of sodium hydride (0.272 g; 60% w/v dispersion in mineral oil; 6.8 mmol) in tetrahydrofuran (100 mL) at 0° C. under nitrogen is treated, dropwise, with methyl (diethylphosphono)acetate (1.43 g) and stirred for 15 minutes. It is then treated with a solution of ethyl (RS)-4-(5-benzyloxy-2-formylphenoxy)-4-(2-methylphenyl)butanoate (1.96 g) in tetrahydrofuran (5 mL) in one portion, and the reaction mixture is stirred at ambient temperature for 15 minutes. The mixture is treated with water (100 mL) and extracted with ethyl acetate (3×100 mL), and the combined organic extracts are washed with brine (50 mL), dried over magnesium sulphate, and filtered and the solvent is removed in vacuo, to give ethyl (E)-(RS)-4-(2-methylphenyl)-4-[2-(2-methoxycarbonylethenyl)-5-benzyloxyphenoxy]butanoate, in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[C:3]=1[N:11]=O.OS([O-])=O.[Na+].[NH2:18]C1C(=O)NC(=O)N(C)C=1N.N([O-])=O.[Na+]>O.C(O)(=O)C>[CH3:8][N:7]1[C:2]2[NH:1][N:18]=[N:11][C:3]=2[C:4](=[O:10])[NH:5][C:6]1=[O:9]
Reactant: Cn1c(N)c(N)c(=O)[nH]c1=O
Reactant: Cn1c(N)c(N=O)c(=O)[nH]c1=O
Agent: O=N[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)[nH]c(=O)c2nn[nH]c21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspersion of 2.42 g (14.3 mmol) of the 6-amino-1-methyl-5-nitrosouracil in water heated to 90° C., was added 30 mL of a 38% solution of NaHSO3 over 10 minutes and the reaction allowed to continue until the reaction mixture was completely decolourized. After cooling the reaction mixture to 0° C., 5,6-diamino-1-methyluracil crystallized from the medium. After filtering off, washing with water, ethanol and diethylether and drying 2.14 g (80%) of the intermediate 5,6-diamino-1-methyluracil was isolated. 8.71 g (55.8 mmol) of 5,6-diamino-1-methyluracil was dissolved in 100 mL water and 50 mL acetic acid upon heating. After cooling to room temperature, a solution of 3.86 g (55.9 mmol) NaNO2 in 17 mL water was added over 5 minutes. The mixture was stirred for 5 minutes and then refluxed for a short time. After standing for two days at room temperature, 3-methyl-8-aza-9H-xanthine crystallized from the mixture. After filtering off, drying, recrystallization from water/ethanol 1:1 and drying 3.57 g (38%) of 3-methyl-8-aza-9H-xanthine was obtained (m.p. 313–320° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.CN(C)C=O.[H-].[Na+].Br[CH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O>[O:25]1[CH2:26][CH2:27][CH:22]([CH2:21][N:7]2[C:6]3[CH:12]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:23][CH2:24]1
Reactant: BrCC1CCOCC1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)N(CC1CCOCC1)C(=O)CO2
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
4.9 g (0.03 mol) of 6-amino-3,4-dihydro-2H-1,4-benzoxazin-3-one is introduced into 50 ml of dimethylformamide. At 5° C., 0.79 g (0.033 mol) of sodium hydride is added, and the mixture is stirred for 30 minutes at this temperature. Subsequently, 5.9 g (0.033 mol) of 4-bromomethyltetrahydropyran is added, the mixture is stirred for 3 hours at 60° C., 200 ml of water is added, extraction is carried out twice with methylene chloride, followed by drying and evaporation of the solvent under reduced pressure. There is obtained 5 g (64%) of 4-(tetrahydropyran-4-ylmethyl)-6-amino-3,4-dihydro-2H-1,4-benzoxazin-3-one as an oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[K+].[Cl-].[NH4+:30].O>C(O)(=O)C>[NH2:30][C:2]1([C:26]#[N:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: [C-]#N
Reactant: [NH4+]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(N)(C#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65 %

Procedure:
A mixture of (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), potassium cyanide (1.3 mmol) and ammonium chloride (10 mmol) in acetic acid (10 ml) was stirred for 14 hours at a temperature 25° C. The reaction mixture was pored in the water and was extracted with chloroform. Evaporation of solvent and silica gel column chromatographic purification of the residue afforded the title compound in 65% yield.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>O1CCCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:12][CH:11]=[CH2:10])=[CH:4][CH:3]=1
Reactant: C=CC[Mg]Br
Reactant: Cc1ccc(C=O)cn1
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc(C)nc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 6-methylpyridine-3-carbaldehyde (20 g, 0.16 mol) in tetrahydrofuran (400 mL) was added allylmagnesium bromide (246 mL, 0.246 mol) drop-wise at −40° C. The mixture was stirred at −20° C. for 10 minutes and a second aliquot of allylmagnesium bromide (82 mL, 82 mmol) was added drop-wise at −20° C. When thin layer chromatography (Eluent: 3:1 petroleum ether/ethyl acetate) indicated the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) at 0° C. The resulting mixture was partitioned between ethyl acetate (200 mL) and water (100 mL), and the aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried, filtered, and concentrated in vacuo to afford the product as a yellow oil. Yield 25 g, 0.15 mol, 94%. 1H NMR (400 MHz, CDCl3) δ 8.42-8.48 (m, 1H), 7.61 (dd, J=8.0, 2.3 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 5.74-5.86 (m, 1H), 5.12-5.22 (m, 2H), 4.77 (dd, J=7.5, 5.5 Hz, 1H), 2.55 (s, 3H), 2.46-2.58 (m, 2H).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=O)[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([Cl:29])=[O:25])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.1 %

Procedure:
A mixture of 20 g of m-tetradecyloxyphenylacetic acid, 10.93 g of oxalyl chloride and 41.95 mg of N,N-dimethylformamide in 250 ml of methylene chloride is stirred at ambient temperature for 5 hours. The solvent is removed and the concentrate dissolved in 1:1 ether:hexane and filtered through diatomaceous earth. filtrate is evaporated to give 21.3 g of the desired product as a light yellow solid.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH2:4]([O:6][C:7](OCC)=[CH:8][C:9]([O:11]CC)=O)[CH3:5].O.S(=O)(=O)(O)O>C(O)C.[Cl-].[Na+].O>[CH2:4]([O:6][C:7]1[CH2:8][C:9](=[O:11])[N:2]([CH3:1])[N:3]=1)[CH3:5]
Reactant: CNN
Reactant: CCOC(=O)C=C(OCC)OCC
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC1=NN(C)C(=O)C1
Yield: 42.5 %

Procedure:
Methylhydrazine (2.6 g, 0.056 mole) was added to a solution of ethyl 3,3-diethoxyacrylate (10.0 g, 0.053 mole) in ethanol (50 mL) and the mixture was heated and held at reflux for 18 hours. After cooling, water, saturated brine, and 3 mL of concentrated sulfuric acid were added; and the product was extracted with ethyl acetate. The combined extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography on silica gel using ethyl acetate/cyclohexane gave 5-ethoxy-2,4-dihydro-2-methyl-3H-pyrazol-3-one (3.2 g, 42% yield) as a white solid, mp=79°-80° C.
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1>CCOCC>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12](=[O:14])[CH3:1])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.6 M Methyl lithium (33.9 mL, 54.17 mmol) was added over 70 min to a stirring 0° C. solution of 3-(4-chlorophenyl)-propionic acid (5.0072 g, 27.08 mmol) in dry Et2O (135 mL, 0.2 M): The ice bath was removed, and the reaction was allowed to stir at room temperature overnight. The reaction was the poured into rapidly stirring ice water containing aq. HCl. The organic layer was removed, washed with NaHCO3 and brine, then dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 98:2 to 95:5 Hexanes:EtOAc) to achieve pure 66 (2.4253 g, 49.0%): 1H (CDCl3, 400 MHz): δ 7.14 (2H, d, J=8.3 Hz), 7.03 (2H, d, J=8.3 Hz), 2.77 (2H, t, J=7.5 Hz), 2.64 (2H, t, J=7.5 Hz), 2.04 (3H, s) ppm. 13C (CDCl3, 100 MHz): δ 207.12, 139.38, 131.59, 129.55, 128.35, 44.62, 29.82, 28.78 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 29.82; CH2 carbons: 44.62, 28.78; CH carbons: 129.55, 128.35 ppm. HPLC: 10.361 min. (Note: SM has HPLC retention time of 9.409 min.)
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][C:22]4([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[O:21][C:20]3=[O:29])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH:2]=C.NC(N)=S.C(Cl)Cl.C[OH:38]>C(=O)=O.CC(C)=O>[O:29]=[C:20]1[N:19]([CH2:18][C:15]2[CH:14]=[CH:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][O:4][CH2:1][CH:2]=[O:38])=[CH:11][CH:10]=3)=[CH:17][CH:16]=2)[CH2:23][C:22]2([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[O:21]1
Reactant: CO
Reactant: C=CCOCc1ccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)cc1
Agent: NC(N)=S
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=CCOCc1ccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
3-(4′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (200 mg, 0.51 mmol) was dissolved in DCM/methanol (4:1, 7.5 mL) and was cooled to −78° C. in dry ice-acetone bath. O3 was bubbled through the solution for 15 min. Thin layer chromatography (TLC) confirmed the completion of the reaction at this stage. Thiourea was added to the reaction mixture and stirred at low temperature for 0.5 hr. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature, and stirred overnight. The reaction mixture was concentrated, and the residue was purified on silica gel eluting with 5˜20% ethyl acetate in hexane to give the product as a white solid (80 mg, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 9.76 (s, 1H), 7.63 (m, 4H), 7.44 (d, 2H), 7.35 (d, 2H), 4.7 (s, 2H), 4.47 (s, 2H), 4.16 (s, 2H), 3.14 (s, 2H), 1.78 (m, 4H), 1.45 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[C:5]#[N:6].Cl[C:13]1[CH:14]=[C:15]2[N:22](C(OC(C)(C)C)=O)[C@@H:21]([CH3:30])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][O:11][C:13]2[CH:14]=[C:15]3[NH:22][C@@H:21]([CH3:30])[CH2:20][N:16]3[C:17](=[O:19])[N:18]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)cc(CO)c1
Product: C[C@H]1Cn2c(cc(OCc3cc(F)cc(C#N)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 3-fluoro-5-(hydroxymethyl)benzonitrile and (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C(O[B:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]1)(C)C.[C-:19]#[C-].[Li+].[Li+].Cl>C1COCC1>[CH3:16][C:13]1([CH3:15])[C:12]([CH3:17])([CH3:18])[O:11][B:10]([C:2]#[C:3][CH:4]([CH3:5])[CH3:19])[O:14]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: [C-]#[C-]
Reactant: [Li]CCCC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C#CB1OC(C)(C)C(C)(C)O1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Ia (7.0 g, 50 mmol) in dry THF (25 mL) at −78° C. was added n-BuLi (1.6 M in n-hexane, 62.5 mL, 100 mmol). After being stirred for 1 hour at −78° C., the reaction mixture was warmed to room temperature and stirred for 1 hour at that temperature. Another flask was charged with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.8 mL, 38 mmol) in dry THF (50 mL) under argon atmosphere, and the reaction mixture was cooled to −78° C. The lithium acetylide from the first flask, which was cooled to −78° C., was slowly added to the second by a double-ended needle. The mixture was stirred at −78° C. for 2 hours, after which anhydrous HCl (100 mmol) was added. Then, reaction mixture was warmed to room temperature. After removal of the precipitated LiCl by filtration and removal of solvents under reduced pressure, the residue was purified by distillation (113-115° C./7 mbar) to afford IIIa (5.9 g, 80%) as an oil.