Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[CH:19]=[C:18](I)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>[Cu](I)I.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>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[CH:19]=[C:18]([C:26]#[C:25][CH2:24][OH:27])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-2-iodo-7-methyl-4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide (Example No. 23) (1.632 g) in diethylamnine (40 mL) is added copper iodide (0.210 g) and Pd(PPh3)2Cl2 (0.125 g) followed by addition of propargyl alcohol (0.29 mL). The reaction is stirred at rt for 18 h. The diethylamine is removed in vacuo and the resulting brown solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield an orange solid which is recrystallized from ethanol to yield 1.06 g (77%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:9]#[N:10].Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH3:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])([CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH3:29])[C:9]#[N:10]
Reactant: CC1CCCCN1CCCl
Reactant: CC(C)N(CCC(C#N)c1ccccc1F)C(C)C
Product: CC1CCCCN1CCC(C#N)(CCN(C(C)C)C(C)C)c1ccccc1F

Procedure:
Substitution of equivalent quantities of α-(o-fluorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile and 1-(2-chloroethyl)-2-methylpiperidine in the procedure of Example 2, Method B and substantial repetition of the procedure detailed therein, affords α-(o-fluorophenyl)-α-[2-(diisopropylamino)ethyl]-α-[2-(2-methyl-1-piperidinyl)ethyl]acetonitrile, as an oil boiling at about 170°-175° C. at 0.5 mm. pressure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]=CC1C=CC(CNC(=O)C2C=CC(N3CCCC3)=CC=2)=CC=1)C.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:36][C:37](=[O:48])[NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46]O)=[CH:42][CH:41]=2)[CH:30]=1>>[CH3:1][O:3][C:4](=[O:28])[CH:5]=[CH:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][NH:38][C:37]([O:36][CH2:35][C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)=[O:48])=[CH:41][CH:42]=1
Reactant: O=C(NCc1ccc(CO)cc1)OCc1cccnc1
Reactant: CCOC(=O)C=Cc1ccc(CNC(=O)c2ccc(N3CCCC3)cc2)cc1
Product: COC(=O)C=Cc1ccc(CNC(=O)OCc2cccnc2)cc1
Yield: 75 %

Procedure:
The titled compound was prepared as described in the process (5-2) using the compound from the process (8-1).
Reaction SMILES: [NH2:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([C:9](=[O:11])[CH3:10])[CH2:7][S:8][C@H:3]12.O1CCCC1.C(=O)(O)[O-].[Na+].[CH:40]([O:42][CH:43]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:44](Cl)=[O:45])=[O:41]>C(OCC)(=O)C>[CH:40]([O:42][CH:43]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:44]([NH:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([C:9](=[O:11])[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:45])=[O:41]
Reactant: O=COC(C(=O)Cl)c1ccccc1
Reactant: CC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]2SC1
Temperature: 5 °C
Yield: 51.2 %

Procedure:
To a cooled (5° C.), stirred solution of 0.270 g. of benzhydryl 7-amino-3-acetyl-3-cephem-4-carboxylate in 20 ml. of dry tetrahydrofuran was added 0.0612 g. of sodium bicarbonate and dropwise, a solution of 0.144 g. of 2-formyloxy-2-phenylacetyl chloride in 2 ml. of tetrahydrofuran. The reaction mixture was allowed to stir with cooling for 30 minutes after which time it was transferred to a separatory funnel with the aid of cold ethyl acetate and washed with water, and brine (2X) and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided a residue which was chromatographed on silica gel using a toluene-ethyl acetate gradient to give 0.194 g. (51.2 percent) of the title product as a white froth:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[N:4][C:5](F)=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].O.[CH2:14]([OH:17])[CH2:15][OH:16]>>[Cl:8][C:6]1[C:5]([O:16][CH2:15][CH2:14][OH:17])=[N:4][C:3]([F:10])=[C:2]([Cl:1])[CH:7]=1
Reactant: Fc1nc(F)c(Cl)cc1Cl
Reactant: OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOc1nc(F)c(Cl)cc1Cl

Procedure:
To a solution of 12 grams (0.065 mole) of 3,5-dichloro-2,6-difluoropyridine in 35 milliliters of ethylene glycol was added over a 10 minute period 2.7 grams of anhydrous sodium hydroxide in 40 milliliters of ethylene glycol. The reaction mixture was maintained at ~70° C. with agitation for 10 minutes, cooled and poured into water. The insoluble material is removed by filtration and the filtrate extracted with methylene chloride and dried. The solid 2-(3,5-dichloro-6-fluoro-2-pyridyloxy) ethanol product was crystallized from hexane and recovered in a yield of 9 grams (61 percent of theoretical). The product melted at 65°-67° C. and was found by analysis to have carbon, hydrogen, chlorine and nitrogen contents of 37.4, 3.1, 31.5 and 6.4 percent, respectively, as compared with the theoretical contents of 37.2, 2.7, 31.4 and 6.2 percent, respectively, calculated for the above-named compound.
Reaction SMILES: [C:1]12([CH3:43])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[C:10]=[C:11]1[CH:42]=[CH:41][C:14]([NH:15][C:16]2[N:21]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26](=[C:29]=[C:30]4[CH2:35][CH:34]5[C:36]([CH3:38])([CH3:37])[C:31]4([CH3:39])[CH2:32][CH2:33]5)[CH2:25][CH:24]=3)[N:19]=[C:18](Cl)[N:17]=2)=[CH:13][CH2:12]1.[CH2:44]([O-:46])[CH3:45].[Na+]>>[C:1]12([CH3:43])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[C:10]=[C:11]1[CH:42]=[CH:41][C:14]([NH:15][C:16]2[N:21]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26](=[C:29]=[C:30]4[CH2:35][CH:34]5[C:36]([CH3:38])([CH3:37])[C:31]4([CH3:39])[CH2:32][CH2:33]5)[CH2:25][CH:24]=3)[N:19]=[C:18]([O:46][CH2:44][CH3:45])[N:17]=2)=[CH:13][CH2:12]1
Reactant: CC12CCC(CC1=C=C1C=CC(Nc3nc(Cl)nc(NC4=CCC(=C=C5CC6CCC5(C)C6(C)C)C=C4)n3)=CC1)C2(C)C
Reactant: CC[O-]
Agent: [Na+]
Product: CCOc1nc(NC2=CCC(=C=C3CC4CCC3(C)C4(C)C)C=C2)nc(NC2=CCC(=C=C3CC4CCC3(C)C4(C)C)C=C2)n1

Procedure:
2,4-Bis(4-camphylidenemethylene-anilino)-6-chloro-1,3,5-triazine is reacted with sodium ethanolate analogously to the instructions of Example 2. The desired product forms to the extent of 43%.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[OH:29][C:6]1[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:10](=[O:22])[N:11]2[CH2:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Temperature: 25 °C
Yield: 13.1 %

Procedure:
A mixture of 5-hydroxy-2-oxo-3-phenyl-1-(tetrahydro-pyran-4-ylmethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (50 mg, 0.13 mmol), β-alanine (678 mg, 7.6 mmol) and NaOMe solution (11 mL, 5.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration. The solid isolated was purified twice by silica gel chromatography (0-15% MeOH/CH2Cl2, then 5-70% EtOAc/hexanes+1% AcOH) to give 7.7 mg of the title compound as a light yellow solid. MS: (+) m/z 452.32 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([S:16][CH3:17])[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC.O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([S:16][CH3:17])[C:14]=1[O:15][CH3:18])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(SC)c(O)c(C(C)(C)C)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC(=O)c1cc(SC)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.5 %

Procedure:
Methyl 3-t-butyl-4-hydroxy-5-methylsulfanylbenzoate (377 mg) was dissolved in N,N-dimethylformamide (7 mL), and potassium carbonate (818 mg) and dimethylsulfuric acid (0.32 mL) were added to the solution, and then the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (344 mg) as a pale yellow oily substance.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([C:11]#[C:12][CH2:13]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C.N1C=CC=CC=1>[C:5]1([C:11]#[C:12][CH2:13][Br:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCC#Cc1ccccc1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: BrCC#Cc1ccccc1
Temperature: 40 °C
Yield: 248.9 %

Procedure:
Phosphorous tribromide (2.62 mL, 27.6 mmol) was added to a solution of 3-phenyl-2-propyn-1-ol (10.0 g, 76 mmol) and pyridine (0.14 mL, 1.77 mmol) in diethyl ether (22 mL) at a rate to maintain reflux. After addition, the mixture was heated at 40° C. for 2 h. The mixture was cooled and poured onto ice. The organic layer was separated and diluted with diethyl ether (100 mL), washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 1-phenyl-3-bromo-1-propyne (13.4 g, 90%). ##STR184## Step 2(E)--Preparation of 2-(benzyloxy)bromoethane
Reaction SMILES: Cl[C:2]1[O:3][C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:6](=[O:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:23]2[C:33]3[S:32][C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[CH2:29][C:28](=[O:38])[C:27]=3[CH:26]=[CH:25][CH:24]=2)O1.C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.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>[N:9]1([C:4]2[O:3][C:2]([C:23]3[C:33]4[S:32][C:31]5[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=5[CH2:29][C:28](=[O:38])[C:27]=4[CH:26]=[CH:25][CH:24]=3)=[CH:7][C:6](=[O:8])[CH:5]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: CC1(C)OB(c2cccc3c2Sc2ccccc2CC3=O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1Cc2ccccc2Sc2c1cccc2-c1cc(=O)cc(N2CCOCC2)o1
Temperature: 90 °C
Yield: 29.6 %

Procedure:
2-Chloro-6-morpholin-4-yl-pyran-4-one (3)(215 mg, 1 mmol), 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-11H-dibenzo[b,f]thiepin-10-one (352 mg, 1 mmol), and ground potassium carbonate (276 mg, 2 mmol) were suspended in 1,4-dioxane (10 ml) and degassed for 5 minutes. Pd(PPh3)4 (57 mg, 0.05 mmol) was then added and the reaction mixture was then heated at 90° C. for 4hours under a vigorous stirring and a N2 atmosphere. The solvent was removed in vaccuo and the residue was then suspended in water (100 ml). The organics were extracted with dichloromethane (3×100 ml), combined, washed with saturated brine and dried over sodium sulphate. The solvent was removed in vaccuo and the residue was purified by column chromatography (silica; ethyl acetate:ethanol; 9:1) to give the title compound as a pale brown solid (0.12 g, 29%). 1HNMR (300 MHz, DMSO-d6): δH=3.40 (4H, t), 3.70 (4H, t), 4.43 (2H, s), 5.55 (1H, d), 6.29 (1H, d), 7.25–7.55 (5H, m), 7.78–7.81 (1H, m), 8.20–8.22 (1H, m); m/z (LC-MS, ESP), RT=4.12 min, (M++1)=406.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.CC(N)C1C=CC=CC=1>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC1CCC(N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Agent: CC(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CC(=O)O)CC1
Reaction time: 2.75 h

Procedure:
To a solution of ethyl 2-[4-[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]cyclohexyl]acetate (1.53 g, 3.47 mmol) in methanol (3 mL) and THF (3 mL) was added NaOH (7.5 mL, 1M aqueous). The resulting solution was stirred for 2.75 hours the acidified with HCl (8 mL, 1M aqueous). This mixture was extracted with ethyl acetate, washed with brine dried over magnesium sulfate and concentrated. The residue was taken up in ether (5 mL). To this solution was added (−) α-methyl-benzylamine (428 μL, 347 mmol) and the resulting solution allowed to stand overnight. The crystalline mass was filtered, washed with ether and the collected solid recrystallized from isopropanol/ether to give 1.1 g of solid. The material was suspended in ethyl acetate, washed with 1M HCl aqueous, followed by brine, dried over magnesium sulfate and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](OB(O)O)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:16][CH:15]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: COc1ccc(OB(O)O)cc1
Product: COc1ccc(-c2cnc3ccccc3c2)cc1
Reaction time: 18 h
Yield: 89 %

Procedure:
The compound is prepared by the reaction of 3-bromoquinoline (500 mg, 2.40 mmol, 1 eq) with 4-methoxyphenylboric acid (365 mg, 2.40 mmol, 1 eq) according to method A in 18 h. Purification by column chromatography with a mixture of hexane/ethyl acetate 9/1 yielded the desired product as a white solid in a yield of 89% (504 mg).
Reaction SMILES: 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.[CH:34]([C:36]1[CH:41]=[CH:40][C:39](/[CH:42]=[CH:43]/[C:44]#[C:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=O)=[CH:48][CH:47]=2)=[CH:38][CH:37]=1)=[O:35].Cl.[CH3:56][NH:57][C:58](=[O:66])[C@H:59]([C:62](=[O:65])[O:63][CH3:64])[NH:60][CH3:61]>O.C(OCC)(=O)C.CN(C=O)C>[CH:34]([C:36]1[CH:37]=[CH:38][C:39](/[CH:42]=[CH:43]/[C:44]#[C:45][C:46]2[CH:47]=[CH:48][C:49]([C:50](=[O:52])[N:60]([CH:59]([C:58]([NH:57][CH3:56])=[O:66])[C:62]([O:63][CH3:64])=[O:65])[CH3:61])=[CH:53][CH:54]=2)=[CH:40][CH:41]=1)=[O:35]
Reactant: O=Cc1ccc(/C=C/C#Cc2ccc(C(=O)O)cc2)cc1
Reactant: CNC(=O)[C@@H](NC)C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#C/C=C/c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
HATU (1.1 g) and DIPEA (1.0 mL) were added to a DMF (5.0 mL) solution of 4-[(E)-4-(4-formylphenyl)but-3-en-1-yn-1-yl)benzoic acid (0.54 g) as obtained in Example 23-(2), and the mixture was stirred for 2 hours and 20 minutes at room temperature. HATU (1.1 g) was further added, and the mixture was stirred for 40 minutes at room temperature. N,N2,O-trimethyl-3-oxoserinamide hydrochloride (Intermediate 5-2, 0.57 g) was added, and the mixture was stirred for 20 minutes at 80° C. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added to isolate the organic layer. The extract was washed sequentially with water and brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered out, and then the solvent was distilled off under reduced pressure. Chloroform, IPE and ethyl acetate were added to the resulting residue, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/methanol=100/0→10/1) to obtain 1-formyl-4-[(1E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-1-en-3-yn-1-yl]benzene (orange oil) (0.61 g, 74%).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[N:4]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[Li]CCCC.CCCCCC.[Si:42]([O:49][CH:50]1[CH2:55][CH2:54][C:53](=[O:56])[CH2:52][CH2:51]1)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]>C1COCC1>[Si:42]([O:49][CH:50]1[CH2:55][CH2:54][C:53]([C:2]2[C:6]3[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=3[N:4]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:3]=2)([OH:56])[CH2:52][CH2:51]1)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: Clc1ncc2c(n1)c(Br)cn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cnc(Cl)nc23)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A solution of 7-bromo-2-chloro-5-trityl-5H-pyrrolo[3,2-d]pyrimidine (2.00 g, 3.2 mmol) in THF (20 mL) was added a 2.5 N solution of BuLi in hexane (2.82 mL, 7.04 mmol) at −78° C. Then 4-((tert-butyldimethylsilyl)oxy)cyclohexanone (1.2 mL) was added after 15 min. The reaction was stirred at −78° C. for 3 hour, quenched with brine and extracted with EtOAc (3×). The combined organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product (1.52 g, 76%). 1H NMR (400 MHz, CDCl3, two isomers) δ 7.64-7.56 (m, 1H), 7.44-7.41 (m, 1H), 7.35-7.31 (m, 9H), 7.16-7.10 (m, 6H), 3.73-3.68 (m, 1H), 2.55-2.51 (m, 1H), 2.42-2.30 (m, 1H), 2.28-2.19 (m, 1H), 2.07-1.94 (m, 2H), 1.91-1.82 (m, 2H), 1.76-1.62 (m, 2H), 0.82 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].O=[C:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1>C1COCC1>[CH2:13]([O:12][C:10](=[O:11])[CH:9]=[C:18]1[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21]1)[CH3:14]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To an ice-cold solution of ethyl 2-diethoxyphosphorylacetate (25.9 g, 116 mmol) in THF (200 mL) was added carefully NaH (60% dispersion in mineral oil, 4.62 g, 116 mmol) over 25 min. The cold bath was removed and after 30 min, tert-butyl 3-oxoazetidine-1-carboxylate (9.88 g, 57.7 mmol) in THF (40 mL) was added over 5 min. After 30 min, the reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. Purification by column chromatography (6/1 Pet ether/ethyl acetate) gave the ester (8.59 g, 62%) as a colourless oil.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1CCCCC1>[CH2:6]([NH:13][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCC1CO1
Reactant: NCc1ccccc1
Solvent: C1CCCCC1
Product: OC(CCl)CNCc1ccccc1
Yield: 55 %

Procedure:
46.25 g of epichlorohydrin, 33.5 g of benzylamine and 250 ml of cyclohexane were stirred together at ambient temperature for 24 hours. The precipitate formed was filtered off and recrystallized from toluene to give N-benzyl-3-amino-1-chloropropan-2-ol (1A), as a crystalline solid, m.p.: 70°-71° C., in 55% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:7]2[C:6]([F:9])=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]=2[F:1])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: Oc1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccc(F)cc2)c(F)c1
Temperature: 25 °C
Yield: 105 %

Procedure:
A mixture of 3,4,5-trifluoronitrobenzene (20.0 g, 113 mmol, commercially available from AsymChem of Durham, N.C.), dry DMF (100 ml), 4-fluorophenol (13.9 g, 124 mmol), and CS2CO3 (56 g, 172 mmol) was stirred under N2 at 60-70° C. for 1-2 hrs. After cooling to room temperature, the reaction mixture was partitioned between H2O and EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc (2×). The EtOAc extractions were washed with sat'd NaCl (1×), dried over Na2SO4, and concentrated in vacuo to give 4-(4-fluorophenoxy)-3,5-difluoronitrobenzene (32.0 g, 105%) which was used in the next step without further purification. 1H NMR (DMSO-d6): δ 7.15 (m, 2H), 7.22 (m, 2H), 8.31 (d, 2H, J=7.6 Hz).
Reaction SMILES: [CH:1]1([N:5]([CH3:27])[C:6](=[O:26])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-])=O)=[CH:16][C:15]=3[CH3:24])[CH:10]=[CH:9][C:8]=2[OH:25])[CH2:4][CH2:3][CH2:2]1>CO>[NH2:21][C:17]1[CH:18]=[C:19]([CH3:20])[C:14]([O:13][C:11]2[CH:10]=[CH:9][C:8]([OH:25])=[C:7]([CH:12]=2)[C:6]([N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH3:27])=[O:26])=[C:15]([CH3:24])[CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Solvent: CO
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Reaction time: 2 h

Procedure:
5-(4-Amino-2,6-dimethyl-phenoxy)-N-cyclobutyl-2-hydroxy-N-methyl-benzamide was prepared from N-cyclobutyl-5-(2,6-dimethyl-4-nitro-phenoxy)-2-hydroxy-N-methyl-benzamide according to a procedure analogous to that described in EXAMPLE 4, Step A. Methanol was used instead of ethanol as a co-solvent. The reaction mixture was hydrogenated for 2 hours. Then, the mixture was filtered through Celite® and concentrated, and the title product of Step F was used in the next step without purification. MS (APCI+) Calc.: 340.4, Found: 341.1 (M+1).