Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[NH2:29][C@@H:30]([CH3:33])[CH2:31][OH:32]>O1CCCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10]([NH:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: C[C@H](N)CO
Reactant: C[C@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(S(C)(=O)=O)nc21
Solvent: C1CCOC1
Product: C[C@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(N[C@@H](C)CO)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a tetrahydrofuran (5 mL) solution of 6-(2,4-difluorophenoxy)-8-((S)-2-hydroxypropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (400 mg, 1 mmol) was added (S)-2-amino-1-propanol (0.38 mL, 5 mmol) and stirred overnight at room temperature. Concentrated under vacuum and chromatographed on silica gel eluding with 2% methanol in dichloromethane and converted to the hydrochloride salt to give 320 mg 6-(2,4-difluoro-phenoxy)-2-((S)-(+)-2-hydroxy-1-methyl-ethylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido [2,3-d]pyrimidin-7-one (mass spec. M+1=407, MP=175.1-179.1° C.).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[C:26]([C:28]1[CH:29]=[C:30]([S:35]([NH:38][C:39]2[S:43][N:42]=[CH:41][N:40]=2)(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1F)#[N:27].Cl>CN(C)C=O>[C:26]([C:28]1[CH:29]=[C:30]([S:35]([NH:38][C:39]2[S:43][N:42]=[CH:41][N:40]=2)(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)#[N:27]
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N
Temperature: 100 °C
Yield: 99.4 %

Procedure:
To a stirred solution of 3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-ol (Preparation 28, 44.1 mg, 0.176 mmol) and potassium carbonate (30.4 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) was added 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 47, 50.0 mg, 0.176 mmol) and the reaction mixture was stirred at 100° C. After stirring for 24 hours, the reaction mixture was cooled to room temperature. A 1M aqueous solution of hydrogen chloride (10 mL) was added to the reaction mixture and the mixture was extracted with dichloromethane (3×10 mL). The combined organic layer was concentrated in vacuo to obtain the title compound (90 mg, 99%).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH:16]([CH3:18])[CH3:17])[NH2:15])[C:3]([OH:5])=[O:4].[CH:20](O)([CH3:22])[CH3:21]>>[CH:20]([O:4][C:3](=[O:5])[C:2]([CH3:19])([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH:16]([CH3:17])[CH3:18])[NH2:15])([CH3:22])[CH3:21]
Reactant: CC(C)O
Reactant: CC(C)C(N)CCCCCCCCC(C)(C)C(=O)O
Product: CC(C)OC(=O)C(C)(C)CCCCCCCCC(N)C(C)C
Yield: 76 %

Procedure:
The procedure described in Example (1b) is repeated, using 50 g (0.185 mole) of 2,2-dimethyl-11-isopropyl-11-aminoundecanoic acid and 100 ml of isopropanol. Distillation yields 44 g (0.141 mole) of 2,2-dimethyl-11-isopropyl-11-aminoundecanoic acid isopropyl ester, corresponding to a yield of 76% of theory;
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:13][C:12](=[O:14])[C:11]2(Cl)Cl)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>[Zn]>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([CH:10]2[CH2:13][C:12](=[O:14])[CH2:11]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2CC(=O)C2(Cl)Cl)CC1
Agent: [Zn]
Product: CCC[C@H]1CC[C@H](C2CC(=O)C2)CC1

Procedure:
0.1 mol of 4A is treated with 0.4 mol of zinc powder in analogy to Example 1C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>>[CH3:30][S:31]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCN(S(C)(=O)=O)C3)cnc21

Procedure:
((R)-1-Methanesulfonyl-pyrrolidin-3-yl)-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and methanesulfonyl chloride using DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6]/[C:5](=[CH:7]\[C:8](O)=[O:9])/[C:4](=[O:11])[O:3]1.C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1([CH3:12])[O:6]/[C:5](=[CH:7]\[C:8]([Cl:16])=[O:9])/[C:4](=[O:11])[O:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)OC(=O)/C(=C/C(=O)O)O1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)/C(=C/C(=O)Cl)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (Z)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-ylidene)acetic acid (0.27 g, 1.6 mmol) in CH2Cl2 (3.9 mL) was added oxalyl chloride (0.13 mL, 1.6 mmol). A few drops of DMF were added, and the reaction mixture was stirred at rt for 2 h to produce a 0.4 M stock solution of (Z)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-ylidene)acetyl chloride (Solution A). An aliquot of Solution A (0.25 mL, 0.1 mmol) was added to each 16×100 mm Wheaton tubes that had been charged separately with CH2Cl2 (0.25 mL), DIEA (0.050 mL, 0.3 mmol) and an amine (0.1 mmol) corresponding to the R5-amide contained in the final example. The vials were capped and the reaction mixtures were agitated at 400 rpm at rt for 16 h using an INNOVA® platform shaker. After removal from the shaker, each reaction mixture was diluted with MeOH (0.25 mL), treated with polystyrene-isocyanate resin (0.091 g, 1.1 mmol/g, 0.1 mmol) and agitated at 400 rpm for 2 h. Following filtration to remove the polystyrene beads, the filtrates were collected and dried under a stream of N2 for 1 h using a ZYMARK® tabletop dryer set to 45° C. The amides thus formed were carried onto the next step without further purification. To a separate reaction vessel was added paraformaldehyde (87 mg, 2.88 mmol), MeOH (10.6 mL) and CH3NH2 (2.0 M in THF; 1.44 mL, 2.88 mmol). This mixture was heated to 60° C. for 5 min using microwave irradiation to provide Solution B. To each vial containing an amide was added a 0.5 mL aliquot of Solution B. The reaction mixtures were agitated at 400 rpm at 80° C. for 16 h on an INNOVA® platform shaker. The reaction mixtures were removed from the shaker, cooled to rt and diluted with MeOH (0.25 mL). Examples 1-12 were purified from their corresponding solutions by RP preparative HPLC using Method H. HPLC/MS data for each compound was collected using Method E, and the molecular masses were determined by MS (ES) by the formula m/z. Both the retention time and MS data for Examples 6, 7 and 9 are listed in Table 2. Note: 2.0 M CH3NH2 in MeOH may be substituted for 2.0 M CH3NH2 in THF.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1>C1C=CC=CC=1>[C:3]1([C:10](=[O:11])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)c2ccccc2)cc1

Procedure:
1-Phenyl-2-(4-methoxyphenyl)ethanone was prepared from benzene and 4-methoxyphenylacetyl chloride (prepared by heating the commercially available carboxylic acid in thionyl chloride and subsequent concentration) using the method described in step A of Example 9. 1-Phenyl-2-(4-methoxyphenyl)ethanone was converted to the title compound following the procedures outlined in steps C-E of Example 1, except for the following modifications: 1) in step C, the acidic hydrolysis reaction, after dilution with H2O, was extracted 2× with Et2O prior to basification, extraction 3× with EtOAc and isolation of the desired amine after concentration; 2) the prep HPLC purification of step D was omitted; and 3) in step E, the final product was purified by prep HPLC using 46% solvent B as eluant.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10][C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][N:20]4[C:16](=[N:17][C:18]([C:24]5[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=5)=[CH:19]4)[C:15]=3[CH:31]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:33].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([S:10]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][N:20]4[CH:19]=[C:18]([C:24]5[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=5)[N:17]=[C:16]4[C:15]=3[CH:31]=2)=[O:33])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: Cc1ccnc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)ccc2OCC3)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccnc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)ccc2OCC3)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of 9-(1-isopropylpiperidin-4-ylsulfanyl)-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 12 (138 mg, 0.317 mmol) in DCM (20 mL) was added TFA (122 μL, 1.59 mmol) followed by a solution of m-CPBA (60 mg, 0.349 mmol) in DCM (2 mL). The resulting mixture was stirred for 15 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 5-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 223 as a colorless foam (114 mg, 80%). LCMS: RT1.94 min [M+H]+ 501.0. 1H NMR (DMSO, 400 MHz): δ 8.70 (1H, d, J=2.27 Hz), 8.38 (1H, d, J=4.97 Hz), 7.92 (1H, s), 7.81 (1H, s), 7.50 (1H, dd, J=8.51, 2.30 Hz), 7.23 (1H, d, J=8.51 Hz), 7.07 (1H, d, J=5.03 Hz), 4.59-4.50 (4H, m), 2.86-2.78 (2H, m), 2.74-2.58 (2H, m), 2.39 (3H, s), 2.15-2.01 (2H, m), 1.76 (1H, bd, J=12.05 Hz), 1.59-1.43 (3H, m), 0.90 (6H, d, J=6.53 Hz)
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[CH:13]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:22](=[O:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:15])[CH3:14].C(Br)C=C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:24]([C@H:23]([CH2:3][CH:2]=[CH2:1])[C:22]([N:17]1[C@@H:16]([CH:13]([CH3:15])[CH3:14])[CH2:20][O:19][C:18]1=[O:21])=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCc1ccccc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1C(C)C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
8.61 ml (13.8 mmoles) of butyllithium (as a 1.6M hexane solution) were added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 1.93 ml (13.8 mmoles) of diisopropylamine in 20 ml of anhydrous tetrahydrofuran. The mixture was stirred for 30 minutes, and then a solution of 3.00 mg (11.5 mmoles) of 4(S)-isopropyl-3-(3-phenylpropionyl)-2-oxazolidinone (prepared as described in Preparation 16) in 10 ml of anhydrous tetrahydrofuran was added dropwise thereto, and the mixture was stirred for 1 hour. At the end of this time, 2.99 ml (34.6 mmoles) of allyl bromide were added to the mixture, and the mixture was stirred for 12 hours, whilst allowing it to return gradually to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 5:1 by volume mixture of hexane and ethyl acetate as eluent), to give 2.14 g (yield 62%) of the title compound as a colorless oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[CH:22]=[CH:21][C:11]2[N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[S:14][C:10]=2[CH:9]=1)([O-])=O.[Cl-].[Ca+2].[Cl-].C(O)C.[CH3:32][N:33]1[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([CH3:41])=[N:34]1>CO.O.[C].[Pd].C(N(CC)CC)C>[CH:18]1([C:16]([NH:15][C:13]2[S:14][C:10]3[CH:9]=[C:8]([O:7][C:6]4[CH:5]=[C:4]([NH:1][C:38]([C:37]5[N:33]([CH3:32])[N:34]=[C:35]([CH3:41])[CH:36]=5)=[O:39])[CH:25]=[CH:24][CH:23]=4)[CH:22]=[CH:21][C:11]=3[N:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: O=C(Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cc2s1)C1CC1
Agent: [Pd]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.3 %

Procedure:
To a solution of N-[6-(3-nitrophenoxy)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (1.80 g, 5.53 mmol) in methanol (20 mL) was added palladium carbon (50% water-containing product, 100 mg), and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Reduced iron (309 mg), calcium chloride (613 mg, 5.53 mmol), ethanol (10 mL) and water (2 mL) were added to the residue, and the mixture was stirred for 2 hr. The reaction mixture was filtered through celite, and the filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Triethylamine (192 μL) and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (220 mg, 1.39 mmol) were added with stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=70/30→0/100) and recrystallized from ethyl acetate-tetrahydrofuran to give the title compound (126 mg, 5.1%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:24])([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=3[F:19])[C:10]2=[O:23])[C:5](=[O:25])[NH:4][C:3]1=[O:26].Cl.N[C:29]1(C)C(=O)N(CCC)C(=O)N[C:30]1=O>>[CH3:24][C:6]1([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=3[F:19])[C:10]2=[O:23])[C:7](=[O:8])[N:2]([CH2:1][CH2:29][CH3:30])[C:3](=[O:26])[NH:4][C:5]1=[O:25]
Reactant: CCCN1C(=O)NC(=O)C(C)(N)C1=O
Reactant: CN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Agent: Cl
Product: CCCN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O

Procedure:
Compound 19b was synthesized in the same manner as described for 19a from 5-amino-5-methyl-1-propylbarbituric acid hydrochloride (0.38 g, 1.50 mmol). The crude product was recrystallized from EtOH (70%) to give 5-methyl-1-propyl-5-(tetrafluorophthalimido)-barbituric acid (19b) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[O:10][C:9](=[O:19])[C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([O:1][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:3][CH:4]=3)=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=3)[C:9](=[O:19])[O:10]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc2c(Cc3ccc(O)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
A mixture of 4-(4-hydroxybenzyl)-7-methoxy-3-(4-trifluoromethyl-phenyl)-chromen-2-one (800 mg, 1.88 mmol), pivaloyl chloride (577 μL, 4.69 mmol), imidazole (268 mg, 3.94 mmol) and DMAP (344 mg, 2.81 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. Additional portions of imidazole (268 mg, 3.94 mmol), DMAP (344 mg, 2.81 mmol) and pivaloyl chloride (577 μL, 4.69 mmol) were added and stirring was continued for a further 20 h, for a total reaction time of 38 h. The solvent was removed in vacuo, the residue was dissolved in AcOEt and the organic layer was washed with H2O. The aq layer was extracted with AcOEt (2×) and the combined organic layers were washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The resultant residue was purified using flash chromatography (silica gel, 5:1 hexanes:AcOEt) to provide the title compound as a white solid (820 mg, 86%). 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J=8.0 Hz, 2H), 7.43–7.37 (m, 3H), 7.08–7.02 (m, 2H), 7.00–6.93 (m, 2H), 6.88 (d, J=2.5 Hz, 1H), 6.77 (dd, J=2.5, 8.8 Hz, 1H), 4.04 (s, 2H), 3.87 (s, 3H), 1.34 (s, 9H); MS (ESI) m/z 511.0 (M+H)+; HPLC tR 7.58 min.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.[NH3:13]>C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH2:13])=[NH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(CC#N)c1
Reactant: N
Agent: Cl
Solvent: CCO
Product: COc1cccc(CC(=N)N)c1
Reaction time: 72 h

Procedure:
Dry hydrogen chloride was passed into a mixture of 3-methoxyphenylacetonitrile (19.7 g.) and dry ethanol (6.8 g., 7.8 ml.) until a weight increase of 5 g. was obtained. The mixture was allowed to stand at room temperature for 3 days and the solid mass was broken up and treated portionwise, with vigorous shaking and occasional cooling, with a saturated solution of ammonia in dry ethanol. Addition was continued until a smell of ammonia persisted. The mixture was allowed to stand at room temperature for 2 days and then warmed and filtered to remove a small amount of ammonium chloride. The filtrate was diluted with ether and the crystalline precipitate was removed and recrystallised from a mixture of ethanol and ether to give pure 3-methoxy-phenylacetamidine hydrochloride, m.p. 142°-144°.
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]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][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O[C:67]1[CH:74]=[CH:73][C:70]([CH:71]=[O:72])=[CH:69][CH:68]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][O:65][C:67]2[CH:74]=[CH:73][C:70]([CH:71]=[O:72])=[CH:69][CH:68]=2)[CH2:21]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][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: O=Cc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C=O)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 0.67 h

Procedure:
(3,4,5-Tris-octadecyloxy-cyclohexyl)-methanol (283 mg, 308 μmol), 4-hydroxy-benzaldehyde (56 mg, 459 μmol), and triphenylphosphine (121 mg, 461 μmol) were dissolved in dehydrated THF (5.5 mL), DIED (93.3 μL, 472 μmol) was added, and the mixture was stirred for 40 minutes. 4-Hydroxy-benzaldehyde, triphenylphosphine, and DIED (each 153 μmol) were added, and the mixture was stirred overnight. Triphenylphosphine and DIED (each 306 μmol) were added, and the mixture was stirred for 2.5 hours. THF was evaporated, and 90% aqueous acetonitrile (6 ml) was added to the residue to allow crystallization. The crystals were collected by filtration and thoroughly washed with acetonitrile to give crude crystals of 4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-benzaldehyde. The crude crystals were purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give the object compound (130 mg, 127 μmol, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[OH:9]
Reactant: Oc1cc(F)ccc1F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)c(O)cc1F
Temperature: -13 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A solution of 2,5-difluorophenol (5 g, 38.4 mmol) in acetic acid (10 mL) was added slowly to a mixture of concentrated nitric acid (10 mL) and acetic acid (10 mL) cooled in an acetonitrile/dry ice bath in a manner that temperature did not exceed −18° C. After everything was added, solution was kept at −30° C. for 30 minutes, stirred at −13° C. for 30 minutes, and then at 0° C. for 1 hour. Solution was transferred into a separatory funnel, diluted with methylene chloride, and extracted three times with water. Organic phase was dried over magnesium sulfate, filtered, and concentrated. Residue was purified by column chromatography on SiO2 (hexane/acetyl acetate 1:1) to give 2,5-difluoro-4-nitro-phenol as a yellow solid (1.74 g, 26%). 1HNMR (MeOD, 400 MHz) δ 7.97-7.93 (m, 1H), 6.95-6.91 (m, 1H), 6.17 (s, 1H).