Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Na+].[Na+].C[C:20]([N:22](C)C)=O>[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[C:20]#[N:22]
Reactant: Fc1cc2ncccc2cc1Br
Reactant: CC(=O)N(C)C
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: N#Cc1cc2cccnc2cc1F
Temperature: 120 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 6-bromo-7-fluoroquinoline (4.90 g, 22.12 mmol) in dimethylacetamide (38 ml), potassium ferrocyanide (2.65 g, 4.86 mmol) and sodium carbonate (2.34 g, 22.12 mmol). The system was purged with nitrogen for 15 min. Palladium acetate (0.248 g, 1.10 mmol) was added under nitrogen and heated to 120° C. After 3 h, the reaction mixture was filtered through celite, washed with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a white solid (3.2 g, 86%). 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.05 (dd, J=4.1, 2.9 Hz, 1H), 8.25 (m, 2H), 7.90 (d, J=10.0 Hz, 1H), 7.53 (dd, J=8.3, 4.3 Hz, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[OH:55].I([O-])(=O)(=O)=O.[Na+].I([O-])(=O)(=O)=O.CO>C(Cl)(Cl)Cl.CO>[CH3:52][C@H:18]1[O:19][C@@H:20]([O:24][C@@H:25]2[CH2:30][C@H:29]3[CH2:31][CH2:32][C@H:33]4[C@@:38]5([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]6[CH2:47][O:46][C:44](=[O:45])[CH:43]=6)[C@@:37]5([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]4[C@@:28]3([CH3:51])[CH2:27][CH2:26]2)[CH2:21][C@H:22]([OH:23])[C@@H:17]1[O:16][C@@H:12]1[O:11][C@H:10]([CH3:53])[C@@H:9]([O:8][CH:6]([O:7][CH:2]([CH:3]=[O:55])[CH3:1])[CH2:5][CH:4]=[O:54])[C@@H:14]([OH:15])[CH2:13]1
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C=O)OC(CC=O)O[C@H]1[C@@H](O)C[C@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3CC[C@@]4(C)[C@H](CC[C@@H]5[C@@H]4C[C@@H](O)[C@]4(C)[C@@H](C6=CC(=O)OC6)CC[C@]54O)C3)O[C@@H]2C)O[C@@H]1C
Reaction time: 0.25 h

Procedure:
Digoxin (0.4985 g, 0.64 mmole) was dissolved in 10 ml of chloroform/methanol (3/1.5) and placed into a 100 ml two-necked flask. Sodium periodate (0.3102 g, 1.4 mmoles) was dissolved in 4 ml distilled water and placed into a pressure equalized addition funnel. The periodate solution was slowly added to the flask while stirring and under nitrogen. A white precipitate was immediately formed and the reaction was complete within 15 minutes after addition of the periodate. Reaction progress was monitored by TLC (E. M. Merck, pre-coated TLC sheets, silica gel 60 F254 0.2 mm thickness) in chloroform/methanol 10/1 by volume [Rf 0.16=dialdehyde, one homogeneous spot; Rf 0.07=Digoxin. Both spots became dark brownish when sprayed the TLC plate with methanol/concentrated sulfuric acid (9/1 by volume) and placed in 100° C. oven). The reaction mixture was evaporated on a rotatory evaporator and brought up in 30 ml of chloroform and 3 ml of water. The cloudy solution was extracted and the aqueous layer washed three times with 10 ml chloroform. The organic phases were combined (60 ml) and dried over magnesium sulfate. The organic solvents were evaporated to dryness. A light yellow brownish oily material was left. This material was used immediately in the next reaction.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:21][CH3:22])[CH2:4][CH2:3]1.[BH4-].[Na+].O>CO>[Si:14]([O:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]([CH2:21][CH3:22])[CH2:4][CH2:3][CH:2]2[OH:1])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CCN1CCC(=O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN1CCC(O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Reaction time: 0.17 h
Yield: 105.3 %

Procedure:
4-oxo-8-t-butyldimethylsilyloxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (2.17 g) was dissolved in methanol (20 ml). To this solution was added sodium borohydride (0.26 g) at room temperature, and the mixture was stirred for 10 minutes. Water was added to the reaction mixture and the solvent was distilled off to give 8-t-butyldimethylsilyloxymethyl-4-hydroxy-1-ethyl-1,2,3,4-tetrahydroquinoline (2.30 g).
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[F:21][C:22]1[CH:23]=[C:24]([NH:29][CH:30]([C:32]2[CH:33]=[C:34]([C:49](O)=[O:50])[CH:35]=[C:36]3[C:41]=2[O:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][C:37]3=[O:48])[CH3:31])[CH:25]=[C:26]([F:28])[CH:27]=1.CCN(C(C)C)C(C)C.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>C(Cl)Cl>[F:21][C:22]1[CH:23]=[C:24]([NH:29][CH:30]([C:32]2[CH:33]=[C:34]([C:49]([N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)=[O:50])[CH:35]=[C:36]3[C:41]=2[O:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][C:37]3=[O:48])[CH3:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: C1COCCN1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N2CCOCC2)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
TSTU (84 mg, 0.28 mmol) at 25° C., was added to 8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (100 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol) dissolved in DCM (1 mL). The resulting solution was stirred at 25° C. for 2 hrs. Morpholine (0.037 mL, 0.42 mmol) was then added, the resulting solution was stirred at 25° C. for 30 minutes then concentrated. The crude was diluted with 1 mL of DMA and purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness, triturated in diethyl ether and collected by filtration to afford 8-(1-(3,5-difluorophenylamino)ethyl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (63.0 mg, 90%) as a yellow solid. Mass Spectrum: M+H+ 500. NMR Spectrum: (DMSOd6) 1.53 (d, 3H), 3.11 (bs, 2H), 3.37-3.71 (m, 10H), 3.71-3.80 (m, 4H), 4.98-5.07 (m, 1H), 5.62 (s, 1H), 6.15 (dd, 2H), 6.25 (ddd, 1H), 6.97 (d, 1H), 7.51 (d, 1H), 7.82 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cc1cccc(C(=O)Cl)c1
Product: Cc1cccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)c1
Yield: 87.9 %

Procedure:
Beginning with 13 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 9.2 mg (0.059 mMol) 3-methylbenzoyl chloride, 17.1 mg (88%) of the title compound were recovered.
Reaction SMILES: C[CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=C[CH:4]=1.C=O.C(O)(=O)C.[CH2:16]([N:23]1CCC(=O)CC1)C1C=CC=CC=1>CO>[CH2:8]1[CH:7]2[CH2:6][NH:9][CH2:2][CH:3]1[CH2:4][NH:23][CH2:16]2
Reactant: CC(N)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: C1NCC2CNCC1C2
Temperature: 25 °C

Procedure:
A mixture of α-methylbenzylamine (10.7 g, 0.088 mol), paraformaldehyde (21.1 g, 0.703 mol), acetic acid (10.2 mL, 0.179 mol) and 1-benzyl-4-piperidone (16.7 g, 0.088 mol) in MeOH (418 mL) was heated at reflux overnight. Upon cooling to room temperature the solvents were removed in vacuo. Water (700 mL) and KOH pellets (11.7 g, 0.209 mol) were added and the mixture was extracted with 3×150 mL CH2Cl2. The organic layer was dried (K2CO3), filtered and the solvent was removed in vacuo. The yellow residues were triturated with hexane and the combined organic solvents were concentrated to provide bispidine (1) as a crude yellow oil (26.7 g, 90%).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][CH:5]([CH2:7][CH2:8][CH2:9][CH:10]([CH2:12][CH:13]=[O:14])[CH3:11])[CH3:6].[Cl-].[NH4+]>CCOCC>[CH3:11][CH:10]([CH2:9][CH2:8][CH2:7][CH:5]([CH3:4])[CH3:6])[CH2:12][CH:13]([OH:14])[CH3:1]
Reactant: CC(C)CCCC(C)CC=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CCCC(C)CC(C)O

Procedure:
Eighty ml. of a 3M solution of methylmagnesium bromide in ether is added slowly to 31 g. of dihydrocitronellal in 250 ml. of dry ether. The mixture is heated at reflux for about one hour, cooled to 0° and treated with saturated aqueous ammonium chloride until reaction subsides. The organic layer is separated and the aqueous layer extracted with ether. The organic layer and ether extracts are combined, washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent gives 4,8-dimethylnonan-2-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10]O.S(Cl)([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][Cl:20]
Reactant: COc1cccc(Oc2cccc(CO)c2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(Oc2cccc(CCl)c2)c1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
The alcohol (5.31 g, 23 mmol) was dissolved in dichloromethane (40 ml) and treated with thionyl chloride (2.6 ml, 35 mmol) and dimethylformamide (catalytic 5 drops). The mixture was stirred overnight. The reaction mixture was evaporated in vacuo and azeotroped with toluene (2×10 ml) to give 3-(3-methoxyphenoxy)benzyl chloride as a light brown oil (5.57 g, 97%). The chloride (5.30 g, 21.3 mmol) was dissolved in dimethyl sulphoxide (20 ml), potassium cyanide (1.45 g, 22.4 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was diluted with water (100 ml) and extracted with ether. The combined extracts were dried (MgSO4) and evaporated to give 3-(3-methoxyphenoxy)phenyl acetonitrile as a brown oil (4.04 g, 79%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([O:14]C)=[O:13])=[O:6])#[N:2].[OH-].[Na+].Cl>COCCOC.O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([OH:14])=[O:13])=[O:6])#[N:2]
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)NCC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: N#CCNC(=O)[C@@H]1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Methyl trans-2-{[(cyanomethyl)amino]carbonyl}cyclopentanecarboxylate (1.08 g, 5.16 mmol) in ethylene glycol dimethyl ether (6.5 mL) was cooled to 0° C. 2.00 M aqueous sodium hydroxide (2.65 mL) was added and the reaction mixture was stirred at 0° C. for 3.5 h. The pH was adjusted to 5 with 2 M aqueous hydrochloric acid and the reaction mixture was diluted with water. The product was extracted into ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated to give trans-2-{[(cyanomethyl)amino]carbonyl}cyclopentanecarboxylic acid as a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH2:12]=O>>[S:1]1[C:2]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH:8][CH2:12][C:3]=2[CH:4]=[CH:5]1
Reactant: C=O
Reactant: N[C@@H](Cc1cccs1)C(=O)O
Product: O=C(O)C1Cc2sccc2CN1
Temperature: 60 °C

Procedure:
A suspension of (D,L) 3-(2-thienyl)-alanine (302 mg, 1.77 mmol) in 37% aq. HCHO (4 mL) was heated at 60° C. for 2 h. The suspension became clear. It was concentrated in vacuo to give the titled compound (323 mg), which was used in the next step without further purification. MS 184.3 (M+H)
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:15]([C:23](OC)=[O:24])[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Li+].[BH4-].C(Cl)Cl.Cl>C1COCC1>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:15]([CH2:23][OH:24])[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1CN(C(=O)c2cccc3ccccc23)CC1c1ccsc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1cccc2ccccc12)N1CC(CO)C(c2ccsc2)C1
Yield: 92.8 %

Procedure:
A solution of 0.48 g (1.31 mmol) of 1-(1-naphthoyl)-3-(SR)-carbomethoxy-4-(RS)-(3-thienyl)pyrrolidine and 2.6 mL (5.24 mmol) of LiBH4 (2M in THF) in 10 mL of THF was stirred at rt for 12 h. To the reaction mixture was added 50 mL of CH2Cl2 and 5 mL of 0.5N HCl. The fractions were partitioned and the aqueous fraction was extracted twice with CH2Cl2. The combined organic fractions were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography to give 0.41 g of the title compound. 1H NMR (CDCl3) δ3.45 (m, 2H), 7.47-7.90 (m, 8H);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:20]C([N-]C(C)C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]([CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CN(C(=O)OC(C)(C)C)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone (structure 68A of Scheme LI, where R1-2 =H) (EXAMPLE 325) (500 mg, 0.002 mol) in THF (5 mL) at -78° C. was added 2.0 M LDA in THF (1.01 mL, 0.002 mol). The reaction mixture was stirred at -78° C. for 15 min and iodomethane (126 mL, 0.002 mol) was added all at once. The temperature was raised to 0° C. and the resulting mixture stirred for 4 h. The reaction was then quenched with sat'd NH4Cl (5 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and concentrated in vacuo to a solid residue that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 95:5) to give 117 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolinone (structure 69A of Scheme LI, where R1-2 =H, R3 =methyl), 128 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethyl-4-quinolinone (structure 70A of Scheme LII, where R1-2 =H, R3-4 =methyl) and 200 mg (40%) of recovered starting material. Data for 1-tert butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.99 (dd, J=7.9, 1.7, 1 H), 7.77 (d, J=8.4, 1 H), 7.48 (ddd, J=7.3, 7.3, 1.7, 1 H), 7.13 (dd, J=7.4, 1.0, 1 H), 4.32 (dd, J=13.4, 4.4, 1 H), 3.69 (dd, J=13.3, 9.8, 1 H), 2.76 (ddq, J=9.8, 7.0, 4.4, 1 H), 1.56 (s, 9 H), 1.24 (d, J=7.0, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:14][NH2:15])[N:11]=[N:12][CH:13]=1.[C:16]([O-])([O-])(OCC)[CH3:17]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[N:12][N:11]2[C:16]([CH3:17])=[N:15][N:14]=[C:10]2[N:9]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNc1nncc(-c2ccccc2F)n1
Product: Cc1nnc2nc(-c3ccccc3F)cnn12

Procedure:
A mixture of 6.15 g. of 5-(o-fluorophenyl)-3-hydrazino-1,2,4-triazine and 50 ml. of ethyl orthoacetate is refluxed for 2.5 hours, cooled and the solid is collected by filtration and washed with hexane and ethanol, giving the desired product as yellow crystals, m.p. 227°-229° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(F)nc1
Solvent: CO
Product: COC(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-fluoronicotinic acid (255 mg, 1.32 mmol) in methanol (5 mL) at room temperature was added (trimethylsilyl)diazomethane (4.0 mL, 2 M in diethyl ether, 8.0 mmol). The reaction mixture was stirred at room temperature for 30 min and concentrated. Methyl 6-fluoronicotinate (129 mg, 47%) was used without further purification: NMR (600 MHz, DMSO-d6) δ 8.79 (d, J=2.6 Hz, 1H), 8.47 (td, J=7.9, 2.6 Hz, 1H), 7.35 (ddd, J=8.5, 2.6, 0.6 Hz, 1H), 3.88 (s, 3H); ESIMS calcd 156.0 (M++H), found 156.1 (M++H).
Reaction SMILES: S(F)(F)(=O)=O.[CH3:6][N:7]([CH3:13])[C:8]([N:10]([CH3:12])[CH3:11])=[NH:9].[CH3:14]N(C)C=O>>[CH3:6][N:7]([CH3:13])[C:8](=[N:9][CH3:14])[N:10]([CH3:12])[CH3:11]
Reactant: CN(C)C(=N)N(C)C
Reactant: CN(C)C=O
Agent: O=S(=O)(F)F
Product: CN=C(N(C)C)N(C)C

Procedure:
A perfluorinated polymer precursor (film thickness: 25 μm, sulfonyl fluoride form, EW1100) was treated with 1,1,3,3-tetramethylguanidine in dimethylformamide (DMF) solution at 90° C. for 24 hr. After washing with water, the membrane was dried under a vacuum plate at 75° C. The absorption by C═N was observed at 1525-1580 cm−1 by FT-IR, and C═N and N—CH3 peak was observed at 162 and 39.5 ppm by C-NMR, respectively. Tetramethlguanidine functionalized perfluorinated polymers were further treated with dimethyl sulfate (DMS) in DMF at 90° C. for 24 hr. Pentamethylguanidine functionalized perfluorinated polymer was obtained. Guanidine functionalized perfluorinated polymers were further treated with 1 M NaOH for 4 hr at boiling temperature followed by washing with water.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15]S(C1C=CC(C)=CC=1)(=O)=O.C([O:28][C:29](=[O:51])[C:30]([CH3:50])([O:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[N:46]=[CH:45][CH:44]=[CH:43]2)[CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)C.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CCO>[CH3:50][C:30]([O:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[N:46]=[CH:45][CH:44]=[CH:43]2)([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:36][CH:37]=1)[C:29]([OH:51])=[O:28]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2ncccc2c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C)(Oc2ccc3ncccc3c2)C(=O)O)cc1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (94 mg, 0.26 mmol), 3-(4-Hydroxy-phenyl)-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethyl ester (77.3 mg, 0.22 mmol) and K2CO3 (61 mg, 0.44 mmol) in 2 mL of EtOH was heated to 80° C. for overnight. Then 5N NaOH (0.26 mL, 1.3 mmol) was added and reaction mixture was stand at same temperature for 2 h. The mixture was cooled off to r.t. and organic solvent was removed under vacuum. Residue was then dissolved in CH2Cl2 and 1N HCl. Aqueous layer was washed with CH2Cl2 (2×). Combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Residue was purified by MS/LC to give title compound as white solid (55.6 mg, 50%). 1H NMR (400 MHz, CDCl3) δδ 8.76 (d, 1H, J=4.4 Hz), 8.28 (d, 1H, J=8.4 Hz), 7.94 (d, 1H, J=9.2 Hz), 7.89-7.87 (m, 2H), 7.51-7.45 (m, 3H), 7.38-7.32 (m, 2H), 7.25-7.23 (m, 1H), 7.20 (d, 1H, J=2.4 Hz), 7.16 (d, 2H, J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz), 4.17 (t, 2H, J=6.6 Hz), 3.29, 3.11 (ABq, 2H, J=13.4 Hz), 2.90 (t, 2H, J=6.6 Hz), 2.33 (s, 3H), 1.42 (s, 3H). HRMS (ES+) m/z exact mass calcd for C31H29N2O5 (m+1) 509.2076, found 509.2095.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO.O.O.[OH-].[Li+]>O1CCCC1>[Cl:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([NH:10][C:8]1[CH:7]=[CH:6][C:5]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([CH:9]=1)[C:3]([OH:27])=[O:2])=[O:19]
Reactant: COC(=O)c1cc(NC(=O)c2cccc(Cl)c2)ccc1Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Oc2ccccc2)c(C(=O)O)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(3-Chloro-benzoylamino)-2-phenoxy-benzoic acid methyl ester (1.56 g, 4.00 mmol) (see Example I1) was dissolved in a mixture of tetrahydrofuran (15 ml), methanol (1.5 ml), and water (1.5 ml). Lithium hydroxide monohydrate (336 mg, 8 mmol) was added and the reaction mixture stirred at ambient temperature for 3 days. The reaction mixture was concentrated and the residue extracted with water and tert-butyl-methyl-ether. The aqueous phase was acidified by the addition of a few drops of concentrated hydrochloric acid and extracted with ethyl acetate. The phases were separated, the organic phase was dried over sodium sulfate and concentrated. The residue was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@@H:7]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:8][CH2:9][C:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)C(O)=O)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:33]([O:32][C:30]([NH:29][C@@H:7]([CH2:8][CH2:9][CH:10]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:37])=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cc1)(C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 88.5 %

Procedure:
A solution of 730 mg (5S)-2-(tert-butoxycarbonyl)-5-[(tert-butoxycarbonyl)amino]-2-(4-hydroxybenzyl)hexanedioic acid 6-tert-butyl ester (1.39 mmol) and 290 mg 4-N,N-dimethylaminopyridine (2.37 mmol) in tetrahydrofuran (10 mL) was heated under reflux for 18 hours. Since the turnover was only approx. 75% then, and to drive the reaction to completion, the mixture was evaporated, the residue dissolved in 1,4-dioxane, and heated under reflux for another 2 hours after which turnover was complete. The mixture was evaporated and the residue was purified by column chromatography on silica gel (2.5→35% ethyl acetate in hexane), to give 590 mg (88% yield) of the target compound featuring an HNMR spectrum in line with the HNMR data for example 12d.