Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:2]=[C:3]([NH2:44])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][CH2:25][C@H:26]4[O:30][C@@H:29]([N:31]5[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH2:34][CH:33]=[CH:32]5)[C@H:28]([OH:40])[C@@H:27]4[OH:41])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:42])[C@H:11]3[OH:43])[C:5]=2[N:6]=1.P([O-])([O-])([O-])=[O:46].[K+].[K+].[K+].CC1[N+](CC2C(N)=NC(C)=NC=2)=CSC=1CCOP(OP(O)(O)=O)(O)=O.C=O>OCC(CO)O>[CH:1]1[N:2]=[C:3]([NH2:44])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][CH2:25][C@H:26]4[O:30][C@@H:29]([N:31]5[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH2:34][CH:33]=[CH:32]5)[C@H:28]([OH:40])[C@@H:27]4[OH:41])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:42])[C@H:11]3[OH:43])[C:5]=2[N:6]=1.[OH:30][CH:29]([OH:46])[C:28](=[O:40])[CH3:27]
Reactant: O=P([O-])([O-])[O-]
Agent: C=O
Agent: Cc1ncc(C[n+]2csc(CCOP(=O)(O)OP(=O)(O)O)c2C)c(N)n1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Solvent: OCC(O)CO
Product: CC(=O)C(O)O

Procedure:
Measurements of conversion rate of formaldehyde to dihydroxyacetone were performed through the enzyme-coupled spectrophotometric assay described in Example 1, wherein the NADH consumption resulting from the reduction of dihydroxyacetone to glycerol is measured. Individual reactions contained 5 μM of the enzyme (BAL, FLS r3a, FLS r3b, FLS r3c, FLS r3d, FLS r4a, and FLS r4b), 0.1 mg/mL glycerol dehydrogenase, 1 mM NADH, 50 mM potassium phosphate buffer at pH 8.0, 0.2 mM thiamine diphosphate 2 mM MgSO4, and formaldehyde ranging from 0 to 50 mM. The change in absorbance at 340 nm was monitored, which resulted from the oxidation-reduction reaction of NADH to NAD and dihydroxyacetone to glycerol catalyzed by the coupling enzyme glycerol dehydrogenase. An increased rate of dihydroxyacetone production from formaldehyde by formolase enzymes resulted in an increased rate of NADH oxidation. The change in absorbance at 340 nm was converted into concentrations using an extinction coefficient of 6220 M−1 cm−1.
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].[C:17](#[N:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:12]([C:17]([NH2:24])([CH2:12][CH2:13][CH2:14][CH3:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH3:15]
Reactant: N#Cc1ccccc1
Reactant: [Li]CCCC
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(N)(CCCC)c1ccccc1
Reaction time: 2 h
Yield: 90 %

Procedure:
Cerium chloride heptahydrate (15.0 g 40.2 mmol) was dried with magnetic stirring at 140°-150° under 0.1 mm vacuum for two hours. Nitrogen was admitted and the flask containing the solid was cooled with an ice bath. Anhydrous tetrahydrofuran (80 mL) was added and the suspension was stirred at room temperature for 2 hours. n-Butyllithium (24 mL of a 1.6M solution in hexanes, 40 mmol) was added below -55° by syringe, and the mixture was stirred in a dry ice acetone bath for 30 minutes. Benzonitrile (1.34 g, 13 mmol) in 2 mL of anhydrous tetrahydrofuran was added, and the cooling bath was removed. Aqueous ammonium hydroxide (25 mL) was added after 2 hours, keeping the temperature below 0°, and the mixture was filtered with the aid of celite™. The solids were washed three times with methylene chloride, and the aqueous layer of the filtrate was extracted twice with methylene chloride. The combined organic phases were dried and concentrated and the residue was short-path distilled to give 2.53 g (90%) of the title compound distilling at a bath temperature of 80°-130° (0.003 mm). 1H-NMR (in CDCl3) ∂0.8 (t, J=6 Hz, 6H), 1.0 (m, 2H), 1.2 (m, 6H), 1.4 (br, 2H), 1.6 (m, 2H), 1.8 (m, 2H), 7.2-7.4 (m, 5H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.BrBr.[C:12](=O)(O)[O-].[Na+]>C(O)(=O)C.CCCCCC>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C([O-])O
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1ccc2c(c1)CCO2
Reaction time: 1 h
Yield: 28 %

Procedure:
To a chilled (10° C.) solution of 10 g (83 mmol) of 2,3-dihydrobenzofuran in 50 mL of acetic acid, 4 mL (78 mmol) of bromine in 6 mL of acetic acid was added dropwise over a 10 minute period. After 1 hour, the mixture was made basic by cautiously pouring the reaction mixture into saturated/solid aqueous sodium bicarbonate and stirring overnight. The mixture was then extracted with three 100 mL portions of EtOAc. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, three 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated to afford a yellow oil. The oil was diluted with hexane and passed through a pad (600 mL funnel) of silica gel eluting with hexane to afford a white solid which was diluted with cold (dry ice-acetone) hexane and collected by filtration to afford 4.7 g (28%) of the title compound as a white solid, m.p. 45° C.-48° C. The filtrate was concentrated to afford 5.1 g of 5-bromo-2,3-dihydrobenzofuran which was 70% pure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH:20]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][CH2:26][CH2:25][CH2:24][O:23][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CC(C)OCCCN
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCCCOC(C)C
Yield: 88 %

Procedure:
The compound prepared in Example 3 was reacted with 3-isopropoxy-propylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 88%).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:12][CH3:13])[C:9]([NH2:11])=[O:10])[C:5](=[O:14])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I>C(#N)C>[I:34][CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:12][CH3:13])[C:9]([NH2:11])=[O:10])[C:5](=[O:14])[CH2:4]1
Reactant: II
Reactant: CC[C@@H](C(N)=O)N1CC(CO)CC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC[C@@H](C(N)=O)N1CC(CI)CC1=O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
In a 10 l 3 necked vessel, fitted with mechanical stirrer and reflux condenser under inert atmosphere, 400 g (2 mole, 1 eq) of (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamide 6 are dissolved in 3 l of acetonitrile. 629 g (2.4 moles, 1.2 eq) of triphenylphosphine are added, followed by 608 g (2.4 moles, 1.2 eq) of iodine in three portions over 5 min. The mixture is heated up to 60° C. in 30 min, and stirred at that temperature for 5 hours. After cooling down, the mixture is concentrated to dryness, the residue suspended in a solution of 750 g of Na2S2O3 in 10 l of water and stirred at 50° C. for 4 hours. The precipitate is filtered off and washed with 3×1 l of water. The combined aqueous phases are treated with 1 kg of NaCl, and extracted with 6×1 l of CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated to dryness to give 482 g of crude 10. It is crystallised from toluene. Several crops are recrystallised together from ethyl acetate to give 425 g of pure 10, 68%.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH:32]=[CH:33][C:34](O)=[O:35]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:34](=[O:35])[CH:33]=[CH:32][C:31]1[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:29]([O:28][CH3:27])[CH:30]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1ccc(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Yield: 73 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 3,4-dimethoxycinnamic acid under the conditions described in example 86 to yield 73% of the desired product.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:49][C:44]1[CH:43]=[C:42]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=3)[CH2:21]2)[CH:47]=[CH:46][C:45]=1[Cl:48]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CS(=O)(=O)OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@@](CCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[[3,5-bis(trifluoromethyl)phenyl]acetyl]pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]2[C:10]3[CH:17]=[CH:16][N:15]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:49][C:50]1[CH:51]=[C:52]([NH:57][CH2:58][C:59](O)=[O:60])[CH:53]=[C:54]([Cl:56])[CH:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:49][C:50]1[CH:51]=[C:52]([NH:57][CH2:58][C:59]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]3[C:10]4[CH:17]=[CH:16][N:15]([S:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=5)(=[O:19])=[O:20])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:2]2)=[O:60])[CH:53]=[C:54]([Cl:56])[CH:55]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCNC4)ncnc32)cc1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of N-(azepan-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.6 g, 1.6 mmol), in DMF (10 mL) was added EDCI (335 mg, 1.9 mmol), HOBt (250 mg, 1.9 mmol), 2-(3,5-dichlorophenylamino)acetic acid (342 mg, 1.6 mmol) and DIEA (301 mg, 2.3 mmol) at 0° C. The reaction mixture was stirred at rt overnight, diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound that purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (800 mg, 87%). LC-MS: m/z [M+1]=587.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2([CH3:11])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:12][CH2:13][C:14]([O:16]CC)=[O:15])=[C:4]([O:19][CH3:20])[CH:3]=1.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2([CH3:11])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CCOC(=O)CNc1cc(C2(C)CC2)c(Cl)cc1OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(C2(C)CC2)cc1NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution of ethyl 2-((4-chloro-2-methoxy-5-(1-methylcyclopropyl)phenyl)amino)acetate (630 mg, 2.12 mmol) in THF (15 mL) and water (5 mL), LiOH.H2O (889 mg, 21.2 mmol) was added and the resulting mixture was stirred at RT for 2 h. The mixture was washed with 20% ethyl acetate/petroleum ether. The aqueous layer was acidified with aqueous HCl (1N) to adjust pH to 3-4 and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford the desired product (200 mg, 33% yield).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]([CH3:29])[N:19]=[N:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)=[CH:11][N:10]=1)=[O:8])C>O.C1COCC1.CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[N:20]=[N:19][N:18]([CH3:29])[C:17]=2[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:7]([OH:8])=[O:6])=[N:10][CH:11]=2)=[N:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)nnn2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of lithium hydroxide monohydrate (59 mg, 1.41 mmol) in water (1.8 mL) was added dropwise to a suspension of 5-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (252 mg, 0.71 mmol) in THF (1.8 mL) and MeOH (0.4 mL). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (180 mg, 78%) as a white solid after trituration with ethyl acetate. MS: m/e=330.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]4)[CH:14]=[N:13][CH:12]=3)[C:4]=2[CH:3]=1.[F:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][C:35]([CH3:47])=[CH:34][N:33]=1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:31][C:32]1[C:37]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]5)[CH:14]=[N:13][CH:12]=4)[C:4]=3[CH:3]=2)=[CH:36][C:35]([CH3:47])=[CH:34][N:33]=1
Reactant: Cc1cnc(F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(-n3ncc4cnc(Cl)cc43)n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cnc(F)c(-c2cc3c(cn2)cnn3-c2cncc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)c1
Temperature: 150 °C
Yield: 83.6 %

Procedure:
A mixture of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl]-1,4-diazepane-1-carboxylate (0.2526 mmol; 108.6 mg), 2-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.3789 mmol; 89.84 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.02526 mmol; 21.1 mg), potassium acetate (0.3789 mmol; 0.38 mL) and sodium carbonate (0.3789 mmol; 0.38 mL) in Acetonitrile (10 mL) in a pressure tube was heated under microwave at 150° C. for 15 min. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated. The residue was purified on silica eluted with 0 to 5% MeOH in DCM with 1% NH4OH to afford tert-butyl 4-[6-[6-(2-fluoro-5-methyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate (106.6 mg, 84%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[C:9]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:8](C(OC(C)(C)C)=O)[C:7]=12.[CH2:37]([O:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)[CH3:38].[F-].[K+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[CH2:37]([O:39][C:40]1[CH:41]=[C:42]([C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:10]([CH2:11][CH2:12][O:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)=[C:9]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:8][C:7]=23)[CH:43]=[CH:44][CH:45]=1)[CH3:38]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1c(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c2n1C(=O)OC(C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c2c(-c3cccc(OCC)c3)nccc2c1CCOc1ccc(OC(F)(F)F)cc1
Reaction time: 4 h
Yield: 91.5 %

Procedure:
To a mixture of 1-tert-butyl 2-ethyl 7-chloro-3-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-1,2-dicarboxylate (88 mg, 0.17 mmol), 3-ethoxyphenylboronic acid (69 mg, 0.42 mmol), KF (38.7 mg, 0.67 mmol), and bis(tri-t-butylphosphine)palladium (0) (8.50 mg, 0.02 mmol) was added dioxane (3.5 mL) under a nitrogen atmosphere. The reaction was then heated to 100 C overnight. Another charge of 3-ethoxyphenylboronic acid (69 mg, 0.42 mmol), KF (38.7 mg, 0.67 mmol), and bis(tri-t-butylphosphine)palladium (0) (8.50 mg, 0.02 mmol) was then added and stirring was continued for 4 h. The crude reaction mixture was then concentrated in vacuo, and the crude material was purified on silica (gradient elution, 0-50% EtOAc/hexanes) to yield the title product (80 mg) as a mixture with Boc'd material 1-tert-butyl 2-ethyl 7-(3-ethoxyphenyl)-3-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-1,2-dicarboxylate. HRMS (ESI) calc (M+H)+=515.1788. found 515.1772.
Reaction SMILES: CCCCC.C([Li])(C)(C)C.O1CCCC1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[N:26]=[C:25]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=3)[N:24]=2)=[CH:19][CH:18]=1.Br[C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][N:51]=1>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>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([C:27]2[N:26]=[C:25]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([CH3:47])([CH3:48])[CH3:46])=[CH:41][CH:40]=3)[N:24]=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([C:50]4[CH:55]=[CH:54][C:53]([C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)=[CH:52][N:51]=4)=[CH:22][CH:21]=3)[N:28]=2)=[CH:34][CH:33]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: Brc1ccc(-c2ccccc2)cn1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccccc5)cn4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Under a stream of argon, 3.5 ml of a pentane solution containing 5.2 mmol of tert-butyl lithium was slowly added to 15 ml of tetrahydrofuran cooled to −78° C., and 10 ml of tetrahydrofuran in which 0.61 g of 2-bromo-5-phenylpyridine had been dissolved was further added dropwise to this solution. After stirring at −78° C. for 30 minutes, 1.64 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 35 ml portion of tetrahydrofuran prepared by dissolving 1.00 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine synthesized by the method of Reference Example 1 and 0.12 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 10 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:dichloromethane=3:2 to 4:3) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-tert-butylphenyl)-6-[4-(5-phenylpyridin-2-yl)phenyl]-1,3,5-triazine (1.05 g, yield 91%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=[O:11])=[O:8].[N+:13]([O-])([O-:15])=[O:14].[K+]>OS(O)(=O)=O>[CH:2]1[C:1]([N+:13]([O-:15])=[O:14])=[CH:6][C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]=2[CH:3]=1)=[O:11])=[O:8]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
6-Nitrobenzoyleneurea was prepared using an adaptation of the method of Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962). To a solution of benzoyleneurea (0.201 g, 1.24 mmol) in 3.0 mL concentrated H2SO4 at 0° C. was added KNO3 (0.139 g, 1.37 mmol) in one portion. The reaction mixture was allowed to warm to room temperature then stirred overnight. The resulting yellow solution was poured onto 10 mL of ice giving a pale yellow precipitate. The precipitate was isolated on a Hirsch funnel and washed with 35 mL of deionized water. The solid was suspended in 25 mL deionized water, refiltered via Hirsch funnel and allowed to dry on the filter under vacuum for 30 minutes affording 0.155 g (60%) title compound as a pale yellow powder. An analytical sample was obtained by recrystallization from 50% glacial acetic acid as a pale brown microcrystalline solid: mp 327°-328° C. (lit., Varma and Singh; Ind. J. Chem. 296:578-81 (1990): 315°-316° C. dec.). FT-IR (cm-1) 3020, 2850, 1713, 1684, 1631, 1602, 1538, 1491, 1444, 1385, 1332, 1303, 1239, 1157. 1H NMR (DMSO-d6 at δ2.49): δ7.30 (d, J8,7 =9 Hz, 1 H, H8); 8.44 (dd, J7,8 =9 Hz, J7,5 =2.4 Hz, 1H, H7); 8.57 (d, J5,7 =2.7 Hz, 1H, H5); 11.71 (s, 1H, NH); 11.76 (s, 1H, NH). EIMS m/z 207 (M+, bp), 164 (43%), 134 (18%), 106 (22%), 90 (29%), 63 (27%). EIHRMS calc. for C8H5N3O4 207.02799, found 207.02910.
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19]([OH:21])=O)[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH:30][CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][N:30]([CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)[C:19](=[O:21])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:9])[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Reactant: OCCNCc1ccccn1
Product: Cc1ccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ccccc2C)cc1

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol