Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[NH:12][C:13]([CH:15]1[CH2:17][CH2:16]1)=O>C(O)(=O)C.[Fe]>[CH:15]1([C:13]2[NH:12][C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=3[N:9]=2)[CH2:17][CH2:16]1
Reactant: COc1cccc([N+](=O)[O-])c1NC(=O)C1CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cccc2nc(C3CC3)[nH]c12
Yield: 78.9 %

Procedure:
Cyclopropanecarboxylic acid (2-methoxy-6-nitro-phenyl)-amide (5013) (7.80 g, 33.1 mmol) and iron powder (7.60 g) were suspended in acetic acid (200 mL) for 25 min at reflux. The reaction was concentrated and redissolved in ethyl acetate, and washed with NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography with 2% MeOH/CH2Cl2 and recrystallization from diethyl ether/hexane (3:1), yielding white crystals of 2-(cyclopropyl)-4-methoxylbenzimidazole (5014) (4.90 g, 26.1 mmol, 79% yield). 1H-NMR (200 MHz, CD2Cl2:) δ7.07 (cm, 2H), 6.65 (cm, 1H), 3.90 (s, 3H, OCH3), 2.17-2.03 (m, 1H), 1.22-0.96 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][C@:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][C:29](=[O:31])[CH3:30])[CH2:19][O:18]1>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([NH:13][CH2:19][C@:17]([OH:18])([CH3:16])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][C:29](=[O:31])[CH3:30])[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: CC(=O)Nc1ccccc1OC[C@@]1(C)CO1
Reactant: NC1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccccc1OC[C@](C)(O)CNC1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 105.6 %

Procedure:
1-(4-chlorobenzyl)-4-piperidinamine (62 mg, 0.276 mmol) and N-(2-{[(2R)-2-methyloxiranyl]methoxy}phenyl)acetamide (61 mg, 0.276 mmol) in ethanol (1.5 ml) was stirred in a sealed vial at 80° C. for 4 hours. The reaction mixture was diluted with water and purified by reversed phase HPLC to give 130 mg (70%) of the title compound as a ditrifluoroacetate after lyophilisation. The optical purity was determined to 86% ee, by chiral HPLC on a Chiralpak AD-column.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:8]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34](=[O:35])[CH2:33][NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=[C:7]2[CH2:6][C:5]2[CH:30]=[CH:31][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(Cn2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: COC(=O)CNc1ccc(Cn2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1-(4-nitro-benzyl)-1H-imidazole (2.6 g, mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {-4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34][CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)[CH:37]=1>>[ClH:34].[ClH:34].[ClH:34].[ClH:34].[CH2:1]([N:8]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:17]=2)[CH2:13][CH2:14]1)[CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)[CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(NCc4ccccc4)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4ccccc4)Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (230 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (158 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a tetrahydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:8]1[C:13](=[O:14])[O:12][C:10](=O)[CH2:9]1)([O-:3])=[O:2].[NH2:18]/[C:19](/[CH3:25])=[CH:20]\[C:21]([O:23][CH3:24])=[O:22].C([OH:30])(C)(C)C>>[OH:30][C:9]12[CH2:10][O:12][C:13](=[O:14])[CH:8]1[CH:7]([C:6]1[CH:15]=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([CH3:25])[NH:18]2
Reactant: O=C1CC(=Cc2cccc([N+](=O)[O-])c2)C(=O)O1
Reactant: CC(C)(C)O
Reactant: COC(=O)/C=C(/C)N
Product: COC(=O)C1=C(C)NC2(O)COC(=O)C2C1c1cccc([N+](=O)[O-])c1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
##STR6## 4 mmol of 3-(3-nitrobenzylidene)-4-oxo-butyrolactone (E/Z mixture) and 4.4 mmol of methyl 3-aminocrotonate are suspended in 5 g of tert.-butanol, and the suspension is stirred for 3 hours at 30° C. It is evaporated down at room temperature in a rotary evaporator, and the residue is crystallized with a small amount of methanol. M.p.: 147°-149° C. (from methanol):
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=3[N:14]=[C:13]2[CH2:22]Cl)[CH2:9]1)=O)(C)(C)C.[CH3:24][S:25]([C:28]1[C:36]2[C:31](=[CH:32][N:33]=[CH:34][CH:35]=2)[NH:30][N:29]=1)(=[O:27])=[O:26]>>[NH:8]1[CH2:9][CH:10]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=3[N:14]=[C:13]2[CH2:22][N:30]2[C:31]3=[CH:32][N:33]=[CH:34][CH:35]=[C:36]3[C:28]([S:25]([CH3:24])(=[O:26])=[O:27])=[N:29]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(n2c(CCl)nc3cc(Cl)ccc32)C1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CNC2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-13 by using 3-(5-chloro-2-chloromethyl-benzoimidazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine instead of 3-(5-chloro-2-chloromethyl-benzoimidazol-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[NH2:44][C:45]1[S:46][C:47]([CH2:50][CH3:51])=[N:48][N:49]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:44][C:45]2[S:46][C:47]([CH2:50][CH3:51])=[N:48][N:49]=2)=[O:42])=[CH:18][CH:17]=1
Reactant: CCc1nnc(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1nnc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-ethyl-1,3,4-thiadiazole (45 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 72 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:43]1([CH3:59])[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]3[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][C:52]=3[N:53]=2)=[CH:45][CH:44]=1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([NH:58][C:55]1[CH:56]=[CH:57][C:51]2[O:50][C:49]([C:46]3[CH:47]=[CH:48][C:43]([CH3:59])=[CH:44][CH:45]=3)=[N:53][C:52]=2[CH:54]=1)=[O:6]
Reactant: Cc1ccc(-c2nc3cc(N)ccc3o2)cc1
Reactant: O=C(O)CCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nc3cc(NC(=O)CCC(F)(F)F)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.5 %

Procedure:
To 4,4,4-trifluorobutanoic acid (128 mg, 0.90 mmol) in dry dimethylformamide (5 mL) was added HATU (397 mg, 1.05 mmol) and diisopropylethylamine (496 μL, 2.85 mmol). The mixture was then stirred at room temperature for 10 min. 2-p-Tolylbenzo[d]oxazol-5-amine (200 mg, 0.95 mmol) was then added and the resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed once with saturated aqueous Na2CO3, followed by another wash with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 40:60 v/v to afford 26.7 mg (8%) of the title compound (LCMS RT=6.77 min, MH+ 348.9)
Reaction SMILES: CS[C:3]1[C@@:8]([O:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][N:4]=1.[CH3:24][O:25][C:26]1[N:31]=[C:30]([C:32]([NH:34][NH2:35])=O)[CH:29]=[CH:28][C:27]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1.C(O)(=O)C>C(OCC)(=O)C>[CH3:24][O:25][C:26]1[N:31]=[C:30]([C:32]2[N:4]3[CH2:5][CH2:6][CH2:7][C@:8]([O:14][C:15]4[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=4)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]3=[N:35][N:34]=2)[CH:29]=[CH:28][C:27]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCN=C1SC
Reactant: COc1nc(C(=O)NN)ccc1-n1cnc(C)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To ethyl (3S)-2-(methylsulfanyl)-3-(3,4,5-trifluorophenoxy)-3,4,5,6-tetrahydropyridine-3-carboxylate (702 mg) and 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carbohydrazide (500 mg) was added acetic acid (3 ml), and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate). The crudely-purified product was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (1.02 g).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@@H:23]3O)=[N:6][C:7]([CH:18]3[CH2:20][CH2:19]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:51]=[N+:52]=[N-:53].CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C1COCC1>[N:51]([C@@H:23]1[CH2:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:22]1[NH:21][C:5]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:7]([CH:18]2[CH2:19][CH2:20]2)[N:6]=1)=[N+:52]=[N-:53]
Reactant: [N-]=[N+]=N
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of (1R,2S)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol (0.76 g, 1.7 mmol) in toluene (10 mL) and THF (10 mL) was added PPh3 (1.14 g, 4.57 mmol). The solution was cooled to 0° C. and HN3 (5.6 mL, 6.38 mmol) and a solution of diethylazodicarboxylate (0.69 mL, 4.37 mmol) in toluene (10 mL) were added. The reaction was stirred at rt overnight. The precipitates were removed by filtration and the filtrate was concentrated. Dissolve residue in 1 N HCl and EtOAc. Extract with EtOAc (3×30 mL). The aqueous phase was neutralized with sat. aq. NaHCO3 to pH 7.5 followed by a small amount of 6 N NaOH to pH 9. The aqueous phase was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 29-39% ethyl acetate/hexanes) to afford 0.8 g (78%) of N-[(1R,2R)-2-azido-2,3-dihydro-1H-inden-1-yl]-3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-amine as a solid: 1H NMR (CDCl3) δ 0.74-1.10, 1.63-1.71, 2.97-3.03, 3.36-3.42, 4.09-4.13, 4.26-4.29, 5.05, 5.57, 7.25-7.53; MS (ESI+) for C25H22Cl2N6 m/z 477 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.[F:32][C:33]1[C:34](I)=[C:35]2[CH:41]=[CH:40][N:39](S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)[C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CC#N>[F:32][C:33]1[C:34]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)=[C:35]2[CH:41]=[CH:40][NH:39][C:36]2=[N:37][CH:38]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(I)c(F)cnc32)cc1
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1nc(C(=O)Nc2cc(-c3c(F)cnc4[nH]ccc34)cc3[nH]ncc23)cs1
Reaction time: 8 h

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (1 g) was dissolved in DMF (4 ml) and 400 μl of the resultant solution was dispensed to 5-fluoro-4-iodo-1-[(4-nitrophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine (0.18 mmol) in DMF (400 μl) in a microwave vessel. Solvias catalyst (4 mg) was added and the reaction was heated in the microwave using initial 700 W to 135° C. for 20 min. The solution was loaded onto C18 SPE (pre-conditioned with 0.1% TFA in MeCN) and flushed through with 0.1% TFA in MeCN (3 ml). The solvent was removed under nitrogen blowdown. The sample was dissolved in DMSO (0.5 ml) and purified by MDAP (method D). The solvent was evaporated in vacuo using the Genevac. The sample was dissolved in IPA (300 μl) and 2M NaOH (aq) (300 μl) was added. The reaction was left overnight. The sample was dissolved in DMSO (0.6 ml) and purified by MDAP (method M). The solvent was evaporated in vacuo using the Genevac to give title compound, 2 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][CH2:12][C@H:13]([CH2:22][OH:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:24]OC(C1C2OC[C@H](CO)N(C3C=CC(CC)=CN=3)C=2C=CC=1)=O.[H-].[Na+].CI>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][CH2:12][C@H:13]([CH2:22][O:23][CH3:24])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1OC[C@H](CO)N2c1ccc(C)cn1
Reactant: CCc1ccc(N2c3cccc(C(=O)OC)c3OC[C@@H]2CO)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@H]1COc2c(C(=O)OC)cccc2N1c1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
3.0 g (9.5 mmol) of (S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-carboxylic acid methyl ester (compound 22) obtained in (34-6) were dissolved in 50 mL of THF. The solution was cooled to 0° C. and 1.1 g (28.6 mmol) of NaH was added slowly. The solution was stirred at 0° C. for 10 min and then at room temperature for 5 min. The solution was re-cooled to 0° C. and 120 uL (19.1 mmol) of MeI was added slowly. The mixture was placed at the same temperature for 1-2 hr and stirred while heating to room temperature. When the reaction terminated, the reaction mixture was neutralized by slow addition of 1N HCl solution, and dissolved in ethyl acetate and washed with distilled water and saturated sodium chloride solution, followed by drying over magnesium sulfate and concentration under reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate/hexane=1/2) to obtain the title compound (2.7 g, yield: 85%).
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[I:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2N)=[CH:11][CH:10]=1>C(O)C>[I:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[N:7]=[C:2]2[CH3:3])=[CH:11][CH:10]=1
Reactant: CCOC(C)=N
Reactant: Nc1ccccc1Nc1ccc(I)cc1
Agent: Cl
Solvent: CCO
Product: Cc1nc2ccccc2n1-c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl acetimidate hydrochloride (6.757 g, 54.9 mmol) was added to a suspension of N-(4-iodophenyl)-1,2-diaminobenzene (6.812 g, 22.0 mmol) in absolute ethanol (30 ml) at room temperature. After 2 hours, 50 ml of ice cold 2N aqueous sodium hydroxide was added and the product was extracted into ethyl acetate (2×100 ml). The extracts were washed with water (3×100 ml), dried (MgSO4) and concentrated under reduced pressure to give 1-(4-iodophenyl)-2-methylbenzimidazole, 6.695 g as a white solid, m.p. 136°-7° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:12][C:11]2=[O:27])[C:7]([CH3:28])=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>CC(O)C.ClC(Cl)C(O)=O>[C:1]([C:4]1[CH:9]=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[C:12]([Cl:29])[C:11]2=[O:27])[C:7]([CH3:28])=[CH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COc2cc(C)n(-c3cc(C(C)=O)ncc3C)c(=O)c2)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COc1ccc(COc2cc(C)n(-c3cc(C(C)=O)ncc3C)c(=O)c2Cl)cc1
Temperature: 60 °C

Procedure:
To a solution of 2′-acetyl-4-((4-methoxybenzyl)oxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one of part C (689 mg, 1.82 mmol) in 2-propanol (15 mL) was added N-chlorosuccinimide (266 mg, 2.00 mmol) and 3 drops of dichloroacetic acid. The slurry was heated at 60° C. for 3 hours. The solution was cooled using an ice bath and the resulting white solid was collected by vacuum filtration. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo and purified using normal phase chromatography (ethyl acetate/heptane) and the desired product was combined with material obtained via filtration (568 mg): MS (M+H) 414.
Reaction SMILES: C(O)C(N)(CO)C[OH:4].Cl.[NH2:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C2C(=NC=CN=2)C(=O)NC=1N>CC1(C)NC2C(N=C(N)NC=2NC1)=O>[NH2:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:4])=[CH:15][CH:14]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NC(CO)(CO)CO
Agent: CC1(C)CNc2[nH]c(N)nc(=O)c2N1
Agent: Cl
Agent: Nc1nc2nccnc2c(=O)[nH]1
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 0.03 h

Procedure:
Spectra were taken of the q-6,6-Me2PH2 synthesized enzymatically from 6,6-Me2PH4, and a comparison made with the chemically produced compound. The spectrophotometer was baseline corrected with sample and reference cuvettes containing all of the reaction components (0.1M Tris.HCl, pH 7.4, 4 mM phenylalanine, 2500 units catalase, 0.3 unit phenylalanine hydroxylase) except pterin in a total volume of 0.99 ml. 6,6-Me2PH4 (10 μl of 10 mM) was then added to the sample and distilled H2O (10 μl) to the reference cuvette. Scanning was begun immediately and spectra taken at 2 minute intervals. The formation of q-6,6-Me2PH2 was complete within 4 minutes. After correction for tyrosine formed and phenylalanine consumed, the spectrum was within 3% of that produced by Br2 oxidation of 6,6-Me2PH4 (FIGURE).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:31]3[CH2:35][CH2:34][NH:33][S:32]3(=[O:37])=[O:36])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:14][CH:13]=4)=[C:9]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:8]=3[CH:30]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:40]I>CN(C=O)C>[CH:1]1([C:4]2[C:5]([N:31]3[CH2:35][CH2:34][N:33]([CH3:40])[S:32]3(=[O:36])=[O:37])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:14][CH:13]=4)=[C:9]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:8]=3[CH:30]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)oc2cc(N3CCNS3(=O)=O)c(C3CC3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)oc2cc(N3CCN(C)S3(=O)=O)c(C3CC3)cc12
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
To a solution of 62 (0.058 g, 0.11 mmol) and dry DMF (5 mL) was added sequentially NaH (5 mg, 0.12 mmol, 50% mineral oil dispersion) and MeI (0.08 mL, 0.14 mmol). The reaction mixture was stirred for 15 min then quenched with H2O and extracted with EtOAc/Et2O. The organic phase was washed sequentially with H2O and brine, dried (MgSO4), filtered and evaporated to afford 30 mg of ethyl 5-cyclopropyl-6-(5-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)-2-(4-phenoxy-phenyl)-benzofuran-3-carboxylate (64). Hydrolysis of the ethyl ester and conversion to the amide was carried out as previously described in steps 12 and 13 of example 3 to afford I-105.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([C:14]3[N:18]=[CH:17][N:16]([CH3:19])[N:15]=3)[CH:11]=[CH:12][CH:13]=2)OC1.Br[C:22]1[N:26]2[N:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:19][N:16]1[CH:17]=[N:18][C:14]([C:10]2[CH:9]=[C:8]([C:28]3[C:29]([C:31]([F:33])([F:34])[F:32])=[N:30][C:25]4[N:26]([CH:22]=[CH:23][N:24]=4)[N:27]=3)[CH:13]=[CH:12][CH:11]=2)=[N:15]1
Reactant: Cn1cnc(-c2cccc(B3OCC(C)(C)CO3)c2)n1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cnc(-c2cccc(-c3nn4ccnc4nc3C(F)(F)F)c2)n1
Yield: 57.9 %

Procedure:
This reaction was carried out as described in Example 37, step e, using 3-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-1-methyl-1H-[1,2,4]triazole (515 mg, 1.9 mmol), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.461 g, 1.73 mmol), 2 M Na2CO3 (1.9 ml) and tetrakis(triphenylphosphine)palladium(0) (0.1 g) in 1,2-dimethoxyethane (4 ml). The crude residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) and triturated with Et2O to yield the title compound (346 mg, 58%). 1H NMR (360 MHz, CDCl3) δ 4.02 (3H, s), 7.64 (1H, t, J 7.9 Hz), 8.11 (1H, s), 8.16 (1H, dt, J 8.2, 1.6 Hz), 8.21 (1H, dt, J 8.2, 1.6 Hz), 8.71 (1H, s), 8.81 (1H, t, J 1.4 Hz), 8.84 (1H, s); MS (ES+) m/z 346 [M+H]+.