Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:16]([CH2:17][OH:18])=[C:15]([C:19]#[N:20])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[C:3]([N:12]2[C:16]([CH:17]=[O:18])=[C:15]([C:19]#[N:20])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: Cn1nc(-n2ncc(C#N)c2CO)c(Cl)c1OC(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cn1nc(-n2ncc(C#N)c2C=O)c(Cl)c1OC(F)F
Reaction time: 1 h

Procedure:
29 g (9.6 mmol) 1-(4-chlor-5-difluormethoxy-1-methyl-3-pyrazolyl)-5-hydroxymethyl-4-pyrazol-carbonitrile is added to 30 ml dichloromethane and 15.2 g pyridinium chlorochromate on aluminium oxide is then added. Stirring continues for 1 hour at room temperature and then the reaction mixture is vacuum filtered through Celite and purified by means of column chromatography using hexane/ethyl acetate.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])[CH3:3].C[O-].[Na+].[Na].[CH:17]12[O:22][CH:18]1[CH2:19][CH2:20][CH2:21]2.Cl>[Cl-].[Na+].O.O.CO>[CH3:1][C:2]([C:7]1[CH:8]=[C:9]([S:11][C@@H:21]2[CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:12])([CH3:4])[CH3:3]
Reactant: C1CC2OC2C1
Reactant: CC(C)(C)c1cc(S)ccc1O
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.6-bis(1,1-Dimethylethyl-4- mercaptophenol (11.5 g, 0.048 mole) was added to a solution of sodium methoxide [prepared from sodium (2.2 g, 0.097 mole)]in methanol (75 ml). After several minutes, cyclopentene oxide (3.86 g, 0.046 mole) was added, and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water (100 ml) containing saturated brine (50 ml) and 1N hydrochloric acid (80 ml). The mixture was extracted twice with 100 ml of diethyl ether. The combined diethyl ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography to give the product as a white solid which was recrystallized from hexane (DSC.m.p. 90° C.). The structure was supported by NMR and elemental analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NCC1[CH:27]=[C:28]([CH:44]=[CH:45]C=1)[C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:33]=1)=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:8][C:9]2[CH:27]=[C:28]([CH:44]=[CH:45][C:10]=2[CH3:11])[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[CH:33]=2)=[O:30])=[O:19])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Reactant: NCc1cccc(C(=O)Nc2cccc(N3CCOCC3)c2)c1
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 18, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with 3-aminomethyl-N-(3-morpholinophenyl)benzamide to give 3-[3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamido]4-methyl-N-(3-morpholinophenyl)benzamide in 42% yield; NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 1.54 (m, 2H), 1.91 (m, 2H), 2.27 (s, 3H), 3.06 (t, 4H), 3.2 (m, 2H), 3.64 (m, 2H), 3.72 (t, 4H), 5.01 (m, 1H), 6.66 (m, 1H), 7.18 (m, 2H), 7.28 (d, 1H), 7.4 (m, 3H), 7.56 (m, 2H), 7.77 (m, 1H), 7.92 (s, 1H), 9.98 (s, 1H), 10.01 (s, 1H).
Reaction SMILES: NC1[O:3][CH:4]2[CH:9]([OH:10])[CH:8]([OH:11])[C:7]([CH2:13][OH:14])([OH:12])[CH:5]2[N:6]=1.O>Cl>[NH2:6][CH:5]1[C:7]([CH2:13][OH:14])([OH:12])[CH:8]([OH:11])[CH:9]([OH:10])[CH:4]1[OH:3]
Reactant: NC1=NC2C(O1)C(O)C(O)C2(O)CO
Agent: Cl
Solvent: O
Product: NC1C(O)C(O)C(O)C1(O)CO
Temperature: 100 °C
Yield: 44.2 %

Procedure:
A solution of 16 mg of powdery 2-amino-4-(hydroxymethyl)-3a,5,6,6a-tetrahydro-4H-cyclopent[d]oxazole-4,5,6-triol dissolved in 2 ml of 6N aqueous hydrochloric acid was sealed in an ampoule and then hydrolyzed by heating at 100° C. for 24 hours. At the end of this time, water was added to the hydrolyzate, and the resulting mixture was concentrated to dryness by evaporation under reduced pressure. The residue was again dissolved in water, and the resulting solution was again concentrated to dryness, to remove the hydrochloric acid, and then the resulting residue was dissolved in 20 ml of water and the pH of the solution was adjusted to a value of 6.0 by the addition of a 1N aqueous solution of sodium hydroxide. The solution was passed through 20 ml of Amberlite CG-50 (NH4+) to hold the 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol by adsorption, and the column was washed with 60 ml of deionized water and then eluted with a 0.2N aqueous ammonia solution. The eluate was concentrated by evaporation under reduced pressure, to yield 5 ml of a concentrate. This concentrate was placed on a column packed with 50 ml of Dowex 1X2 (OH-), and the column was washed with 200 ml of deionized water and then eluted with 20% v/v aqueous methanol. The eluate was fractionated in 5 ml portions. Fractions 5-23, which exhibited an inhibitory activity against β-glucosidase were combined and concentrated by evaporation under reduced pressure. The concentrate was lyophilized to give 6.2 mg of 5-amino-1-(hydroxymethyl)cyclopentane-1,2,3,4-tetraol as a colorless powder having the properties described hereinabove.
Reaction SMILES: FC1C(F)=CC(C2C=CC(OCC3C=C4C(C=CN4)=CC=3)=CC=2)=C(OC)C=1.C(OC([N:35]1[C:43]2[C:38](=[C:39]([CH2:44][O:45][C:46]3[CH:51]=[CH:50][C:49]([C:52]4[CH:57]=[C:56]([F:58])[C:55]([F:59])=[CH:54][C:53]=4[O:60][CH3:61])=[CH:48][CH:47]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1)=O)(C)(C)C>>[F:59][C:55]1[C:56]([F:58])=[CH:57][C:52]([C:49]2[CH:50]=[CH:51][C:46]([O:45][CH2:44][C:39]3[CH:40]=[CH:41][CH:42]=[C:43]4[C:38]=3[CH:37]=[CH:36][NH:35]4)=[CH:47][CH:48]=2)=[C:53]([O:60][CH3:61])[CH:54]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3C(=O)OC(C)(C)C)cc1
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cc[nH]c3c2)cc1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ccc23)cc1

Procedure:
4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole was synthesized by a procedure similar to 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole from starting material 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic acid tert-butyl ester to yield the product was a white solid (156 mg, 99%). LC-MS (ES) calculated for C22H17F2NO2, 365.1; found m/z 366 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)[CH2:23][CH3:24])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:35]([OH:38])[C:36]#[CH:37]>>[CH2:23]([N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:37]#[C:36][CH2:35][OH:38])=[CH:3][CH:4]=3)=[N:9][S:10][C:11]=2[CH:16]=1)[CH3:24]
Reactant: CCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1)CCO[Si](C)(C)C(C)(C)C
Reactant: C#CCO
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(C#CCO)cc3)nsc2c1

Procedure:
In analogy to example 36.1, {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amine and 2-Propyn-1-ol were converted to yield 3-[4-(6-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-benzo[d]isothiazol-3-yl)-phenyl]-prop-2-yn-1-ol as yellow oil, MS: 425 (MH+).
Reaction SMILES: [Na].[Cl:2][C:3]1[N:8]=[C:7](Cl)[C:6]([F:10])=[CH:5][N:4]=1.[CH3:11][OH:12]>>[Cl:2][C:3]1[N:8]=[C:7]([O:12][CH3:11])[C:6]([F:10])=[CH:5][N:4]=1
Reactant: CO
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [Na]
Product: COc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a mixture of sodium (450 mg, 19 mmol) in methanol (20 mL) was added a solution of 2,4-dichloro-5-fluoropyrimidine (3.25 g, 19 mmol) in methanol (10 mL). The reaction mixture was stirred at room temperature overnight before being partitioned between water and diethyl ether. The organic phase was separated, washed with brine and evaporated to dryness to give the title compound as an orange oil (80%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH:30]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:37][CH2:36][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCC3CCCCC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with cyclohexanemethylamine (0.026 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(cyclohexylmethylaminomethyl)indol-2-yl]isoindolinone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[N:28]1([C:24](=[O:26])[CH2:25][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:6]=2[C:22]([OH:23])=[O:27])[CH2:31][CH2:30][CH2:29]1
Reactant: C1CNC1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Solvent: ClCCl
Product: O=C(O)c1c(CC(=O)N2CCC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
To a solution of 6-fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (1.0 mmole) in CH2Cl2 (3 ml) was added azetidine(5 mmole) and stirring was continued at 22° C. until completion of the reaction. The mixture was evaporated and the residue partitioned between aqueous HCl and AcOEt. The organic layer was dried, evaporated and the residue triturated with diethylether to give 3-(2-azetidin-1-yl-2-oxo-ethyl)-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid as a white solid. MS: 417.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][OH:9].[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47](O)[CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:29])([F:30])[F:31])[C:2]=3[Cl:1])[CH2:10][CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2)CC1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a stirring solution of 3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propan-1-ol (448 mg, 1.0 mmol) in toluene (30 mL) was added 4-(3-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (419 mg, 1.50 mmol). Polymer bound triphenylphosphine (500 mg, 1.50 mmol, 3 mmol/g, Fluka Chemie) was then added, and the mixture stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (303 mg, 1.50 mmol) was added in a dropwise fashion. After stirring at room temperature overnight, the crude reaction mixture was filtered and the solid washed with toluene. Concentration of the filtrate in vacuo followed by purification by flash silica gel chromatography (silica gel 60, EM science; 15% EtOAc:hexane) afforded title compound as an oil (0.59 g, 84%). MS(ES) m/e 708.4 (M+).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:8]=3[N:9]=[C:2]12.[C:19](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:19][N:6]1[CH2:5][CH2:4][N:3]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:8]=3[N:9]=[C:2]2[CH2:1]1
Reactant: CCOC(=O)c1ccc2c(c1)nc1n2CCNC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc2c(c1)nc1n2CCN(C)C1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Ethyl 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (0.98 g, 4.00 mmol) prepared in the Step 38-1-5 was dissolved in methanol (100 ml), and acetic acid (1.00 ml) and a 37% formaldehyde aqueous solution (1.2 ml) were added thereto. Thereafter, sodium cyanoborohydride (0.57 g, 9.07 mmol) was added to the mixture, and the resulting mixture was stirred. After 30 minutes, the mixture was concentrated under a reduced pressure. Chloroform was added to the concentrate, and the resulting mixture was washed with a saturated sodium bicarbonate solution. The washed product was dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (958 mg, 92%) as a light-brown powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][N:5]([S:21](=[O:31])(=[O:30])[NH:22]C(OC(C)(C)C)=O)[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C(O)=O.ClCCl>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][N:5]([S:21](=[O:30])(=[O:31])[NH2:22])[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)CN(c1c(F)cccc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN(c1c(F)cccc1OCc1ccccc1)S(N)(=O)=O

Procedure:
A solution of N-(t-butoxycarbonylsulfamoyl)-N-(2-benzyloxy-6-fluorophenyl)glycine methyl ester (980 mg, 2.09 mmol) 10 mL of trifluoroacetic acid:dichloromethane(1:1) is stirred at RT for 15 min. The solvent is removed under reduced pressure and the residue chromatographed on an Isco Companion (80 g silica gel cartridge, 30-60% gradient of hexane/ethyl acetate) to give N-sulfamoyl-N-(2-benzyloxy-6-fluorophenyl)glycine methyl ester. MS (M−1)−: 367 NMR (CDCl3): δ 7.41 (m, 5H), 7.25 (m, 1H), 2.21 (m, 2H), 5.13 (d, 2H, J=5.0 Hz), 5.02 (br s, 2H), 4.39 (dd, J=32 and 19 Hz, 2H), 3.70 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:9][N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:4][CH:3]=1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[N:28]=1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC>CN(C=O)C.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:22]([NH:21][C:19]([C:8]1[C:6]2=[N:7][C:2]([C:27]3[C:35]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH3:36])[N:28]=3)=[CH:3][N:4]=[C:5]2[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cn1nc(I)c2cccnc21
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cccnc21
Temperature: 125 °C
Yield: 68.2 %

Procedure:
To a solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (400 mg, 936 μmol) and 3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine (364 mg, 1.4 mmol) in DMF (8 mL) was added hexabutylditin (814 mg, 709 μL, 1.4 mmol) then the mixture was purged with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium (0) (54.1 mg, 46.8 μmol) was added and the reaction mixture was heated at 125° C. After 18 h the mixture was filtered through a pad of Celite to remove catalyst, then the filtrates were concentrated in vacuo and purified by chromatography (silica, 10-70% ethyl acetate in hexanes) to obtain N-tert-butyl-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (306 mg, 638 μmol, 68%) as an off-white powder. MS (M+H)+=480.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3]([OH:5])=O.[C:9]1([C@H:15]2[CH2:19][O:18][C:17](=[O:20])[NH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[Cl-].[Li+]>C(OCC)(=O)C>[CH3:1]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3]([N:16]1[C@@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:19][O:18][C:17]1=[O:20])=[O:5]
Reactant: CC/C=C(\C)C(=O)O
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC/C=C(\C)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 75 °C
Yield: 89.2 %

Procedure:
A 20 L jacketed reactor was fitted with a reflux condenser and a nitrogen inlet. To the flask was charged 1006 g (8.81 mol) of (E)-2-methyl-2-pentenoic acid, 1250 g (7.661 mol) of (S)-(+)-4-phenyl-oxazolidin-2-one, 2179 g (8.81 mol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 81 g (1.915 mol) of lithium chloride, and 12.5 L of ethyl acetate (EtOAc). The reaction was heated to 75° C. for 20 hours and then cooled to room temperature. The reaction solution was extracted 3× with 4 L aliquots of 1N HCl and 1× with 4 L of 0.2N NaOH. The 20 L reactor was fitted with a distillation head. The organic layer was distilled to remove, in succession: 6.5 L of EtOAc, after which 8 L of heptane was added back to the reactor; 4 L of EtOAc/heptane, after which 4 L of heptane was added to the reactor; and 4 L of EtOAc/heptane, after which 8 L of heptane was added to the reactor. After an additional 2 L of EtOAc/heptane was removed by distillation, the reaction mixture was cooled to an internal temperature of 40° C., and the reactor contents were charged to a filter and filtered under 5 psig of nitrogen washing with 8 L of heptane. The solids were dried under 5 psig of nitrogen overnight to give 1772 g of the titled compound: 1H-NMR (DMSO) 7.363-7.243 (m, 5H), 6.137-6.096 (m, 1H), 5.434-5.394 (m, 1H), 4.721-4.678 (t, 1H, J=8.578), 4.109-4.069 (m, 1H), 2.119-2.044 (m, 2H), 1.703-1.700 (d, 3H, J=1.364), 0.945-0.907 (t, 3H, J=7.603); Anal Calc'd for C15H17N1O3: C, 69.48; H, 6.61; N, 5.40. Found: C, 68.66; H, 6.60; N, 5.60; MS (Ion Mode: APCI) m/z=260 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.[Sn].CN(C=O)C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[F:13][C:10]([F:11])([F:12])[C:8]1[CH:9]=[C:4]([NH2:1])[C:5]([NH2:14])=[N:6][CH:7]=1
Reactant: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Sn]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(C(F)(F)F)cnc1N
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-nitro-5-trifluoromethyl-pyridin-2-ylamine from step (a) above (1.2 g, 5.59 mmol), tin (TI) chloride dihydrate (3.9 g, 17.3 mmol, Aldrich), and DMF (19 mL) was heated to 60° C. for 4 h. The reaction mixture was cooled to room temperature and NaHCO3 (150 mL) was added. The mixture was stirred for 0.5 h, diluted with EtOAc (300 mL), stirred for 0.5 h and filtered. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×300 mL). The combined organic extracts were dried over MgSO4 and filtered. The solvent was removed in vacuo to give the title compound, which was used in the next step without additional purification. MS (ESI, positive ion) m/z: 178 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:16])[C:5]2[N:6]([N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=1.[IH:17]>CCO>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:5]2[C:4]([NH2:16])=[N:3][C:2]([I:17])=[CH:7][N:6]2[N:8]=1
Reactant: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Reactant: I
Solvent: CCO
Product: Nc1nc(I)cn2nc(-c3ccco3)nc12
Yield: 92 %

Procedure:
A solution of 6-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (600 mg; see Examples 1 and 2 above) and 57% HI (10 mL) in EtOH (50 mL) was refluxed for 1 hour. The solvent was removed in vacuo and the residue was triturated with H2O to afford 2-furan-2-yl-6-iodo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine as a brown solid (642 mg, 92%). 1H NMR (300 MHz, DMSO-d6) δ 6.8 (dd, J3.4, 1.8 Hz, 1H), 7.2 (dd, J=3.4, 0.8 Hz, 1H), 7.95 (s, 1H), 8.6 (s, 1H). MS: m/z 327 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>C1C=CC=CC=1.FC(F)(F)C(O)=O.O>[C:18]1([CH:17]2[C:8]3[NH:9][C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]=3[CH2:6][C@@H:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)C(c2ccccc2)N1
Temperature: 25 °C
Yield: 80 %

Procedure:
To the solution of 0.06 mol of L-tryptophan methyl ester and 0.05 mol of benzaldehyde in 150 ml of benzene, 0.5 ml of trifluoroacetic acid and 2 g of molecular sieves (4 Å) were added. The reaction mixture was refluxed for 1 hour, and then 0.138 mol (3 equiv.) of trifluoroacetic acid was added and the mixture was further refluxed for 3 hours. The reaction mixture was cooled down to room temperature and diluted with water and basified with 30% solution of NaOH. The organic layer was separated, dried over MgSO4 and the solvent was removed in vacuo. The residue was washed with diethyl ether, and the precipitate thus formed was filtered off to give the required product (80% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[N:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[N:16][CH:15]=[CH:14][C:11]=1[C:12]1[NH:22][N:21]=[N:20][N:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccncc1Nc1ccc(I)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Fc1cc(I)ccc1Nc1cnccc1-c1nnn[nH]1
Temperature: 100 °C

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]isonicotinonitrile (100 mg, 0.29 mmol), ammonium chloride (28 mg, 0.52 mmol), and sodium azide (35 mg, 0.54 mmol) were dispended into a seal tube equipped with a stirring bar. The seal tube was degassed by vacuum and recharging with nitrogen three times before addition of anhydrous DMF (3 mL). The mixture was heated at 100° C. for three days. The mixture was diluted with saturated NaHCO3 and washed with EtOAc. The aqueous phase was acidified with concentrated HCl to pH<1, and washed with EtOAc. The aqueous layer was dried to give the desired product. LC/MS [Method B: rt: 6.008 min; m/z: 383 (M+1)].