Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[NH:23])OC)=[CH:15][CH:14]=2)[N:10]=1)(=[O:4])[CH3:3].[Cl-].[NH4+:25].N>CCO.CO>[ClH:1].[NH2:25][C:20](=[NH:23])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)=[CH:14][CH:15]=1
Reactant: [NH4+]
Reactant: COC(=N)Cc1ccc(CCc2csc(NC(C)=O)n2)cc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCO
Solvent: CO
Product: CC(=O)Nc1nc(CCc2ccc(CC(=N)N)cc2)cs1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
Methyl 2-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethanimidoate hydrochloride (600 mg) was dissolved in EtOH (12 ml). Then ammonium chloride (136 mg) and ammonia in methanol (2 ml) were added to the solution. The reaction mixture was refluxed for 4 hours under N2 atmosphere. After cooled to r.t., the suspension was filtered in vacuo. The filtrate was concentrated in vacuo, and the residue was solidified with EtOH/diethyl ether to give N-(4-{2-[4-(2-amino-2-iminoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide hydrochloride (338.6 mg) as an off-white solid.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][O:16]C(=O)C)[CH:11]=2)[O:8][C@@H:7]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([Cl:44])=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:6]1[O:45]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)(Cl)Cl.C(Cl)Cl.O>[Cl:44][C:23]1[N:22]=[C:21]2[C:26]([N:27]=[CH:28][N:20]2[C@H:7]2[C@H:6]([OH:45])[C@H:5]([OH:4])[C@@H:9]([C:10]3[O:14][N:13]=[C:12]([CH2:15][OH:16])[CH:11]=3)[O:8]2)=[C:25]([NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:24]=1
Reactant: CC(=O)OCc1cc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](OC(C)=O)[C@H]2OC(C)=O)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: OCc1cc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of acetic acid (2R,3R,4S,5S)-4-acetoxy-5-(3-acetoxymethyl-isoxazol-5-yl)-2-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-tetrahydro-furan-3-yl ester (Step CG1) in MeOH/chloroform (3:1 MeOH/chloroform) is treated with saturated potassium carbonate solution. After stirring at RT overnight, the reaction is diluted with DCM/water and the organic portion is separated. The organic portion is concentrated in vacuo to afford the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH:11]=2)[CH:7]=[N:6]1.[OH-].[Li+]>C1COCC1.O.CO>[F:1][C:2]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)ccc4F)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)ccc5F)c4)c3c2)c1
Yield: 90.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) methanesulfonamide (250 mg, 0.39 mmol) was hydrolyzed with lithium hydroxide (66 mg, 1.57 mmol) in THF/water/methanol (5/4/3 ml) mixture to afford 170 mg (89.94% yield) of the pure product. 1H NMR (DMSO-d6, 300 MHz): δ 11.83 (s, 1H), 8.47-8.32 (m, 3H), 7.97 (s, 1H), 7.799-7.794 (d, 1H), 7.64-7.55 (m, 3H), 7.49-7.44 (m, 3H), 7.32-7.21 (m, 2H), 5.44 (s, 2H), 3.03 (s, 3H) MS: m/z=479.8 (M+1), HPLC: 73.14% in method A.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][NH:15][C:16]([C@:18]2([CH3:40])[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([O:25][CH2:26][CH:27]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=O)=[CH:9][CH:8]=1>C1(C)C(C)=CC=CC=1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:5][C:16]([C@:18]3([CH3:40])[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([O:25][CH2:26][CH:27]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]4[C:39]3=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:24])=[N:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: C[C@@]1(C(=O)NCC(=O)c2ccc(Br)cc2)CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: C[C@@]1(c2ncc(-c3ccc(Br)cc3)[nH]2)CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 48.5 %

Procedure:
A mixture of ammonium acetate (844 mg; 10.97 mmol) and (S)-(9H-fluoren-9-yl)methyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-2-methylpyrrolidine-1-carboxylate (intermediate LS31; 1.00 g; 1.83 mmol) was heated to 140° C. in 25 mL xylene for 2.5 h at which time the reaction mixture was concentrated and loaded with dichloromethane onto a Biotage 40 samplet. Purification via Biotage (5 to 60% ethyl acetate/hexane over 1000 mL with 400 mL hold time) provided (S)-(9H-fluoren-9-yl)methyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (intermediate LS32; 469 mg; 49%) as an amber liquid. LC (Cond'n 12): RT=3.09 min; MS: Anal. Calcd. for [M+H]+ C29H26BrN3O2: 528.1; found 528.5.
Reaction SMILES: CON(C)[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>C1COCC1>[C:11]1([C:7]2[N:6]=[C:5]([C:4]([C:23]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:17])[CH:10]=[CH:9][CH:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Reactant: CON(C)C(=O)c1cccc(-c2ccccc2)n1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cccc(-c3ccccc3)n2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
To a solution of 38c (0.210 g, 0.86 mmol.) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 3.5 mL, 1.73 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with water, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure 1c as white needle crystals (78%). 1H NMR (CDCl3) δ 8.10 (d, br, 2H), 8.02-8.00 (m, 1H), 7.97-7.96 (m, 2H), 7.66 (s, 2H), 7.49-7.43 (m, 3H), 3.97 (s, 3H), 3.89 (s, 6H); MS (ESI) m/z 372.6 (M+Na)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:19]2[CH2:28][CH2:27][C:22]3(OCC[O:23]3)[CH2:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:19]2[CH2:28][CH2:27][C:22](=[O:23])[CH2:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1cc(C2=CCC3(CC2)OCCO3)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2=CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 68 %

Procedure:
A solution of 20% TFA in DCM (25 mL) was added to 8-[3-(methyloxy)-4-nitrophenyl]-1,4-dioxaspiro[4.5]dec-7-ene (900 mg, 3.09 mmol) and the mixture was stirred at rt for approximately 14 h. The reaction was then concentrated under vacuum. The residue was dissolved in EtOAc and aqueous (saturated) NaHCO3. The organic layer was separated, washed with H2O, dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step D (520 mg, 2.10 mmol, 68%) as a tan solid. MS (ESI): 248 [M+H]+.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.C[Si]([C:35]#[CH:36])(C)C>ClCCl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:35]([C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)#[CH:36]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#Cc1oc2c(O)c(OC)ccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
To a stirred solution of 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (50 mg, 0.10 mmol) in dichloromethane (1 ml) and triethylamine (0.5 ml) was added Pd(Ph3P)2Cl2 (3.5 mg, 5 mol %) and the reaction vessel was evacuated and backfilled with nitrogen three times. Trimethylsilylacetylene (30 mg, 0.30 mmol) and copper (I) iodide (3 mg, 15 mol %) were added sequentially and the resulting dark mixture was stirred for two hours at room temperature. After this time the reaction was concentrated under vacuum and treated with methanol (1 ml) and potassium hydroxide (30 mg, excess). Stirring was continued for 0.5 hours then the crude mixture was concentrated onto silica and chromatographed (silica gel, gradient elution—2:1 hexanes:ethyl acetate, 1:1 hexanes:ethyl acetate) to afford the product as a tan solid (10 mg, 26%); 1H NMR (CDCl3) δ 7.26 (d, J=8.6 Hz, 1H), 7.20 (s, 2H), 6.98 (d, J=8.6 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.87 (s, 6H), 3.51 (s, 1H); LRMS (ESI) m/z=383 (M+H+).
Reaction SMILES: [Br:1]Br.[Br:3][CH:4]([F:16])[C:5]([F:15])([F:14])[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[Br:1][C:9]1[CH:8]=[C:7]([O:6][C:5]([F:14])([F:15])[CH:4]([Br:3])[F:16])[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: Oc1ccc(OC(F)(F)C(F)Br)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Oc1ccc(OC(F)(F)C(F)Br)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
7.2 g of bromine in 30 ml of chloroform were added dropwise, at 25° C., to a solution of 12.2 g of 4-(2-bromo-1,1,2-trifluoroethoxy)-phenol in 100 ml of anhydrous chloroform, and the mixture was stirred for 12 hours at 25° C. The solvent was removed, and the residue was distilled at 100° C./0.4 mbar to give 15.5 g of pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C@H:15]([NH:19][C:20]([N:22]2[C:28](=[O:29])[C@@H:27]([CH2:30][C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])[CH2:26][NH:25][C:24](=[N:40][N:41]([CH3:43])[CH3:42])[CH2:23]2)=[O:21])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].Cl.C1(C)C=CC=CC=1>C(O)(=O)C>[NH2:1][C:2]1[CH:14]=[C:13]([C@H:15]([NH:19][C:20]([N:22]2[C:28](=[O:29])[C@@H:27]([CH2:30][C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])[CH2:26][NH:25][C:24](=[N:40][N:41]([CH3:43])[CH3:42])[CH2:23]2)=[O:21])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCC[C@@H](NC(=O)N1CC(=NN(C)C)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c(N)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCC[C@@H](NC(=O)N1CC(=NN(C)C)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
To the compound 21 (16 mg), 1 M hydrochloric acid in acetic acid solution was added, and the mixture was stirred at room temperature for 4 hours. To the reaction solution, toluene (5 ml) was added and the precipitated solid was collected by filtration to obtain the title compound (12.7 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[Cl:20])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Temperature: 55 °C
Yield: 84.5 %

Procedure:
A mixture of 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (8.7 g, 0.037 mol), thionyl chloride (120 ml, 1.65 mol) and DMF (1 ml) was stirred and heated to 55° C. for 6 hours. The mixture was cooled to room temperature and thionyl chloride was evaporated. The solid was dissolved in chloroform and the solution was washed with sodium bicarbonate and brine, the chloroform was evaporated under reduced pressure to give 7.9 g of a gray product. MS (ESI) m/z: 253 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](F)[CH:7]=1.Cl.[NH2:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].CCN(C(C)C)C(C)C.CN1CCCC1=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: C[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: N#Cc1ncc(F)cc1Br
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNc1cnc(C#N)c(Br)c1)NC(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
To a microwave vial were added 3-bromo-5-fluoropyridine-2-carbonitrile (150 mg, 0.746 mmol), tert-butyl [(2S)-1-aminopropan-2-yl]carbamate hydrochloride (157 mg, 0.755 mmol), DIPEA (0.260 mL, 1.49 mmol), and N-methyl-2-pyrrolidone (1.5 mL). The mixture was then heated by microwave irradiation to a temperature of 150° C. for 30 minutes. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate and washed with water. The organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford tert-butyl {(2S)-1-[(5-bromo-6-cyanopyridin-3-yl)amino]propan-2-yl}carbamate. MS ESI calc'd. for C14H20BrN4O2 [M+H]+ 355 and 357. found 355 and 357.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([CH:11]=[N:12][OH:13])=[CH:9][CH:8]=1.ClN1C(=O)CCC1=O.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[C:28]#[CH:29].C(N(CC)CC)C>CN(C=O)C.CCOCC>[CH2:32]([O:31][C:27]([C:28]1[O:13][N:12]=[C:11]([C:10]2[CH:14]=[CH:15][C:7]([O:6][CH2:5][C:4]3[CH:16]=[CH:17][CH:18]=[C:2]([F:1])[CH:3]=3)=[CH:8][CH:9]=2)[CH:29]=1)=[O:30])[CH3:33]
Reactant: C#CC(=O)OCC
Reactant: ON=Cc1ccc(OCc2cccc(F)c2)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1cc(-c2ccc(OCc3cccc(F)c3)cc2)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
4-(3-Fluoro-benzyloxy)-benzaldehyde oxime (which may be prepared as described in Preparation of Intermediate 3; 2 g, 8.2 mmol) was dissolved in DMF (4.8 mL) and the solution was cooled to 0° C. in an ice-water bath. N-Chlorosuccinimide (1.09 g, 8.2 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was poured into ice-water (125 mL) and the resulting suspension was extracted with EtOAc (200 mL). The organic extract was dried over Na2SO4, filtered, and evaporated. The residue was dissolved in Et2O (20 mL). A mixture of ethyl propiolate (1.1 mL, 10.9 mmol) and triethylamine (1.5 mL) in Et2O (20 mL) was added dropwise, and the mixture was stirred at room temperature for 9 days. Silica gel was added and the solvent was evaporated. The resulting mixture was purified by chromatography (5-15% EtOAc/hexane) to give 3-[4-(3-fluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (160 mg, 6%) as a white crystalline solid, which contained some of the undesired 4-carboxylic acid ethyl ester regioisomer.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[C:13]2[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CCCCCC.C(OCC)(=O)C.O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)[C:14]([CH3:19])=[C:13]2[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: COc1ccc2[nH]c(C)c(CC(=O)OC(C)(C)C)c2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)n2c(C)c(CC(=O)OC(C)(C)C)c3cc(OC)ccc32)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine sodium hydride (0.66 g, 60% in oil, 13.1 mmol) and dimethylformamide [50 mL). Cool to 0° C. using an ice-bath. Add t-butyl (5-methoxy-2-methyl-indol-3-yl]-acetate (3 g, 10.9 mmol). Stir until gas evolution ceases. Add 4-methoxybenzoyl chloride (2.23 g, 13 mmol). Warm to ambient temperature. After 18 hours, add water. Partition the reaction mixture between ethyl acetate and water. Separate the organic layer and extract with a saturated sodium chloride solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/4 ethyl acetate hexane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[NH:10])[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])=[NH:10])[CH:3]=2)=[CH:24][CH:23]=1
Reactant: COc1ccccc1CNC(=N)Nc1cc(Br)ccn1
Reactant: OB(O)Oc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1CNC(=N)Nc1cc(-c2ccc(F)cc2)ccn1
Temperature: 110 °C
Yield: 27.7 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.150 g (0.447 mmol) N-(4-bromopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine, 0.093 g (0.671 mmol) (4-fluorophenyl)boric acid, 0.142 g (1.343 mmol) sodium carbonate, and 0.036 g (0.031 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block for 17.5 hr at 110° C. under a nitrogen atmosphere. After appropriate workup and purification via preparative HPLC, 50.9 mg (0.124 mmol, 27%) pure N-[4-(4-fluorophenyl)pyridin-2-yl]-N′-(2-methoxybenzyl)guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[O:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C(OCC)(=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>[O:9]1[CH:13]=[CH:12][C:11]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:10]1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccoc1
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: CCO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2ccoc2)cn1
Yield: 92.5 %

Procedure:
A mixture of 2-amino-5-bromopyrazine (300 mg, 1.724 mmol), tetrakis(triphenylphosphine)palladium(0) (340 mg, 0.294 mmol), furan-3-boronic acid acid (300 mg, 2.681 mmol), and a saturated aqueous sodium carbonate solution (2 mL) in ethylene glycol dimethyl ether (5 mL) and ethanol (5 mL) was heated under reflux for 45 min. The reaction mixture was cooled, diluted with ethyl acetate, and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/3 hexanes/ethyl acetate to ethyl acetate) afforded 5-furan-3-yl-pyrazin-2-ylamine (256.9 mg, 92.5%) as a yellow solid: LRMS for C8H7N3O (M+H)+ at m/z=162.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[NH:7][C:8]([C:10]3[C:14]([N+:15]([O-])=O)=[CH:13][NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1>[Pd].C(O)C.CN(C=O)C>[CH3:21][O:20][C:19]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:9][C:8]([C:10]3[C:14]([NH2:15])=[CH:13][NH:12][N:11]=3)=[N:7][C:6]=2[CH:18]=1
Reactant: COc1cc2nc(-c3n[nH]cc3[N+](=O)[O-])[nH]c2cc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1OC
Yield: 53.6 %

Procedure:
A mixture of 5,6-dimethoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole (2.08 g, 7.2 mmol) and 10% palladium on carbon (200 mg) in ethanol (150 ml) and DMF (50 ml) was hydrogenated at room temperature and pressure overnight. The reaction mixture was filtered through Celite and the solvent removed in vacuo. The resulting solid was azeotroped with methanol and toluene and the solvent removed in vacuo. The crude material was purified by flash chromatography, eluting with DCM:MeOH:acetic acid:water (120:18:3:2) [DMAW120] followed by DCM:MeOH:acetic acid:water (90:18:3:2) (DMAW90). Product fractions were combined and the solvent removed in vacuo to yield 3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (˜1 g, 53%).
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][CH:15]([SH:17])[CH3:16]>CN(C=O)C.CCOC(C)=O>[F:10][C:9]1[C:2]([S:17][CH:15]([CH3:16])[CH3:14])=[C:3]([CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1cc([N+](=O)[O-])cc(F)c1F
Reactant: CC(C)S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Sc1c(F)cc([N+](=O)[O-])cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 11A (51 mg, 0.273 mmol) in DMF (1 mL), were added TEA (0.057 mL, 0.409 mmol) and propane-2-thiol (0.030 mL, 0.327 mmol). The mixture was stirred at rt for 1 h, then was diluted with EtOAc. The organic phase was washed with H2O (2×), 10% LiCl and brine, dried (Na2SO4), filtered though a 1″ pad of SiO2 and concentrated to give 20A (64 mg, 0.263 mmol, 97% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 10.69 (1H, s), 8.57 (1H, dd, J=2.4, 1.1 Hz), 8.15 (1H, dd, J=8.5, 2.5 Hz), 3.72 (1H, dt, J=13.4, 6.7 Hz), 1.33 (6H, d, J=6.0 Hz).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[CH:14][C:13](=[O:16])[CH2:12][N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+].[I:31]I>CN(C)C1C=CN=CC=1.C1COCC1.CCOCC>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([I:31])[C:13](=[O:16])[CH2:12][N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C=C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: II
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)C(I)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
To a solution of (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 50, 10 g, 29.28 mmol) and 4-dimethylaminopyridine (0.894 g, 7.32 mmol) in THF (100 mL)/water (100 mL) at room temperature was added potassium carbonate (3.24 g, 23.42 mmol) and iodine (8.92 g, 35.14 mmol). After stirring for 15 minutes, the reaction mixture was diluted with ether and washed with saturated sodium thiosulfate twice, then 5% citric acid and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-15% ethyl acetate/hexanes) afforded the desired product as a tan oil (11.6 g, 85%).