Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (Aldrich; 3 g, 16.21 mmol), 4-Amino-1-methylpiperidine (Fluorochem; 2.03 g, 17.83 mmol), HATU (6.77 g, 17.83 mmol), DIPEA (8.5 mL, 48.63 mmol) and DMF (30 mL) were combined and stirred at ambient temperature for 18 hrs. Solvents evaporated and partitioned between DCM (200 ml) and water (100 ml). The aqueous phase was re-extracted with DCM (100 ml). The combined organic phases were dried (MgSO4) and evaporated. The resultant material was taken up in DCM and purified on silica eluting with a gradient of 0-5% 2M ammonia in MeOH/DCM then 5% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to give the title compound as a yellow solid (2.67 g, 59%)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=3[CH3:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C)c4C)c3O2)cc1
Product: CNCC1Cc2cccc(-c3cccc(C)c3C)c2O1

Procedure:
The title compound was prepared (0.046 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.23 mmol) and methylamine (0.072 g, 2.3 mmol). mp 197-199° C.
Reaction SMILES: [C:1]([N:6]1[C@@:10]2([CH2:14][CH2:13][N:12]([C@@H:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2=[O:30])[CH2:9][CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].CC=CC(Cl)=O>>[CH3:4][C:2](=[CH2:3])[C:1]([N:6]1[C@@:10]2([CH2:14][CH2:13][N:12]([C@@H:15]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2=[O:30])[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)C[C@H](C(=O)OCc1ccccc1)N1CC[C@]2(CCCN2C(=O)C(C)C)C1=O
Agent: CC=CC(=O)Cl
Product: C=C(C)C(=O)N1CCC[C@]12CCN([C@H](CC(C)C)C(=O)OCc1ccccc1)C2=O
Yield: 50 %

Procedure:
Following the procedure described for the synthesis of 13, starting from 11 (200 mg, 0.43 mmol) and methylacryloyl chloride (89 mg, 0.86 mmol), the title compound (70 mg, 50%) was obtained as a colourless oil, after purification by LC (silica ge, hex-EtOAc, 2:1). HPLC [Column Novapack C18 (Waters), 3.9×150 mm, Φ=1 ml/min, λ=214 nm, eluent: ACN/0.05% TFA, (25/75)] Rt=6.38 min.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCOC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCOC3)c2n1
Reaction time: 16 h
Yield: 63.7 %

Procedure:
2-Butoxy-8-methoxy-9-[2-(tetrahydro-2H-pyran-3-yl)ethyl]-9H-purin-6-amine (108 mg) was dissolved in methanol (2 ml) and 4N hydrogen chloride in dioxan (1 ml) added. After 16 h the reaction mixture was stripped, quenched with water then saturated sodium hydrogen carbonate added, when a solid precipitated. This was filtered, washed with water and dried. The solid was treated with hot methanol and was filtered after allowing to cool to yield 66 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].CCN(CC)CC.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>C1C=CC=CC=1>[CH3:20][N:21]([CH3:25])[C:22]([O:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:5]=[CH:4][N:2]([CH3:1])[CH3:3])=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)C=Nc1ccncc1O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1ccncc1OC(=O)N(C)C

Procedure:
4-[[(Dimethylamino)methylene]amino]-3-pyridinol (1.65 g) was refluxed for 1 hour in 20 ml of benzene containing 1.10 g of Et3N and 1.10 g of N,N-dimethylcarbamyl chloride. At the end of this time, the reaction mixture was applied directly to a silica column and eluted with 5% Et3N/ethyl acetate. Concentration of the product-containing fractions gave 2.05 g of chromatographically pure product which was distilled in a bulb to bulb apparatus (oven temperature=175° C.) to give analytically pure material, m.p. 64°-66° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[C:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:13]([Cl:15])=[CH:14][C:8]=2[O:7]1)=[O:5])C.NC(N)=N.O>CN(C)C=O>[Cl:15][C:13]1[C:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][C:9]2[O:10][CH:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:14]=1
Reactant: CCOC(=O)C1Oc2cc(Cl)c(S(=O)(=O)c3ccc(Cl)cc3)cc2O1
Agent: N=C(N)N
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1Oc2cc(Cl)c(S(=O)(=O)c3ccc(Cl)cc3)cc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.88 g (0.0069 mol) of 5-chloro-6-(4-chlorophenylsulphonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester are dissolved in 20 ml of dimethylformamide and are added to 0.71 g (0.012 mol) of guanidine at room temperature. The mixture is stirred for 2 hours at room temperature, then poured out onto 200 ml of water. After stirring for 1/2 hour, a crystalline suspension has formed. This is filtered, washed with water, and the crude product is dried in a vacuum drying chamber at 30°-40°. The crude product is then digested with 25 ml of ethyl acetate, partial dissolution and recrystallisation occurring. The whole is cooled for 1/2 hour in an ice-bath, filtered and dried, yielding, in the form of beige crystals, 5-chloro-6-(4-chlorophenylsulphonyl)-1,3-benzodioxole-2-carboxylic acid guanidide having a melting point of from 215° (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH2:19](Br)[CH3:20].C(N(CC)C(C)C)(C)C.CN(C)C=O>[I-].[Na+]>[CH2:19]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]=2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9]1)[CH3:20]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CNC2
Reactant: CCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CC(=O)N(C)c2cc([N+](=O)[O-])c(OC)cc2C1
Yield: 71.6 %

Procedure:
A mixture of 7-Methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0020 mol), Ethyl bromide (0.297 mL, 0.00401 mol), Sodium iodide (0.0029 g, 0.000019 mol) and N,N-Diisopropylethylamine (0.87 mL, 0.0050 mol;) in N,N-Dimethylformamide (4 mL, 0.05 mol;) was reacted in an analogous manner to example 743-C to give 4-Ethyl-7-methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a tan solid (0.40 g, 72%). Mp129-131° C.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[C:13]([O:17][CH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Na+].[Na+].O.CN(C)C=O>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>[C:13]([O:17][CH2:18][C:19]1[CH:24]=[C:23]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]3)=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OCc1cccc(B(O)O)c1
Reactant: CSc1ncc2ccc(Br)n2n1
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: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2ccc(-c3cccc(COC(C)(C)C)c3)n2n1
Temperature: 60 °C

Procedure:
7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.370 g, 1.52 mmol), 3-(tert-Butoxymethyl)phenylboronic acid (0.564 g, 2.71 mmol), Bis(tri-tert-butylphosphine)palladium (47 mg, 0.092 mmol), 2.00 M of Sodium Carbonate in Water (3.0 mL, 6.0 mmol), and N,N-Dimethylformamide (12.0 mL, 155 mmol) were combined in a reaction vial, partially degassed and backfilled with Nitrogen, and the mixture was heated at 60° C. overnight under an atmosphere of Nitrogen. The reaction mixture was diluted with water (25 mL) and DCM (25 mL). The aqueous was extracted with DCM (2×, 10 mL) and combined organics diluted with 1:1 EtOAc:hexane (50 mL), followed by washes with water (2×, 25 mL) and brine (25 mL). The organics were dried over sodium sulfate and conc. in vacuo to afford 7-(3-tert-Butoxymethyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine which was then oxidized, analogous to Example 1504a, to afford 7-(3-tert-Butoxymethyl-phenyl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (398 mg, 73%). 1H-NMR (DMSO-d6): 9.37 (s, 1H), 8.22 (s, 1H), 8.10 (d, 1H, J=7.77 Hz), 7.81 (d, 1H, J=4.97 Hz), 7.53 (t, 1H, J=7.77 Hz), 7.44 (d, 1H, J=4.97 Hz), 7.41 (d, 1H, J=7.77 Hz), 4.50 (s, 2H), 3.46 (s, 3H), 1.26 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=1
Reactant: Clc1cnccn1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1ccc(-c2cnccn2)cc1
Temperature: 80 °C
Yield: 71.7 %

Procedure:
A mixture of 2-chloropyrazine (0.230 ml, 2.62 mmol), 4-(hydroxymethyl)phenylboronic acid (517 mg, 3.41 mmol), tetrakis(triphenylphosphine)palladium (0) (303 mg, 0.262 mmol) and 2 M potassium phosphate aqueous solution (2.62 ml, 5.24 mmol) in dioxane (10 mL) was heated at 80° C. overnight under nitrogen. The mixture was cooled down, poured into water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give the title compound (350 mg) as an off-white solid. LCMS m/z=187.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 4.79 (s, 2H), 7.52 (d, J=8.1 Hz, 2H), 8.02 (d, J=8.1 Hz, 2H), 8.51 (d, J=2.5 Hz, 1H), 8.63 (dd, J=2.4 and 1.6 Hz, 1H), 9.03 (d, J=1.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:42]([OH:43])[C@@H:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:40]([CH2:52][OH:53])[O:39][C@H:10]1[O:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][C@H:18]([C@@H:20]1[C@:37]2([CH3:38])[C@H:23]([C@H:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][CH2:25]3)[CH2:22][CH2:21]1)[CH3:19])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54](Cl)(=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:42]([OH:43])[C@@H:41]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@@H:40]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[O:39][C@H:10]1[O:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][C@H:18]([C@@H:20]1[C@:37]2([CH3:38])[C@H:23]([C@H:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][CH2:25]3)[CH2:22][CH2:21]1)[CH3:19])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)CO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)CO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Temperature: -2.5 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Compound 26 (647 mg, 0.885 mmol) was dissolved in pyridine (13 mL). To the solution, pivaloyl chloride (138 μl, 1.15 mmol) was added, and the mixture was stirred at −5 to 0° C. for 0.5 hour. Pivaloyl chloride (138 μl, 1.15 mmol) was further added thereto, and the mixture was stirred at −5 to 0° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, and filtered through Celite, and the filtrate was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:AcOEt=10:1) to obtain Compound 27 (663 mg, 91.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:20][N:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[N:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:40]([O:42][CH3:43])=[O:41])[CH2:26][CH2:25]4)=[CH:22][CH:23]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To the solution of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1 (20 mg, 0.05 mmol) in THF (1 mL) was added DIEA (19 mg, 0.15 mmol) and methyl chloroformate (5.2 mg, 0.055 mmol). The reaction was stirred at room temperature for 40 min. The solvent was removed by rotary evaporation and the residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 132 as off-white solid. MS m/z 446.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.55 (s, 1H), 8.72 (d, 1H), 8.18 (s, 1H), 8.08 (m, 1H), 7.96 (d, 1H), 7.90 (d, 2H), 7.84 (d, 1H), 7.50 (d, 2H), 7.35 (dd, 1H), 3.72 (s, 2H), 3.54 (s, 3H), 3.43 (t, 4H), 3.03 (t, 3H), 2.65 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N12CCN(CC1)CC2.CN(C)C=O.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[S:30]>O>[CH3:27][N:28]([C:29](=[S:30])[O:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:32]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1OC(=S)N(C)C
Temperature: 50 °C
Reaction time: 7 h
Yield: 76.5 %

Procedure:
To a mixture of 350 g of methyl 2-hydroxy-4-methoxybenzoate, 648 g of 1,4-diazabicyclo[2.2.2]-octane (DABCO) and 3 L of dimethylformamide was added 712 g of dimethylthiocarbamoyl chloride. The mixture was warmed to 50° C. and held for 7 hours, then allowed to cool overnight. The mixture was poured into 10 L water; the aqueous mixture was extracted with 8 L of benzene-hexane (4:1). The organic solution was washed with 1N HCl, 10% NaOH, and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave 396 g of the title compound, m.p. 95°-105° C. Further extraction of the aqueous mixture gave additional product, 171 g, m.p. 117°-120° C. Recrystallization of a portion of the crude product from methanol gave pure material, m.p. 122°-124° C.
Reaction SMILES: [Br-].C([O:6][C:7](=[O:54])[C:8]([O:11]/[N:12]=[C:13](/[C:41]1[N:42]=[C:43]([NH:46]C(OC(C)(C)C)=O)[S:44][CH:45]=1)\[C:14]([NH:16][C@@H:17]1[C:20](=[O:21])[N:19]([S:22]([OH:25])(=[O:24])=[O:23])[C@@H:18]1[CH2:26][N:27]1[CH:31]=[C:30]([CH2:32][NH:33][C:34](=[O:40])[CH2:35][N+:36]([CH3:39])([CH3:38])[CH3:37])[N:29]=[N:28]1)=[O:15])([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:46][C:43]1[S:44][CH:45]=[C:41](/[C:13](=[N:12]/[O:11][C:8]([C:7]([OH:54])=[O:6])([CH3:9])[CH3:10])/[C:14]([NH:16][C@H:17]2[C@@H:18]([CH2:26][N:27]3[CH:31]=[C:30]([CH2:32][NH:33][C:34](=[O:40])[CH2:35][N+:36]([CH3:37])([CH3:38])[CH3:39])[N:29]=[N:28]3)[N:19]([S:22]([O-:25])(=[O:24])=[O:23])[C:20]2=[O:21])=[O:15])[N:42]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cc(CNC(=O)C[N+](C)(C)C)nn2)cs1
Agent: CC[SiH](CC)CC
Agent: [Br-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1Cn1cc(CNC(=O)C[N+](C)(C)C)nn1)c1csc(N)n1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
To a slurry of 2-(((1-(((2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxo-1-sulfoazetidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-N,N,N-trimethyl-2-oxoethanaminium bromide (50 mg, 0.0635 mmol) In DCM (640 μL) at 0° C. was added TFA: DCM (1:1, 1.92 mL) followed by triethylsilane (31 μL, 0.19 mmol). The reaction mixture was stirred at 0° C. for 30 min and slowly warmed to room temperature. After 2 h at rt, it was concentrated in vacuo and triturated with MTBE:Heptane (1:2) whereupon a solid was observed. The crude solid was purified by reverse phase prep HPLC (C18 column, acetonitrile: water solvent system with 0.1% formic acid modifier) to afford the title compound (11 mg, 27%). LCMS: m/z=630.9 (M−1); 1H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J=8.6 Hz, 1H), 9.06 (t, J=5.6 Hz, 1H), 8.06 (s, 1H), 7.32 (s, 2H), 6.71 (s, 1H), 5.28 (dd, J=8.6, 5.5 Hz, 1H), 4.89-4.64 (m, 2H), 4.38 (t, J=5.1 Hz, 2H), 4.22 (q, J=5.3 Hz, 1H), 4.08 (s, 2H), 3.22 (s, 9H), 1.33 (s, 3H), 1.26 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCOCC>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:2]([CH3:3])[CH3:1])=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNC
Reactant: COc1ccc(CC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(C=C(c2ccc(OCc3ccccc3)cc2)N(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
Dimethylamine (55 mL, 0.15 mol) in 100 mL of toluene was added over ten min at 0°-5° C. to a 600 mL toluene suspension of 1-(4-benzyloxyphenyl)-2-(4-methoxyphenyl)ethan-l-one (50 g, 0.15 mol), then stirred 15 min at 0° C. A 50 mL toluene solution of TiCl4 (9.8 mL, 0.09 mol) was added dropwise over 1 h to the reaction mixture, keeping the temperature below 5° C. The brown suspension was stirred 16 h at rt then filtered through Hyflo Super Cel to give a yellow filtrate. Two Et2O washes of the filter bed were combined with the filtrate and the solution was concentrated to a thick amber oil. The oil was triturated with Et2O/ pet. ether and filtered to give 41 g (77%) of yellow solid: mp 60° C.; 1H NMR (CDCl3) d 2.64 (s, 6H, NMe2), 3.71 (s, 3H, OCH3), 5.07 (s, 2H, OCH2), 5.42 (s, 1H, =CH), 6.57-6.60 (d, 2H, J=9 Hz, ArH), 6.67-6.70 (d, 2H, J=9 Hz, ArH), 6.86-6.89 (d, 2H, J=9 Hz, ArH), 6.90-6.93 (d, 2H, J=9 Hz, ArH), 7.18-7.21 (d, 2H, J=9 Hz, ArH), 7.40-7.45 (m, 5H, ArH); MS(FD) 360[M+1]+Anal. Calcd for C24H25NO2 : C, 80.19; H, 7.01; N, 3.90. Found: C, 80.41; H, 7.12; N, 4.09.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.Cl.[CH3:14][NH:15][C:16]1[CH:58]=[CH:57][C:19]([O:20][CH2:21][C:22]([NH:24][C@H:25]([C:30]([NH:32][C@@H:33]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:34]([OH:49])[C:35]([N:37]2[CH2:48][CH2:47][CH2:46][C@H:38]2[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[O:31])[CH2:26][C:27](=[O:29])[NH2:28])=[O:23])=[CH:18][CH:17]=1.Cl>CN(C)C=O>[Br:1][CH2:2][C:3]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([NH:24][C@H:25]([C:30]([NH:32][C@@H:33]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C@H:34]([OH:49])[C:35]([N:37]2[CH2:48][CH2:47][CH2:46][C@H:38]2[C:39]([NH:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[O:31])[CH2:26][C:27](=[O:29])[NH2:28])=[O:23])=[CH:57][CH:58]=1)[CH3:14])=[O:4]
Reactant: O=C(Cl)CBr
Reactant: CNc1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)CBr)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Reaction time: 24 h
Yield: 68.5 %

Procedure:
0.59 ml (7.2 mmol) of bromoacetyl chloride and 1.6 ml (11.7 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 3.0 g (4.5 mmol) of 1-[(2S,3S)-3-{N2 -[4-(methylamino)phenoxyacetyl]-L-asparaginyl}amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide hydrochloride (prepared as described in Example 20) in 10 ml of dimethylformamide, and the resulting mixture was stirred for 1 day. At the end of this time, the reaction mixture was neutralized by the addition of 1N aqueous hydrochloric acid. It was then concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The resulting diluted solution was washed with 1N aqueous hydrochloric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography, using a 1:15 by volume mixture of methanol and methylene chloride as the eluent, to give 2.3 g of the title compound as a colorless powder, melting at 116°-122° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][N:19]=1.C1C(=O)N([Br:28])C(=O)C1.C([O-])(O)=O.[Na+]>CC#N>[Br:28][C:18]1[N:19]=[C:14]([C:10]2[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH:13]=[N:12][N:11]=2)[C:15]([NH2:20])=[N:16][CH:17]=1
Reactant: Nc1nccnc1-c1nncn1-c1cccc(F)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(Br)nc1-c1nncn1-c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine (700 mg, 2.55 mmol) in dry CH3CN (20 mL) was added NBS (550 mg, 3.09 (mmol). The solution was stirred at RT for 1 h and poured into saturated NaHCO3 solution. The precipitate was collected by vacuum filtration and washed with water (700 mg, 78%) to produce 5-bromo-3-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine [LC-MS m/e=353/354.6 (M+H)]. Using the same procedure, 5-bromo-3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 5-bromo-3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 5-bromo-3-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, 5-bromo-3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, and 5-bromo-3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine can be produced from 3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 3-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, 3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, and 3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, respectively.