Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:21](OS(C(F)(F)F)(=O)=O)([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]>C(Cl)Cl>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:7][CH:6]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C

Procedure:
To methyl 2-(4-hydroxyphenyl)acetate (E1) in CH2Cl2 at 0° C. was added 2,6-lutidine and TIPS-OTf. The ice bath was removed and the solution was allowed to warm to room temperature and stirred. After 4 h the solution was poured into NH4Cl(sat) and CH2Cl2 and the organic layer was further extracted with NH4Cl(sat). The organics were dried (Na2SO4) filtered and evaporated. Column chromatography (0-15% EtOAc/Hexanes) gave pure methyl-2-(4-(triisopropylsilyloxy)phenyl)acetate (E2).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH:14]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.N1C=CC=CC=1>O>[CH:14]1([NH:21][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NC1CCCCCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC1CCCCCC1)c1cnc2ccccc2n1
Yield: 12.4 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), cycloheptylamine (115 μL, 102 mg, 0.90 mmol), pyridine (5 mL), and water (100 mL) yielding 30 mg (12%) of (229):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(Cl)cc24)C3=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: O=C1/C(=C/c2c[nH]c3ccc(Cl)cc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 273.1 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(5-chloro-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0710 g, 0.139 mmol) in methylene chloride (3.0 mL) was added with trifluoroacetic acid (3.0 mL), and then the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, then a solution of the resulting residue in methanol (8 mL) was added with a 5% solution of hydrogen chloride in methanol (2 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to obtain (Z)-2-[(5-chloro-1H-indol-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.0611 g, 98%).
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce].[Cl:7][C:8]1[CH:17]=[C:16]([Cl:18])[C:15]2[C:10](=[C:11]([O:21]C)[CH:12]=[CH:13][C:14]=2[O:19]C)[N:9]=1>CC#N.O>[Cl:7][C:8]1[CH:17]=[C:16]([Cl:18])[C:15]2[C:14](=[O:19])[CH:13]=[CH:12][C:11](=[O:21])[C:10]=2[N:9]=1
Reactant: COc1ccc(OC)c2c(Cl)cc(Cl)nc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1C=CC(=O)c2c(Cl)cc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75 %

Procedure:
Cerium ammonium nitrate (CAN 21.4 g, 39.03 mmol) is added portionwise to a solution of 2,4-dichloro-5,8-dimethoxyquinoline (2.85 g, 11.04 mmol) in a CH3CN/H2O mixture (150 ml/75 ml). The reaction mixture is stirred at ambient temperature for 40 min. The acetonitrile is subsequently evaporated and 50 ml of water and 200 ml of a saturated NaHCO3 solution are added. The aqueous phase is extracted with CH2Cl2 (5 times 200 ml). After drying over MgSO4, the solvent is evaporated on a rotary evaporator to give the expected compound in the form of a brown powder (1.9 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[C:14]([Cl:25])[CH:15]=[C:16]3[C:20]=1[N:19]([CH2:21][CH:22]([CH3:24])[CH3:23])[N:18]=[CH:17]3)[C:6](=[O:26])[CH2:5]2.CC1(C)C2[C:49](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:48][C:30]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(CC)CC)C.[O:76]1CCCC1>CO.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[CH3:30][O:48][C:49]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[C:14]([Cl:25])[CH:15]=[C:16]3[C:20]=1[N:19]([CH2:21][CH:22]([CH3:23])[CH3:24])[N:18]=[CH:17]3)[C:6](=[O:26])[CH2:5]2)=[O:76]
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CN3C(=O)Cc4cc(Br)ccc43)c21
Reactant: C1CCOC1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CC(=O)N2Cc1cc(Cl)cc2cnn(CC(C)C)c12
Temperature: 150 °C

Procedure:
A mixture of compound 64 (0.1 g, 0.231 mmol), molybdenumhexacarbonyl (0.03 g, 0.115 mmol), Hermann's catalyst (0.022 g, 0.023 mmol), Xantphos (0.027 g, 0.0426 mmol), triethylamine (0.643 mL, 0.462 mmol) in a mixture of tetrahydrofuran (3 mL) and methanol (0.9 mL) was heated at 150° C. under microwave conditions for 10 minutes. Then, the reaction was quenched by adding water and diluted with ethyl acetate. The organic layer was separated, washed with Brine, dried (MgSO4), filtered and the solvent was evaporated. Then, the residue was purified by chromatography column on a 20 g SPE cartridge to give the title compound as a colorless solid. (0.043 g, 45%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: Cc1c(N)cccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(N)c1C
Temperature: 70 °C
Yield: 23 %

Procedure:
To 3-amino-2-methylbenzoic acid (500 mg, 3.3 mmol) in methanol (20 ml) was added sulfuric acid (500 μl) and heated to 70° C. for 22 h, at which point the volume was reduced by rotary evaporation. The residue was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The resultant organic layer was dried over sodium sulfate, filtered, and then concentrated to afford a tan oil (125 mg, 23%) of methyl 3-amino-2-methylbenzoate, which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 6.99-6.93 (m, 1H), 6.89-6.86 (d, 1H), 6.81-6.78 (d, 1H), 5.12-5.07 (br. s, 2H), 3.78 (s, 3H), 2.16 (s, 3H). MS (EI) for C9H11NO2: 166 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:20])[NH:10][CH2:11][C:12]1([C:15]([O:17]CC)=[O:16])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O.O>[CH2:1]([NH:8][C:9](=[O:20])[NH:10][CH2:11][C:12]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(CNC(=O)NCc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)NCC1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To the solution of ethyl 1-((3-benzylureido)methyl)cyclopropanecarboxylate (Compound V-3) (1.6 g, 5.8 mmol) in tetrahydrofuran/methanol/water (2:3:1, 20 ml), lithium hydroxide monohydrate (487 mg, 11.6 mmol) was added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water (25 ml) and washed with ether (25 ml). The aqueous layer was acidified with 10%-citric acid (15 ml) and extracted with chloroform (30 ml). The organic layer was washed with brine (25 ml) and dried over magnesium sulfate and then filtered. The filtrate was concentrated in vacuo to obtain the title compound (1.08 g, 77%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].Br.BrC[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.[CH3:33]N(C)C=O>>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:33][C:32]2[CH:31]=[N:30][CH:29]=[CH:28][CH:27]=2)[CH2:10]1)=[O:8]
Reactant: CN(C)C=O
Reactant: BrCc1ccncc1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C(=O)C2CN(Cc3cccnc3)c3ccccc3C2=O)cc1C

Procedure:
Compound 4p was prepared following the procedure outlined in Step 3 of Example 1 using 32 mg (0.8 mmol) of sodium hydride (60%), 86 mg (0.31 mmol) of 3-(3,4-dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a, 3 mL of anhydrous dimethylformamide, and 101.2 mg (0.40 mmol) of 4-bromomethylpyridine hydrobromide. The crude product was purified by flash chromatography to yield 27 mg of yellowish solid 4p: LC-MSD, m/z for C24H20N2O2, [M+H]+=369.4, [M+2H]+=370.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.334 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.30 (d, 6H), 5.4 (s, 2H), 7.10 (d, 1H), 7.16-7.22 (m, 2H), 7.42 (t, 1H), 7.52-7.66 (m, 3H), 8.26 (d, 1H), 8.48 (m, 1H), 8.58-8.64 (m, 2H).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]1([SH:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:21][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Sc1cccc2ccccc12
Reactant: O=C(O)c1ccccc1I
Product: O=C(O)c1ccccc1Sc1cccc2ccccc12

Procedure:
According to the same process, starting from 2-iodobenzoic acid and 1-naphthalenethiol, also 2-(naphthalene-1-ylsulfanyl)-benzoic acid (Table 2; compound 4) was obtained.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].C(=O)(O)[O-].[Na+].Cl.[CH2:20]([O:23][NH2:24])[CH:21]=[CH2:22].Cl>O.C(OCC)(=O)C>[CH2:20]([O:23][N:24]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11])[CH:21]=[CH2:22]
Reactant: C=CCON
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.1 %

Procedure:
To a solution of 2-(2-formamidothiazol-4-yl)glyoxylic acid (30 g) and sodium bicarbonate (12.6 g) in water (1300 ml) was added allyloxyamine hydrochloride (19.8 g), and the mixture was stirred for 7 hours at ambient temperature at pH 6. To the reaction mixture was added ethyl acetate (500 ml). After the mixture was adjusted to pH 1.9 with 10% hydrochloric acid, the ethyl acetate layer was separated. The ethyl acetate layer was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and then the solvent was distilled off. The residue was pulverized in diisopropyl ether, collected by filtration and then dried to give 2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer)(25.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC1CCCN1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1CCCN1c1ccc(Br)cc1C=O
Temperature: 110 °C

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (15 g, 73.8 mmol) in DMSO (150 mL) and water (40 mL) were added 2-methylpyrrolidine (9.8 mL, 96 mmol) and sodium carbonate (15.7 g, 148 mmol). The resulting mixture was heated at 110° C. for 8 hours. The reaction mixture was cooled at RT, diluted with water (1000 mL) and extracted with MTBE (2×100 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a yellow oil (17 g, 85%). 1H NMR (DMSO-d6, 400 MHz) δ 9.94 (1H, s), 7.75 (1H, s), 7.51 (1H, d), 6.93 (1H, d), 3.92 (1H, m), 3.68 (1H, m), 2.97 (1H, t), 2.49-2.18 (1H, m), 1.88 (1H, m), 1.57-1.68 (2H, m), 1.10 (3H, d).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C1C=CC=CC=1.[CH:11]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:13]([NH:14][CH2:15]3)[CH2:12]1)[CH2:19]2.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:1]([N:14]1[CH2:15][CH:16]2[CH2:21][CH:11]3[CH2:19][CH:18]([CH2:20][CH:13]1[CH2:12]3)[CH2:17]2)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C1NC2CC3CC1CC(C3)C2
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: C=CCN1CC2CC3CC(C2)CC1C3
Temperature: 0 °C

Procedure:
To a well stirred solution of 1.2 gm. (0.01 mole) of allyl bromide in 50 ml. of benzene, a solution of 1.5 gm. (0.01 mole) of 4-azatricyclo[4.3.1.13,8 ]undecane in 50 ml. of benzene is added dropwise. The mixture is refluxed 1 hr., cooled, and 1 gm. of acetic anhydride is added. The mixture is refluxed an additional 2 hrs., cooled, poured into ice water and acidified with acetic acid. The layers are separated and the aqueous layer is extracted with ether. The acidic aqueous layer is made basic with NaOH, and extracted with chloroform. The chloroform extract is washed with water, dried over magnesium sulfate, filtered and the solvent evaporated to give 4-allyl- 4-azatricyclo[4.3.1.13,8 ]undecane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[C:11]=2[NH2:23])=[C:5]([CH3:24])[CH:4]=1.[C:25](OCC)(=[O:29])[C:26]([CH3:28])=O>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:11]3[N:23]=[C:26]([CH3:28])[C:25](=[O:29])[N:16]([C@@H:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[C:12]=3[N:13]=[CH:14][N:15]=2)=[C:5]([CH3:24])[CH:4]=1
Reactant: CCOC(=O)C(C)=O
Reactant: CC[C@H](COC)Nc1ncnc(-c2cc(C)c(OC)cc2C)c1N
Solvent: CCO
Product: CC[C@H](COC)n1c(=O)c(C)nc2c(-c3cc(C)c(OC)cc3C)ncnc21
Reaction time: 18 h

Procedure:
(R)-6-(4-Methoxy-2,5-dimethyl-phenyl)-N4-(1-methoxymethyl-propyl)-pyrimidine-4,5-diamine (0.22 g, 0.68 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.76 ml, 6.8 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 8.0 mg of (R)-4-(4-methoxy-2,5-dimethyl-phenyl)-8-(1-methoxymethyl-propyl)-6-methyl-8H-pteridin-7-one (Example 1013a). 1H NMR (300 MHz, CDCl3) δ ppm 9.05 (s, 1 H), 7.21 (s, 1 H), 6.79 (s, 1 H), 4.86 (m, 1 H), 3.91 (s, 3 H), 2.55 (m, 3 H), 2.38 (m, 1 H), 2.22 (s, 3 H),), 2.22 (s, 3 H), 2.04 (m, 1 H), 1.25 (m, 1 H), 0.89 (t, J=7.51 Hz, 3 H), 0.77 (m, 1 H), 0.50 (m, 1 H), 0.39 (m, 1 H), 0.18 (m, 1 H). MS (EI) 379.3 [(M+H)+, 100].
Reaction SMILES: [N:1]([C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O)=[N:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6]C)=O.[CH2:17]([NH2:20])[CH:18]=[CH2:19]>CO>[N:2]([C:3]([CH3:8])([CH3:9])[C:4]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:6])=[N:1][C:10]([CH3:16])([CH3:15])[C:11]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:13]
Reactant: C=CCN
Reactant: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Solvent: CO
Product: C=CCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCC=C

Procedure:
Dimethyl 2,2'-azobis(2-methylpropionate) in an amount of 41.9 g, 48 ml of methanol, and 43 g of a 28% CH3ONa methanol solution were mixed and stirred for dissolution, followed by dropwise addition of 25 g of allylamine to react at 19° to 21° C. for 20 hours.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10])=[O:4].[F:15][C:16]([F:21])([F:20])[C:17](N)=[NH:18]>C(Cl)(Cl)Cl>[C:11]([C:7]1[S:6][C:5]2[C:3]([OH:4])=[N:18][C:17]([C:16]([F:21])([F:20])[F:15])=[N:10][C:9]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: N=C(N)C(F)(F)F
Reactant: COC(=O)c1sc(C(C)(C)C)cc1N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2nc(C(F)(F)F)nc(O)c2s1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
3-Amino-5-tert-butyl-thiophene-2-carboxylic acid methyl ester (0.50 g, 2.34 mmol, 1 eq.) and trifluoroacetamidine (263 mg, 2.34 mmol, 1 eq.) were heated neat at 150° C. until reaction was complete by TLC. Cooled to rt then dissolved resultant solids in chloroform. Dried and stripped in vacuo to give 540 mg of white solids as product. LCMS detects (M+H)+=277.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[ClH:30].[NH2:31][OH:32].N1CCCCC1>CS(C)=O.O>[Cl:30][C:6]1[CH:5]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22](=[NH:23])[NH:31][OH:32])=[CH:18][N:17]=2)=[O:14])[CH:3]=[CH:2][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C#N)cn2)cc1Cl
Reactant: Cl
Solvent: CS(C)=O
Solvent: C1CCNCC1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C(=N)NO)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-cyano-pyrazin-2-yl)-3-cyclopentyl-propionamide (400.0 mg, 0.924 mmol) in dimethyl sulfoxide (6 mL) at 25° C. was treated with hydroxylamine hydrochloride (330.0 mg, 4.749 mmol). The reaction mixture was then treated with piperidine (500 μL, 5.056 mmol) and then was stirred at 25° C. for 1 h. The reaction mixture was then diluted with water and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/1 to 2/1 ethyl acetate/hexanes) afforded the 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxy-carbamimidoyl)-pyrazin-2-yl]-propionamide (274.5 mg, 63.8%) as a white solid: (ES)+-HRMS m/e calcd for C20H24ClN5O4S (M+H)+ 466.1311, found 466.1315.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][N:28]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([OH:26])=[N:28][CH:29]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: Cc1cnc(CN(CCCCN)C2CCCc3cccnc32)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(CCCCNC(=O)c2ccc(O)nc2)C2CCCc3cccnc32)c(C)c1
Yield: 19.6 %

Procedure:
Using General Procedure G: To a solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (202 mg, 0.60 mmol) in dry DMF (3 mL) was added 6-hydroxy-nicotinic acid (108 mg, 0.78 mmol) followed by EDCI (149 mg, 0.78 mmol), HOBT (106 mg, 0.78 mmol), and DIPEA (0.21 mL, 1.21 mmol). Purification of the crude material by radial chromatography on silica gel (1 mm plate, 10:1:1 CH2Cl2-MeOH—NH4OH) provided 54 mg (20%) of the free base of the title compound as a white foam. Using General Procedure D: Conversion to the HBr salt gave COMPOUND 366 as a white solid. 1H NMR (D2O) δ 1.29-1.42 (m, 2H), 1.49-1.58 (m, 2H), 1.90-2.01 (m, 1H), 2.22-2.35 (m, 2H), 2.54 (s, 3H), 2.56 (s, 3H), 2.57-2.67 (m, 2H), 2.79-2.87 (m, 1H), 3.11-3.15 (m 2H), 3.29-3.40 (m, 2H), 4.33 (d, 1H, J=18.0 Hz), 4.52 (d, 1H, J=18.0 Hz), 4.63 (dd, 1H, J=10.8, 5.7 Hz), 6.82 (d, 1H, J=9.6 Hz), 7.96-8.01 (m, 2H), 8.10 (d, 1H, J=2.1 Hz), 8.23 (s, 1H), 8.46 (d, 1H, J=8.1 Hz), 8.55 (s, 1H), 8.73 (d, 1H, J=5.1 Hz); 13C NMR (D2O) δ 16.89, 17.47, 20.49, 20.74, 25.72, 26.63, 27.82, 39.10, 52.31, 52.90, 62.08, 115.63, 119.37, 125.79, 136.06, 137.16, 137.16, 137.29, 137.49, 139.30, 140.49, 140.88, 147.96, 148.85, 149.33, 151.25, 165.45, 166.46; ES-MS m/z 460 (M+H). Anal. Calcd. For C27H33N5O2.3.0HBr.3.5H2O: C, 42.37; H, 5.66; N, 9.15; Br, 31.32. Found: C, 42.16; H, 5.50; N, 9.26; Br, 31.61.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12]C(Cl)C>>[Cl:12][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][CH:10]=1
Reactant: CC(Cl)Cl
Reactant: c1ccc(-c2cc[nH]n2)cc1
Product: Clc1c[nH]nc1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3-phenyl-1H-pyrazole (3 g, 20.81 mmol) in dichloroethane (60 ml) N-chlorosuccinimide (2.92 g, 21.85 mmol) was added and the mixture was stirred over night at room temperature. The mixture was then concentrated under reduced pressure and the remainder was purified via chromatography on silica gel (eluent: cyclohexane/ethyl acetate 0-30% (v/v)). Concentration of the combined fractions gave 3.54 g of a slightly yellow amorphous solid; ESI-MS [M+H]+: 179.0
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH3:13][O:14][CH2:15][C:16]([CH2:18][O:19][CH3:20])=O.[CH2:21](N(CC)CC)C.C=O>ClCCCl>[CH3:13][O:14][CH2:15][CH:16]([N:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=1)[CH3:21])[CH2:18][O:19][CH3:20]
Reactant: COCC(=O)COC
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: C=O
Agent: Cl
Solvent: ClCCCl
Product: COCC(COC)N(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In 1,2-dichloroethane (50 ml) were suspended p-nitrobenzylamine hydrochloride (3 g), 1,3-dimethoxyacetone (1.9 g) and triethylamine (2.2 ml), and to the mixture was added, under ice-cooling, triacetoxy sodium boro hydride (4.7 g). Under nitrogen atmosphere, the mixture was stirred at room temperature for 5 hours, and to the mixture were added, under ice-cooling, 37% formalin (1.8 ml) and triacetoxy sodium boro hydride (5 g). Under nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. The residue was neutralized withlN sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give N-(1,3-dimethoxypropan-2-yl)-N-methyl-4-nitrobenzylamine (3.2 g) as yellow oil.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:16]3[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[N:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.[C:41](O)(=[O:44])[CH:42]=[CH2:43]>ClCCl.O>[C:1]([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:16]3[CH:17]=[C:18]([NH:21][C:41](=[O:44])[CH:42]=[CH2:43])[CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[N:8][CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1cncc(-n2cnc3ccc(N)cc32)n1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)Nc1ccc2ncn(-c3cncc(NC(C)(C)C)n3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 1-[6-(tert-butylamino)pyrazin-2-yl]-1H-benzimidazol-6-amine (22 mg, 0.08 mmol) in anhydrous dichloromethane (2 mL) under N2 was added triethylamine (33 μL, 0.24 mmol), EDAC.HCl (22 mg, 0.12 mmol), 4-(1-pyrrolidino)pyridine (cat.) and acrylic acid (8 μL, 0.12 mmol). The resulting mixture then stirred at RT for 3 days and was the diluted with H2O (10 mL), the organic phase separated and the aqueous phase extracted with CH2Cl2 (10 mL). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography using dichloromethane-methanol (98:2-93:7) as eluant to separate the pure product (10 mg).