Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2].[H][H]>[Pd].C(O)C>[NH:4]=[C:3]([C:7]1[C:8](=[O:19])[N:9]([CH3:18])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:11][C:6]=1[OH:5])[CH2:1][CH3:2]
Reactant: CCc1noc2cc(-c3ccccc3)n(C)c(=O)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC(=N)c1c(O)cc(-c2ccccc2)n(C)c1=O

Procedure:
A mixture of 7.2 g. (0.0314 mole) of 3-ethyl-5-methyl-6-phenyl-isoxazolo[4,5-c]pyridin-4(5H)-one, 160 ml. ethanol and 0.800 g. 10% palladium on carbon is hydrogenated at 50 psi and room temperature. The hydrogenation is ceased after 1 equivalent of hydrogen is absorbed (ca 4 hours). The mixture is filtered to remove the catalyst and the solvent removed in vacuo. The residue is crystallized from ether to give 3-(1-iminopropyl)-4-hydroxy-6-phenyl-1-methyl-2(1H)-pyridone, m.p. 145° to 147° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C@:20]([CH3:33])([OH:32])[C@@H:19]([CH2:34][O:35][Si](C(C)(C)C)(C)C)[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC#N.O.CCOC(C)=O>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C@:20]([CH3:33])([OH:32])[C@@H:19]([CH2:34][OH:35])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:17])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](OCc2ccccc2)[C@@H](OC(=O)Oc2ccccc2)[C@]1(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@]1(O)[C@H](OC(=O)Oc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCC[Si](C)(C)C)O[C@@H]1CO
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a stirred solution of 5.10 (4.7 g, 7.6 mmol) in CH3CN (30 mL) and H2O (30 mL) was added p-toluenesulfonic acid monohydrate (115 mg, 0.76 mmol). The reaction was stirred for 3 h then diluted with EtOAc and washed sequentially with saturated aqueous NaHCO3, H2O, and brine. After concentration of the organic phase in vacuo, the crude residue was purified by silica gel chromatography (50% EtOAc/petroleum ether) to afford the title compound (3.7 g, 7.3 mmol, 96%). 1H NMR (500 MHz, CDCl3): δ ppm 7.39-7.22 (m, 8H, PhH), 7.10 (d, J=7.3 Hz, 2H, PhH), 4.94, 4.67 (ABq, J=11.2 Hz, 1H each, OCH2Ph), 4.88 (d, J=9.8 Hz, 1H, H-3), 4.53 (d, J=7.8 Hz, 1H, H-1), 4.04-3.96 (m, 1H, OCHHCH2SiMe3), 3.91 (dd, J=11.7, 4.9 Hz, 1H, H-6), 3.78 (dd, J=11.7, 6.8 Hz, 1H, H-6), 3.67-3.59 (m, 1H, OCHHCH2SiMe3), 3.46 (dd, J=6.8, 5.4 Hz, 1H, H-5), 3.39 (dd, J=10.0, 7.6 Hz, 1H, H-2), 1.29 (s, 3H, Me), 1.04 (t, J=8.5 Hz, 2H, OCH2CH2SiMe3), 0.04 (s, 9H, SiMe3); 13C NMR (125 MHz, CDCl3): δ ppm 154.43, 151.15, 138.34, 129.61, 128.50, 127.81, 127.73, 126.31, 121.06, 103.64, 84.03, 79.21, 77.45, 74.92, 73.40, 68.21, 61.05, 18.73, 15.90, −1.27; HRMS calcd for C26H40NO8Si [M+NH4]+: 522.2523. found 522.2501.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: [H][H]
Reactant: Nc1cc2ccccc2cn1
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2c(cn1)CCCC2
Yield: 2.3 %

Procedure:
Using the method of Example 63, Step A, 75 mg of 3-aminoisoquinoline (7.73 mmoles) and 8.7 mg platinum oxide in 2 mL of trifluoroacetic acid was shaken under 40 psi of hydrogen for 3 h. The mixture was filtered and catalyst was washed with ethyl acetate. After concentrating the filtrate, the residue was dissolved in 10 mL of ethyl acetate and washed with 5 mL of saturated aquous sodium bicarbonate. The organic solution was dried (sodium sulfate), decanted, and concentrated to give a yellow syrup. Flash coumn chromatography on 19 g of silica gel, eluting with 600 mL of 50% ethyl acetate/hexane gave 26.5 mg (34% yield) of 3-amino-5,6,7,8-tetrahydroisoquinoline as a pale yellow solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)=[C:2]=[O:3].Br.Br[CH2:22][CH2:23][CH:24]([NH2:26])[CH3:25].C(N(CC)CC)C.CC(C)([O-])C.[K+]>C(#N)C.C1COCC1>[CH3:25][CH:24]1[CH2:23][CH2:22][N:1]([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]2)[C:2](=[O:3])[NH:26]1
Reactant: CC(N)CCBr
Reactant: O=C=NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: CC1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of benzyl 4-isocyanatopiperidin-1-carboxylate (0.26 g) in acetonitrile (10 mL) was added to a solution of 4-bromobutan-2-amine hydrobromide (0.17 g) and triethylamine (0.10 g) in acetonitrile (10 mL), followed by stirring at room temperature for one hour. Potassium tert-butoxide (0.29 g) and THF (20 mL) were added thereto, and the mixture was further stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1) to obtain the title compound (0.15 g, 45%) as a light brown solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Mg]Cl)(C)C.[CH:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=[O:13]>C1COCC1>[OH:13][CH:12]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Brc1nccs1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2nccs2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
2-Bromothiazole (2.72 ml, 30.5 mmol) was taken up in THF (60 ml) and cooled to −20° C. Isopropylmagnesium chloride (16.00 ml, 32.0 mmol) was added drop wise. After stirring for 1 h (−10° C. to 0° C.), the reaction was cooled to −78° C., and methyl 4-formylbenzoate (5.50 g, 33.5 mmol) in THF (10 ml) was added drop wise. The reaction was stirred for 30 min at −78° C., then warmed to room temperature. After 1 h at room temperature, the reaction was quenched with aqueous saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (10-75% EtOAc/hexanes) to provide methyl 4-[hydroxy(1,3-thiazol-2-yl)methyl]benzoate (7.29 g, 29.2 mmol, 96% yield) as an off-white solid. MS ESI: [M+H]+ m/z 250.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[C:11]=[O:12])[CH:5]=1.[NH3:14]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH2:14])=[O:12])[CH:5]=1
Reactant: N
Reactant: COC(=O)c1cccc(N=C=O)c1
Solvent: C1COCCO1
Product: COC(=O)c1cccc(NC(N)=O)c1
Reaction time: 48 h

Procedure:
3-Isocyanato-benzoic acid methyl ester (500 mg, 2.82 mmol) was treated with 0.5 M NH3 in dioxane (20 mL). The mixture was agitated for 48 h, and the product, 3-ureido-benzoic acid methyl ester (200 mg, 1.03 mmol), was isolated by filtration as a white solid (404 mg, 73.7%). This intermediate was dissolved in methanol (2 mL) and Amberlyst A26® (OH− form) was added. The resulting mixture was agitated overnight. The resin was then filtered and washed with methanol (3×2 mL). The product was eluted with a solution of 20% formic acid in methanol (3×2 mL) and the resin was washed with methanol (1 mL) and DMF (2×2 mL). The combined eluant solvents were evaporated to provide 139 mg (75% yield) of the urea 3-ureido-benzoic acid. This reagent was then coupled with 3-aminomethyl-N-(4-dimethylaminomethyl-phenyl)-benzamide using the same coupling procedure described in Example 14 to provide the title compound; MS, electrospray, 446 (M+H)
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1.[NH:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1.Cl.CN(C1C=CC=CN=1)C>O1CCCC1>[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1)=[O:24])([OH:22])=[O:21]
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C(O)CCCCCCCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCCCCCCCCC(=O)n1nnc2ccccc21
Yield: 15.8 %

Procedure:
A solution of eicosanedioic acid (3.43 g, 10.0 mmol), dicyclohexylcarbodimide (2.06 g, 10.0 mmol), benzotriazole (1.19 g, 10.0 mmol) and dimethylamino-pyridine hydrochloride in anhydrous tetrahydrofuran (200 ml) was stirred for two days at room temperature. The resulting suspension was filtered, and the filtrate evaporated to dryness under reduced pressure. The residue was suspended in dichloromethane (100 ml), and undissolved material was isolated by filtration. The dried filter cake (2.0 g) was recrystallised from acetone (200 ml) yielding 0.70 g (16%) of white crystalline 1-(19-carboxynonadecanoyl)benzotriazole, melting at 111.9° C. (DSC peak value).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:17])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37]([C:42](Cl)=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:42]([C:37]3[C:36]([C:33]4[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:45])[F:46])=[CH:31][CH:32]=4)=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:43])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(N)cc2C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1Cc2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2C1
Reaction time: 16 h

Procedure:
To a solution of the title C compound ((5-amino-indan-2-yl)-carbamic acid tert-butyl ester; 12.5 mmol) in methylene chloride (75 mL) is added diisopropylethyl amine (3.3 g, 25 mmol) followed by a 0.5 M solution of the title D compound (4′-trifluoromethyl-2-biphenyl carboxylic acid chloride, 12.6 mmol) in methylene chloride (25.3 mL). After stirring 16 h, the reaction mixture is poured into ethyl acetate and washed with 1N HCl, 8% NaHCO3 solution, and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give a solid. Recrystallization from toluene gives {5-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]-indan-2-yl}-carbamic acid tert-butyl ester in two crops; mp 198-201° C. MS (ES+), m/z 514 (M+NH+4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[C:12](=[O:33])[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)[C:14]2[C:19]([C:20]=1O)=[CH:18][CH:17]=[CH:16][N:15]=2)=O.O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[C:11]2[C:12](=[O:33])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:30])[F:31])[CH:23]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20]=2[NH:36][N:35]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1Cl)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3Cl)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-(2-chlorophenylacetyl)-4-hydroxy-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridine-2(1H)-one (622 mg, 1.3 mmol) produced in Synthesis Example 29 in DMF (6 mL) was added hydrazine monohydrate (purity of 80%, 210 μL), and the mixture was stirred at 110 to 120° C. for 3 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-chlorobenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (579 mg, yield 94%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=O.C(N(CC)CC)C.[CH2:13]([N:16]=[C:17]=[S:18])[CH:14]=[CH2:15].Cl>O.N1C=CC=CC=1>[CH2:13]([N:16]1[C:3](=[O:5])[CH2:2][NH:1][C:17]1=[S:18])[CH:14]=[CH2:15]
Reactant: NCC(=O)O
Reactant: C=CCN=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: C=CCN1C(=O)CNC1=S
Temperature: 55 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Glycine (30 g, 0.40 mol), triethylamine (44 g, 0.44 mol), pyridine (100 mL), and water (100 mL) were mixed in a flask equipped with a magnetic stirrer and a temperature controller. Allyl isothiocyanate (44 g, 0.44 mol) was added, and the temperature was raised to 55° C. (the mixture became homogeneous at ca. 30°). When the mixture reached this temperature, it was allowed to cool to room temperature. The mixture was extracted with 3×200 mL of toluene to remove the pyridine and excess isothiocyanate and was then treated with 66 mL (0.8 mol) of concentrated hydrochloric acid. The mixture was heated at 90° C. for 2.5 hr and was then stirred rapidly while it cooled to room temperature. A solid mass of crystals formed instantaneously when the solution was seeded with a fragment of a crystal of authentic product. After the suspension stood at room temperature overnight, the product was collected and pressed with rubber dam. The filter cake was washed with 3×60 mL of water (the filter cake was pressed with rubber dam after each wash). After the material had dried to constant weight in a hood draft, it weighed 49 g (71% yield). NMR (CD3OD) δ 4.9-6.1 (m, 3H), 4.6 (s, 1H), 4.3 (d, 2H), 4.0 (s, 2H). HPLC analysis showed no other components at several wavelengths.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]([O:26][CH3:27])([O:24][CH3:25])[CH2:15][CH2:14]1)(=[O:12])=[O:11].OC[CH:30]([NH:33][C:34](=[O:36])[CH3:35])CO.C(O[Si](C)(C)C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:34]([NH:33][CH:30]1[CH2:25][O:24][C:16]2([CH2:15][CH2:14][CH:13]([S:10](=[O:11])(=[O:12])[NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[O:26][CH2:27]1)(=[O:36])[CH3:35]
Reactant: CC(=O)NC(CO)CO
Reactant: CCOC(=O)C1=CC(OC)(OC)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: CC(C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCC(NC(C)=O)CO2
Reaction time: 66 h
Yield: 49.3 %

Procedure:
500 mg (1.19 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 205 mg (1.54 mmol) of N-(2-hydroxy-1-hydroxymethylethyl)acetamide were dissolved in 20 ml of dichloromethane, and 0.84 ml (4.74 mmol) of isopropoxytrimethylsilane and 43 μl (0.24 mmol) of trimethylsilyl trifluoromethanesulfonate were added sequentially with stirring under ice-cooling, followed by stirring for 30 minutes at the same temperature, and further for 66 hours at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate methanol=39:1) to give 288 mg of the title compound as an amorphous substance (yield: 50%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22])OC1C=CC=CC=1)#[N:2].Cl.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][NH2:32].C(N(CC)CC)C>C(O)(C)C>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:1]([NH2:2])[N:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[F:24])[N:32]=1
Reactant: NNc1ccccc1F
Reactant: COc1ccc(N=C(NC#N)Oc2ccccc2)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1ccc(Nc2nc(N)n(-c3ccccc3F)n2)c(OC)c1
Temperature: 100 °C
Yield: 89.3 %

Procedure:
A mixture of N-cyano-N′-(2,4-dimethoxyphenyl)-O-phenylisourea (0.10 g, 0.34 mmol), 2-fluoro-phenylhydrazine hydrochloride (0.08 g, 0.50 mmol) and triethylamine (0.01 mL, 0.68 mmol) in isopropanol (3 mL) was heated at 100° C. for 18 h and evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes provided the title compound (0.10 g, 85% yield).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37].C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36]([OH:38])=[O:37]
Reactant: O=C(O)C1CCCCN1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCCCC4C(=O)O)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and piperidine-2-carboxylic acid (25.6 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 19 mg of 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-2-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (2H, dd, J=8.35, 2.20 Hz), 7.77 (2H, dd, J=7.91, 1.54 Hz), 7.52-7.64 (5H, m), 5.20 (1H, d, J=18.24 Hz), 3.67 (2H, br. s.), 2.87-3.01 (2H, m), 1.99-2.21 (2H, m), 1.69-1.88 (4H, m), 1.64 (2H, dq, J=15.24, 7.59 Hz), 1.39-1.56 (3H, m), 0.92 (3H, t, J=7.36 Hz). MS (m+1)=503. HPLC Peak RT=3.47 minutes (Analytical Method A). Purity=88%.
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[C:11]([NH:21][S:22]([C:25]2([CH2:28][O:29]CC3C=CC=CC=3)[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[C:12]2[S:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16].C(S)C>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([C:25]2([CH2:28][OH:29])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[C:12]2[S:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(COCc3ccccc3)CC2)c2n(c1=O)CCS2
Solvent: CCS
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CO)CC2)c2n(c1=O)CCS2
Temperature: 40 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 21A, 1-benzyloxymethyl-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-8-yl]-amide (0.2 g, 0.321 mmol) was reacted with BF3OEt2(0.79 mL, 6.24 mmol) and ethane thiol (0.2 mL, 3.21 mmol). The resulting mixture was stirred at 40° C. for 6 hours. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 100 mg of the product (55% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[C:17](OC)(OC)(OC)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:17])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: COC(C)(OC)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 2-nitro-4-trifluoromethylbenzoic acid (23.5 g, 0.10 mol), trimethyl orthoacetate (60.1 g, 0.50 mol) and toluene (60 ml) was heated at 80° C. for 16 h. The reaction mixture was concentrated in vacuo. Toluene was added and concentrated again to remove excess reagent. The residue was purified by column chromatography on silica gel with a 1-10% ethyl acetate/n-hexane gradient mixture to give 24.9 g (0.50 mol 100%) of the title compound as a colorless oil.
Reaction SMILES: C(OC([NH:8][C:9]([NH:23]C(OC(C)(C)C)=O)=[N:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=2)[CH2:12]1)=O)(C)(C)C.[ClH:31]>ClCCl.O1CCOCC1>[ClH:31].[ClH:31].[CH3:22][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([N:13]2[CH2:14][CH2:15][CH:11]([NH:10][C:9]([NH2:23])=[NH:8])[CH2:12]2)[CH:21]=1
Reactant: Cc1ccnc(N2CCC(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccnc(N2CCC(NC(=N)N)C2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(1-(4-methylpyridin-2-yl)pyrrolidin-3-yl)guanidine (210 mg) in dichloromethane (4 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at ambient temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 10% methanol in ethyl acetate (50 ml). The resultant precipitate was collected by filtration and dried under reduced pressure to give (1-(4-methylpyridin-2-yl)-pyrrolidin-3-yl)guanidine dihydrochloride (140 mg).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([O:26][CH3:27])=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.[ClH:29]>CO.O1CCOCC1>[ClH:29].[ClH:29].[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[C:21]=1[O:26][CH3:27]
Reactant: COc1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Yield: 100 %

Procedure:
[(S)-1-(6-Fluoro-7-methoxy-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (349 mg, 0.91 mmol) was dissolved in methanol (1 mL) and hydrochloric acid in dioxane (3 mL, 4M) and the reaction stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo to yield the title compound as an off-white solid (321 mg, 100%). LCMS (Method C): RT=2.02 min, [M+H]+=286.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].CN(C)C1C=CC=CC=1.S(=O)(=O)(O)O.[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22]>C(Cl)(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:4]
Reactant: CC(C)(C)O
Reactant: CC(Br)C(=O)Br
Agent: O=S(=O)(O)O
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)OC(C)(C)C
Yield: 86.7 %

Procedure:
A solution of 2-bromopropionyl bromide (25 g.) in dry chloroform (50 ml.) was dropwise added with stirring and ice-cooling to a solution of N,N-dimethylaniline (24 g.) in t-butanol (11 g.) and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into 6 N sulfuric acid (150 ml.) and extracted with ether. The extract was in turn washed with 6 N sulfuric acid, water, a 10% potassium carbonate aqueous solution and water and dried over magnesium sulfate. The solvent was distilled off to give oil of t-butyl 2-bromopropionate (21 g.).