Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=C[CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[C:17]([N:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=O)[CH3:18]>O>[CH3:5][C:4]1[CH:18]=[C:17]([N:20]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:2][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(N2CCCNCC2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 53.6 %

Procedure:
Fluoronitrobenzene (9.1 g, 0.0586 mol) is dissolved in water (50 ml) and then potassium carbonate (9.7 9, 0.0703 mol) and 1-acetyl-[1,4]diazepane (10 g, 0.0703 mol) are added. The medium is heated at 95° C. for 6 hours, and an orange-coloured solution is obtained. The medium is then cooled to room temperature, and an orange-coloured sticky paste then appears. The maximum amount of water is removed from the reaction medium. Isopropanol is then added to the paste until a yellow solid precipitates. The medium is filtered and, after drying in a vacuum oven at 45° C., a yellow powder is obtained which corresponds to 1-(3-methyl-4-nitrophenyl)-[1,4]diazepane (1). (8.7 g; Yield=53.6%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH:2]=1.[H][H]>CC(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH:2]=1
Reactant: [H][H]
Reactant: N#CCCCC#Cc1cccnc1
Agent: [Pd]
Solvent: CC(C)O
Product: N#CCCCCCc1cccnc1
Reaction time: 48 h
Yield: 81.1 %

Procedure:
A solution of 62.82 g of 6-(3-pyridinyl)-5-hexynenitrile in 500 ml of 2-propanol was hydrogenated over 3.0 g of 10% palladium on carbon at atmospheric pressure. Two additional 3.0 g charges of catalyst were added as the rate of hydrogen uptake slowed. After two days, the reaction mixture was filtered, concentrated, the residue was evaporatively distilled and the distillate was dissolved in 300 ml of 2-propanol and was reduced over 3.0 g of 10% palladium on carbon. Filtration, evaporation, and distillation gave 52.15 g (82%) of 6-(3-pyridinyl)hexanenitrile, bp 150°/0.3 mm which gave a main peak consisting of 93% of the total by gas chromatography analysis. A portion was further purified by silica gel chromatography eluting with 1:1 ethyl acetate-hexane containing 1% triethyl amine and was evaporatively distilled to give an analytical sample.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[O:14][CH2:13][CH2:12][N:11](CC4C=CC=CC=4)[CH2:10]3)=[N:8][C:4]=2[CH:3]=1.Cl.C(Cl)Cl>CO.[Pd]>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[O:14][CH2:13][CH2:12][NH:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2[nH]c(C3CN(Cc4ccccc4)CCO3)nc2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Fc1ccc2[nH]c(C3CNCCO3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 5-fluoro-2-[4-(phenylmethyl)-2-morpholinyl]-1H-benzimidazole (3.0 g, 9.64 mmol), and hydrogen chloride (0.703 g, 19.27 mmol) in CH3OH (50 mL) stirred under nitrogen at room temperature was added palladium on carbon (0.103 g, 0.964 mmol), and the reaction mixture was stirred under hydrogen at 25° C. overnight. CH2Cl2 was added and the mixture was filtered. The filtrate was concentrated in vacuo and the residue was triturated with EtOAc, filtered and dried to afford a hydrochloride salt of the title compound as a off-white solid (2.0 g). LC-MS (ES) m/z=222 [M+H]+.
Reaction SMILES: CS(O[C:6]1([CH2:23][CH3:24])[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[CH3:25][NH:26][CH3:27]>C(O)(C)C>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:9][C:6]([CH2:23][CH3:24])([N:26]([CH3:27])[CH3:25])[CH2:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNC
Reactant: CCC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC(C)O
Product: CCC1(N(C)C)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C
Yield: 25.3 %

Procedure:
A mixture of 1-(diphenylmethyl)-3-ethyl-3-azetidinyl methanesulfonate (1.00 g, 2.89 mmol) (Ellsworth, Edmund Lee; Hoyer, Denton Wade; Hutchings, Kim Marie; Kendall, Jackie Diane; Murphy, Sean Timothy; Starr, Jeremy Tyson; Tran, Tuan Phong. WO 2005049605), dimethylamine (2 M in THF, 14.45 ml, 28.9 mmol) and TEA (0.80 ml, 5.78 mmol) in isopropanol was heated to 70° C. overnight. Standard work-up followed by RP-HPLC provided 1-(diphenylmethyl)-3-ethyl-N,N-dimethyl-3-azetidinamine (0.215 g, 25.3%). LCMS: (M+H)+ 295.2.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH2:26]([NH2:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:26]([NH:28][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:23])[CH3:27]
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2CC

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid ethylamide (70.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (150.0 mg), ethylamine (2.0 M solution in THF, 1.0 mL), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 401; and 1H NMR (DMSO-d6, 400 MHz): δ 8.44 (1H, m), 8.08 (1H, m), 7.95-7.92 (1H, m), 7.75-7.64 (2H, m), 7.53-7.51 (1H, m), 7.41-7.38 (1H, m), 4.21-4.19 (2H, m), 3.32-3.28 (2H, m), 1.34-1.32 (3H, t), 1.17-1.13 (3H, t), —NH proton signal was not observed.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:50]([SH:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:1]([C:18]([O:20][CH2:21][CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:19])[C@H:2]([C:15]([S:57][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)SCc2ccccc2)cc1

Procedure:
4.6 g (10.0 mmol) Fmoc-Tyr(But)-OH, 2.1 g (10.1 mmol) dicylohexylcarbodiimide (DCC), 1.26 g (10.1 mmol) benzylmercaptan and 0.12 g DMAP were reacted in DCM as described by Ho and Ngu (J. Org. Chem. 58:2315 (1993), which is incorporated herein by reference). After workup, Fmoc-Tyr(But)-S—CH2C6H5 was isolated and, upon reduction of the thioester by stirring with triethylsilane in the presence of 10% Pd on carbon and purification by flash chromatography, gave a 81% yield of Fmoc-Tyr(But)-H. The NMR and mass of the product were in accordance with the expected range.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([CH3:24])[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:16][C:17]=1[OH:18])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:18][C:17]1[N:16]=[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([CH3:24])=[N:13][C:12]=1[CH2:11][CH2:10][CH2:9][OH:8]
Reactant: CCOC(=O)c1nc(O)c(CCCOCc2ccccc2)nc1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1nc(O)c(CCCO)nc1C
Temperature: 25 °C

Procedure:
A suspension of ethyl 5-[3-(benzyloxy)propyl]-6-hydroxy-3-methylpyrazine-2-carboxylate (2.91 g, 8.80 mmol) and palladium hydroxide (1.06 g) in ethanol (60 mL) was refluxed for 7 h. After being cooled to ambient temperature, the reaction mixture was filtrated through celite with ethanol. The filtrate was combined and concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform to chloroform:methanol=19:1) to give ethyl 6-hydroxy-5-(3-hydroxypropyl)-3-methylpyrazine-2-carboxylate. MS (APCI): m/z 241 (M+H).
Reaction SMILES: CN(C)CCOC1C=C[C:9]([NH:12][C:13]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[CH:23][CH:24]=2)=[O:14])=CC=1>C(Cl)Cl.CO>[NH:17]1[CH:16]=[CH:21][N:20]=[C:9]1[NH:12][C:13]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:23][CH:24]=1)=[O:14]
Reactant: CN(C)CCOc1ccc(NC(=O)c2ccc(-c3ccccc3F)c3nccnc23)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ncc[nH]1)c1ccc(-c2ccccc2F)c2nccnc12

Procedure:
The title compound was prepared in analogy to the procedure described in Example 14 but using 8-(2-fluoro-phenyl)-quinoxaline-5-carboxylic acid (Example 44) in Step 14.1. Title compound: ESI-MS: 334.0 [M+H]+; tR=3.39 min (System 1); TLC: Rf=0.54 (DCM/MeOH, 9:1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>>[OH:10][C:8]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: Ic1ccncc1
Reactant: CC(=O)c1ccc(-c2ccc(C#N)nc2)cn1
Product: CC(O)(c1ccncc1)c1ccc(-c2ccc(C#N)nc2)cn1
Yield: 18.4 %

Procedure:
Using 4-iodo pyridine (0.22 g, 1.076 mmol), and 6′-acetyl-[3,3′-bipyridine]-6-carbonitrile (0.12 g, 0.54 mmol) and procedure described for example 7 and step 4, crude product was obtained. The crude product was purified by preparative TLC (5% methanol in ethyl acetate) to obtain 6′-(1-hydroxy-1-(pyridin-4-yl)ethyl)-[3,3′-bipyridine]-6-carbonitrile as off-white solid (30 mg, 18% yield) in 98% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.94 (s, 1H), 8.46 (d, 2H), 8.38 (dd, 1H), 8.23 (dd, 1H), 8.14 (d, 1H), 7.82 (d, 1H), 7.49 (d, 2H), 6.27 (s, 1H), 1.9 (s, 3H); LC-MS m/z calculated for [M+H]+303.12. found 303.1.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([F:27])[CH:26]=1>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:23]1[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc(F)cc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (3.0 g) in tetrahydrofuran (70 mL), 3,5-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 25.7 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 3.0 g of the title compound as a pale yellow oil. The property values of the compound are as follows.
Reaction SMILES: [OH:1][CH:2]([CH2:30]O)[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]3[C:22]([O:28]C)=[N:23][CH:24]=[C:25]([F:27])[CH:26]=3)=[N:12][C:11]=12)=[O:6].[ClH:32]>>[Cl:32][CH2:30][CH:2]([OH:1])[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]3[C:22](=[O:28])[NH:23][CH:24]=[C:25]([F:27])[CH:26]=3)=[N:12][C:11]=12)=[O:6]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCC(O)CO)c2n1
Reactant: Cl
Product: O=C(NCC(O)CCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 85 °C

Procedure:
A mixture of N-(2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.232 mmol) and HCl (4 N, dioxane, 5.8 mL) was sealed in a pressure tube and heated at 85° C. overnight. After the clear solution was decanted, the crude product was obtained as a brownish oily residue, which was vacuum-dried and used directly in the next step without further purification. MS (apci) m/z=435.0 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.CCN(CC)CC.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:31][C:30]1[CH:32]=[CH:33][C:27]([S:24]([O:1][CH2:2][CH:3]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccsc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(NC(=O)OC(C)(C)C)c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl 2-hydroxy-1-(thiophen-3-yl)ethylcarbamate (E1) in CH2Cl2 was added NEt3, DMAP, and TsCl. The solution was stirred at room temperature for 3 hours and then poured into NH4Cl (sat) and extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 30% EtOAc/Hexanes) gave pure 2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)ethyl 4-methylbenzenesulfonate (E2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:4]([N+:22]([O-])=O)[CH:3]=1.O.NN>C(O)C.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH2:12][CH2:11]2)=[C:4]([NH2:22])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
N-(4,5-Dichloro-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D38) (320 mg) was dissolved in ethanol (20 ml) and Raney nickel (50% aqueous suspension, 0.5 ml) was added at room temperature; the mixture was heated to 40° C. and hydrazine monohydrate (0.4 ml) was added over 20 min. After 30 min more, the reaction mixture was cooled to room temperature, filtered through Celite and the solvent was evaporated. Chromatography on silica gel eluting with methanol-dichloromethane mixtures yielded the title compound, 150 mg.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][NH:28][C:29]3=S)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH3:34].O1CCOCC1>>[NH2:34][C:29]1[C:30]2[C:25](=[CH:24][CH:23]=[C:22]([N:7]3[C:8]([NH:10][C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=4[Cl:21])=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]3)[CH:31]=2)[CH2:26][CH2:27][N:28]=1
Reactant: N
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(=S)NCC3)n1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(N)=NCC3)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
1-[3-t-Butyl-1-(1-thioxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea (0.170 g, 0.348 mmol) was dissolved in 0.5M NH3/dioxane (30 mL). Mercuric chloride (0.142 g, 0.522 mmol) was added and the mixture was stirred at 80° C. After 18 h, H2O (2 mL) was added. The mixture was stirred for 30 min and filtered through a pad of Celite®. The solvent was removed under vacuum and the residue was purified by reverse-phase chromatography to yield 1-[1-(1-amino-3,4-dihydroisoquinolin-7-yl)-3-t-butyl-1 H-pyrazol-5-yl]-3-(2,3-dichlorophenyl)urea (25 mg, 15% yield). 1H NMR (400 MHz, CD3OD): □ 8.14 (d, J=2.0 Hz, 1H), 7.99-7.96 (m, 1H), 7.84 (dd, J=8.0, and 2.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.23-7.21 (m, 2H), 6.46 (s, 1H), 3.62 (t, J=6.8 Hz, 2H), 3.14 (t, J=6.8 Hz, 2H), 1.35 (s, 9H); MS (ESI) m/z: 471.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(OOC(=O)C1C=CC=CC=1)(=[O:31])C1C=CC=CC=1.BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:31])[C:5]=1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(C=O)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 165.4 %

Procedure:
To a solution of 1.0 g (2.985 mmol) of the product of Example 3 in 100 mL of carbon tetrachloride was added 0.20 g of dibenzoyl peroxide and 1.168 g (6.568 mmol) of N-bromosuccinimide. The resulting mixture was refluxed for 18 h, cooled, washed with sodium bisulfite solution and water, dried over MgSO4, filtered and concentrated in vacuo. The residue was diluted with 10 mL of THF and 10 mL of 1N sodium hydroxide solution and the mixture was stirred at room temperature for 3 h. The reaction mixture was then acidified with 5% HCl and extracted with ether. The organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether to provide 0.477 g (47%) of the product as a white solid. Electrospray Mass Spec: 350.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[F:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[F:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(C)Oc2cccc(F)c2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 29.2 %

Procedure:
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 3-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(3-fluorophenoxy)ethyl)benzoate (400 mg, 29%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=1[F:27])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=1[F:27])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
1.31 g of (R)-t-butyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate, 16 mL of methylene chloride, and 16 mL of trifluoroacetic acid were added to 100 mL flask and the resulting reaction solution was stirred for 6 hours. After completing the reaction, the reaction solution was concentrated under reduced pressure and 16 mL of methanol was added to the concentrated residue. The reaction solution was cooled to 0° C., 2.82 g of sodium hydrogen carbonate and 0.77 mL of di-t-butyl dicarbonate were added, and then stirred for 6 hours while the reaction temperature was naturally increased to room temperature. After completing the reaction, the reaction solution was concentrated under reduced pressure; then 30 mL of ethyl acetate and 30 mL of water were added; and then stirred for 10 minutes. An aqueous layer was isolated, cooled to 0° C., and then 2 N hydrochloric acid aqueous solution was dropped to adjust to pH 3-4. The aqueous layer was extracted with methylene chloride:methanol=10:1 solvent, dehydrated with magnesium sulfate, and then concentrated under reduced pressure to obtain 828 mg of a title compound.
Reaction SMILES: [C:1]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23](C=O)[CH:22]=1)(=[O:17])[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][CH3:16].[OH-:30].[K+].OO>C(O)(C)C.O>[C:1]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:30])[CH:22]=1)(=[O:17])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OCCc1ccc(O)c(C=O)c1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCC(=O)OCCc1ccc(O)c(O)c1
Temperature: 35 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
The aldehyde from example 2 (23.6 g, 58.5 mmole mmole) was dissolved in 100 mL of isopropyl alcohol at 45° C. The solution was cooled to 35° C. and 8.8 g of 45% KOH (70 mmoles) in 150 mL of water was dripped in at 30-35° C. The solution was cooled 20-25° C. and a solution of 8 g of 35% hydrogen peroxide (82 mmole) in 10 mL of water was dripped in over about 20 min at 20-25° C. A mild exotherm was noted, but the temperature was easily held by a water bath. The product precipitated during the addition of the peroxide. The slurry was held 1 hr at which time it exhibited a weak peroxide test (starch-iodide paper). Acetic acid (2mL) was added to reduce the pH from ca. 8 to ca. 6. The slurry was filtered, washed with water, and the product was air-dried to give 20.8 g (91%) of white solid. HPLC analysis indicated an area % product of 93.6, the melting point was 61-62° C., and the H1 NMR was consistent with the structure. The composition of Example 3 prior to isolation by HPLC: 91% product, 1% formate ester 9, 3% starting material.
Reaction SMILES: Cl.[CH2:2]([NH2:12])[C:3]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][O:6][C:5]=2[CH:4]=1.[O-:13][C:14]#[N:15].[Na+]>O>[CH2:7]1[O:8][C:9]2[CH:10]=[CH:11][C:3]([CH2:2][NH:12][C:14]([NH2:15])=[O:13])=[CH:4][C:5]=2[O:6]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)NCc1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
61.5 ml of 5N HCl was added within 30 minutes to a stirred emulsion of 38.51 ml (300 mM) of 97% piperonylamine and 20.40 g of sodium cyanate in 500 ml of water. After stirring overnight the foamy solid is collected, dried, suspended in 500 ml of ether and collected again: 52.57 g (90.2%) of urea with a melting point of 183-84° C.