Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:16][C@H:15]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([OH:22])[C@H:13]1[OH:23].[CH2:24]([CH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)[C:25]#[CH:26]>C(#N)C.[Cu]I.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>[CH3:21][CH2:20][NH:19][C:17]([C@H:15]1[O:16][C@@H:12]([N:6]2[C:7]3[N:8]=[C:9]([C:26]#[C:25][CH2:24][CH:27]4[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]4)[N:10]=[C:2]([NH2:1])[C:3]=3[N:4]=[CH:5]2)[C@H:13]([OH:23])[C@@H:14]1[OH:22])=[O:18]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(I)nc32)[C@H](O)[C@@H]1O
Reactant: C#CCC1CCC(C(=O)OC)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(C#CCC4CCC(C(=O)OC)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 70 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
To a degassed solution of 25 mg (0.063 mmol) of [(2S,3S,4R,5R)-5-(6-amino-2-iodopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]-N-ethylcarboxamide (6.9), 16.9 mg (0.094 mmol) (5.5), and 0.75 mg CuI in 5 mL each of TEA and acetonitrile was added 15 mg of Pd(PPh3)4. The solution was stirred for 24 hours at 70° C. after which time the solution was filtered through celite and chromatographed on silica gel with MeOH—CHCl3 (5:95) to give DWH-146e (24%).
Reaction SMILES: [C:1]([O:6][CH:7]1[CH:13]2O[CH:15]3[CH:8]1OC(=O)[CH:11]3[CH2:12]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:17][C:18]1C=C[C:21](C=C)=[CH:20][CH:19]=1>>[C:1]([O:6][C:7]1[C:8]2[C:15](=[C:18]([OH:17])[CH:19]=[CH:20][CH:21]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=Cc1ccc(O)cc1
Reactant: C=C(C)C(=O)OC1C2CC3C(=O)OC1C3O2
Product: C=C(C)C(=O)Oc1cccc2c(O)cccc12

Procedure:
3-oxo-2,7-dioxatricyclo[4.2.1.04,8]nonan-9-yl methacrylate:PAG Monomer 1=0.30:0.30:0.30:0.10
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(Cc3ccccc3)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1Cc1ccccc1

Procedure:
The 2-trifluoroacetamido-3-benzyl-6-benzoyl-imidazo[1,2-a]pyridine (2.14 g, 5.06 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 1.29 g. (78.2%). EA, MS(FD).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:22]3[C:21](=O)[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]3[CH2:14][CH2:13][CH2:12][C:11](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+].C(O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[C:11](=[O:24])[CH2:12][CH2:13][CH2:14][C:15]=3[NH:16][C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1CCCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCCC1)N2
Temperature: 70 °C
Yield: 63.4 %

Procedure:
A mixture of 9-(3-bromo-4-fluorophenyl)-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (1.8 g), sodium borohydride (1.74 g), ethanol (40 mL) and pyridine (14 mL) was heated at 70° C. for three and one half hours. The solvent was removed, the residue partitioned between water and ethyl acetate, the organic layer dried and the solvent removed. Chromatography (methylene chloride/ethyl acetate; 7/3) gave the title compound (1.1 g), as a yellow solid, mp 254°-257° C.; NMR: 1.41-1.51 (m,3, CH2), 1.60-1.88 (m,5, CH2), 2.03-2.13 (m,4, CH2), 2.38-2.44 (m,2, CH2), 4.18 (s,1, CH), 7.13-7.24 (m,2, Ar), 7.38 (dd,1, J=6.9, 2.0, Ar), 8.45 (s,1, NH); (CI, CH4) MS: m/z=378(M+1). Analysis for C19H19FBr: Calculated: C, 60.65; H, 5.09; N, 3.72; Found: C, 60.68; H, 5.09; N, 3.65.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18].[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][Cl:24])[CH3:20].C(=O)([O-])O.[Na+]>C(O)C>[ClH:24].[ClH:18].[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][S:15][C:13]1[NH:14][C:10]2[CH:9]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=[CH:16][C:11]=2[N:12]=1)[CH3:20]
Reactant: CCN(CC)CCCl
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)CCSc1nc2ccc(Cc3ccccc3)cc2[nH]1

Procedure:
6 g (25 mmoles) of 5-benzyl-benzimidazoline-2-thione, 5.16 g (30 mmoles) of 2-(diethylamino)-ethylchloride hydrochloride and 2.55 g of sodium hydrogen-carbonate are reacted in 40 ml of ethanol. After filtering off the inorganic salt and concentration of the solution, the title product is precipitated by hydrochloric ethanol.
Reaction SMILES: I[CH2:2][CH3:3].[F:4][CH2:5][CH2:6][O:7][C:8]1[C:16]([O:17][CH2:18][CH2:19][F:20])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[F:4][CH2:5][CH2:6][O:7][C:8]1[C:16]([O:17][CH2:18][CH2:19][F:20])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH2:2][CH3:3])=[O:11]
Reactant: O=C(O)c1cccc(OCCF)c1OCCF
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCOC(=O)c1cccc(OCCF)c1OCCF
Temperature: 25 °C
Yield: 89.3 %

Procedure:
Under a dry nitrogen atmosphere 0.91 gram (0.0058 mole) of iodoethane was added dropwise to a stirred mixture of 1.2 gram (0.0049 mole) of 2,3-di(2-fluoroethoxy)benzoic acid (Compound 105) and 1.4 grams (0.0097 mole) of potassium carbonate in 40 ml of acetone. The reaction mixture was heated at reflux for 24 hours and then was allowed to cool to room temperature. The solvent was evaporated under reduced pressure leaving a residue. This residue was dissolved in diethyl ether, and the solution was washed with water followed by an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.2 gram of ethyl 2,3-di(2-fluoroethoxy)benzoate as an oil, Compound 107 of Table 1.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[C:7](C)=[C:8]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:9][N:10](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:11][CH:12](OC)OC.Cl[CH2:33]Cl>>[F:30][C:29]1[C:28]([CH3:33])=[C:27]2[C:8](=[CH:7][C:6]=1[F:5])[CH:9]=[N:10][CH:11]=[CH:12]2
Reactant: COC(CN(Cc1ccc(F)c(F)c1C)S(=O)(=O)c1ccc(C)cc1)OC
Reactant: ClCCl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1c(F)c(F)cc2cnccc12
Temperature: 50 °C

Procedure:
Aluminium trichloride (112 g, 838 mmol) was suspended in dichloromethane (250 mL) at 0° C. A solution of N-(3,4-difluoro-2-methylbenzyl)-N-(2,2-dimethoxyethyl)-4-methylphenyl-sulphonylamine (42, 68.3 g) in dichloromethane (250 mL) was added. The reaction mixture was heated at 50° C. for 2 hours, before being cooled to 0° C. and poured on ice. The organic layer was separated, and the aqueous layer extracted twice more with dichloromethane/isopropanol (3:1). The combined organic phase was extracted twice with saturated sodium bicarbonate solution and dried over magnesium sulphate, before filtration and evaporation gave 63.5 g of crude dark brown semi-solid product. This was purified by chromatography on silica gel. Elution with ethyl acetate/heptane (5%:95% to 35%:65%) gave 11.3 g of the title compound 43 as a tan-coloured solid. Rt=0.86 min (Method 10). Detected mass: 180.1 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cc(F)ccc2F)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cc(F)ccc3F)cc2=O)n1
Yield: 63 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,5-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 46) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2,5-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.76 g, 63%); ES+-HRMS m/e calcd for C25H29N5O4F2 [M+H+] 502.2261 found 502.2259. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.24-1.77 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.68 (s, 1H), 5.47 (dd, J=4.1, J=11.0 Hz, 1H), 6.00 (d, J=2.7 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.24-7.35 (m, 1H), 7.53 (d, J=2.1 Hz, 1H), 7.53-7.62 (m, 2H), 8.21 (d, J=2.7 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[CH:11]/[C:12](=O)[CH2:13][C:14](=O)/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:19][CH:18]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O.[NH2:34][NH2:35]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14](/[CH:15]=[CH:16]/[C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)=[CH:19][CH:18]=4)[NH:35][N:34]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NN
Reactant: O=C(/C=C/c1ccc(OCc2ccccn2)cc1)CC(=O)/C=C/c1ccc2[nH]ccc2c1
Solvent: O
Solvent: CC(=O)O
Product: C(=C/c1cc(/C=C/c2ccc3[nH]ccc3c2)n[nH]1)\c1ccc(OCc2ccccn2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
In 0.34 mL of acetic acid was dissolved 15 mg (35 μmol) of (1E,6E)-1-(1H-indol-5-yl)-7-[4-(2-pyridylmethoxy)phenyl]hepta-1,6-diene-3,5-dione. To this solution was added 34 μL (0.70 mmol) of hydrazine monohydrate at room temperature and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was neutralized with a saturated sodium bicarbonate aqueous solution and extraction with ethyl acetate was performed. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol). The resulting solid was washed with an organic solvent to give 3.5 mg (24% yield) of the title compound as a pale yellowish white powder with the following properties.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC1C=CC=CC=1.[Br:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:23][CH2:22][CH2:21][Br:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(O)c2ccccc2n1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Nc1ccccc1
Product: Cc1cc(OCCCBr)c2ccccc2n1
Yield: 64 %

Procedure:
A mixture of 2-methylquinolin-4-ol (1.59 g, 10 mmol) (synthesized from aniline and acetoacetic ester according to a procedure known in the art: see Leonard et al. (1946) J. Am. Chem. Soc. 68:1279-1281), 1,3-dibromopropane (8.08 g, 40 mmol) and potassium carbonate (1.659 g, 12 mmol) in acetone (50 mL) was refluxed until the starting material disappeared. The reaction mixture was filtered and after evaporation of solvent residue was purified by column chromatography on silica gel (1% MeOH: 99% CH2Cl2 as eluent). The product was obtained as light yellow solid (1.793 g, 64%). 1H NMR (400 MHz, CDCl3): 2.48 (2H, m), 2.69 (3H, s), 3.69 (2H, t, J=6.3 Hz), 4.33 (2H, t, J=5.8 Hz), 6.6 (1H, s), 7.43 (1H, t, J=7.5 Hz), 7.66 (1H, t, J=7.8 Hz), 7.95 (1H, d, J=8.5 Hz), 8.12 (1H, d, J=8.3 Hz).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[N+:11]([O-:17])([O:13][CH2:14][CH2:15]Br)=[O:12]>C(O)C>[O:13]([CH2:14][CH2:15][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])[N+:11]([O-:17])=[O:12]
Reactant: O=[N+]([O-])OCCBr
Reactant: O=Cc1cccc(O)c1
Agent: [Na]
Solvent: CCO
Product: O=Cc1cccc(OCCO[N+](=O)[O-])c1
Yield: 19 %

Procedure:
1.42 g of sodium were dissolved in 200 ml of ethanol. 7.5 g of 3-hydroxybenzaldehyde and 10.5 g of bromoethyl nitrate were added and the resulting solution was refluxed for 5 hours. The compound was purified by column chromatography (silica, CH2Cl2). Yield 19%. Melting point: oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([NH:42][C@@H:43]([CH3:46])[CH2:44]O)=[C:26]([CH:41]=1)[C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1)=[O:28])#[N:21].C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:44][C@@H:43]([NH:42][C:25]1[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:41][C:26]=1[C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1)=[O:28])[CH3:46]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CO)cc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CBr)cc1OC
Temperature: 25 °C
Yield: 68.8 %

Procedure:
Triphenylphosphine (156 mg) was added to a mixture of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide (200 mg) and carbontetrabromide (215 mg) in dichloromethane (4 mL), and the mixture was stirred for an hour at ambient temperature. After evaporation of the solvent, the residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (9:1) to give (S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (161 mg) as a solid substance.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[CH:22][CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(-n2ccnc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-imidazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 199 (M+H)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]([CH3:19])([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>CN(C)C=O>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[CH2:10][C:11]([CH3:18])([CH3:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(C)(C)Cc1nc2ccccc2[nH]1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)(C)Cc1nc2ccccc2n1Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
9 g of ethyl 4-(benzimidazol-2-yl)-3,3-dimethylbutanoate, prepared in Example 40, are added to a suspension of 21.5 g of 60% sodium hydride in 50 ml of anhydrous dimethylformamide. The mixture is stirred for 1 hour at 50° C., 5.6 g of 4-chlorobenzyl chloride are then added and the solution obtained is heated for 5 hours at 90° C. The solvents are concentrated under vacuum and the residue is taken up with water and then extracted with ether. The ether phase is washed with water and then dried over magnesium sulfate and the ether is evaporated off to dryness to give 12.9 g of ethyl 4-[1-(4-chlorobenzyl)benzimidazol-2-yl]-3,3-dimethylbutanoate in the form of an oil, which is used as such for the next step.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[C:3]([NH:5][NH2:6])=[O:4].[N+:12]([C:15]([N+:24]([O-:26])=[O:25])([N+:21]([O-:23])=[O:22])[CH2:16][CH2:17][C:18](Cl)=[O:19])([O-:14])=[O:13].Cl.C(=O)(O)[O-].[Na+]>C(OCC)C.N1C=CC=CC=1>[N+:12]([C:15]([N+:21]([O-:23])=[O:22])([N+:24]([O-:26])=[O:25])[CH2:16][CH2:17][C:18]([NH:6][NH:5][C:3](=[O:4])[C:2]([F:11])([F:1])[C:7]([F:8])([F:9])[F:10])=[O:19])([O-:14])=[O:13]
Reactant: NNC(=O)C(F)(F)C(F)(F)F
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)C(F)(F)F
Reaction time: 0.08 h

Procedure:
A mixture formed by adding 0.77 g (0.0043 mole) of N-(perfluoropropionyl)hydrazine to a solution of 1.05 g (0.0043 mole) of 4,4,4-trinitrobutyryl chloride in 30 mL of anhydrous diethyl ether was stirred at 20° C during the dropwise addition of 0.35 mL of pyridine. After 5 minutes, dilute hydrochloric acid (10 mL) was added, and the ether layer was separated and dried (MgSO4). Removal of volatiles gave a semisolid which was stirred with dilute sodium bicarbonate to give 1.0 g, mp 105°-118° C. Crystallization from 1,2-dichloroethane gave the product, N-(4,4,4-trinitrobutyryl)-N'-(perfluoropropionyl)hydrazine, 0.65 g (41%), mp 123°-125° C.; 1H NMR (acetone-d6 +D2O): 2.95 (t, 2H); 3.85 (t, 2H).
Reaction SMILES: [N+](=[C:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])=[N-].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:13][OH:14]>C(Cl)Cl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][O:14][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:18]
Reactant: CCOC(=O)CO
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COC(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
To a solution of dimethyl diazopropanedioate (4 g, 25 mmol), prepared according to Peace, Carman, Wulfman, Synthesis, 658-661, (1971), in DCM (10 mL) was added ethyl glycolate (1.2 mL, 12.8 mmol) followed by rhodium (II) acetate dimer (2 g, 20% mol). The reaction mixture was stirred at room temperature for 24 h. The resulting suspension was filtered through a pad of Celite® and the solvent was removed in vacuo. The crude residue was purified by column chromatography (silica gel) using a 0-60% EtOAc/hexanes gradient to provide the desired product as an oil (3 g, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:18](=[O:40])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:18](=[O:40])[N:17]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2CC(=O)OCC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-[1-(2,2-Dimethylpropionyloxymethyl)-2,6-dioxo-7-(2-vinylphenyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (80 mg) was dissolved in N,N-dimethylformamide (2 ml), ethyl bromoacetate (19 μl) and potassium carbonate (22 mg) were added to the solution, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 89 mg of the title compound
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[CH:28]=3)[CH:20]=2)[C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[K].[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][B-](F)(F)F)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCCC1>[C:1]([C:5]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]([O:15][CH3:16])=[C:7]([NH:17][C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH:20]=2)[O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH2:49][N:46]3[CH2:47][CH2:48][N:43]([C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])[CH2:44][CH2:45]3)[CH:28]=2)=[O:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C[B-](F)(F)F)CC1
Reactant: COC(=O)c1cc(C(C)(C)C)cc(NC(=O)c2ccc(C)c(Oc3ccnc(Cl)c3)c2)c1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(C)(C)C)cc(NC(=O)c2ccc(C)c(Oc3ccnc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1OC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 414 mg methyl 5-tert-butyl-3-[3-(2-chloro-pyridin-4-yloxy)-4-methyl-benzoylamino]-2-methoxy-benzoate, 370 mg potassium-(4-tert-butyloxycarbonyl-piperazin-1-ylmethyl)-trifluoroborate, 0.84 g Cs2CO3, 0.80 ml of water and 8 ml of tetrahydrofuran is flushed for 10 min with argon. Then 200 mg of 2-dicyclohexylphosphinyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (XPhos) and 20 mg palladium(II)acetate are added, and the mixture is heated to 80° C. The reaction mixture is stirred overnight at 80° C. in an argon atmosphere. After cooling to ambient temperature the mixture is evaporated down and the residue is taken up in ethyl acetate and water. The organic phase is separated off, washed with water and aqueous saturated saline solution and dried (MgSO4). The solvent is removed, and the residue is chromatographed on silica gel with dichloromethane/methanol (99:1→90:10) and then chromatographed by reversed phase (HPLC, Xbridge C18) with methanol/water/ammonia.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:19][C:20](=[O:25])[C@H:21]([CH2:23][SH:24])[NH2:22])[CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:24][CH2:23][CH:21]([C:20]([O:19][CH2:17][CH3:18])=[O:25])[N:22]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CSC(C2CCN(C(=O)OC(C)(C)C)CC2)=N1

Procedure:
4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was dissolved under inert conditions in 40 ml toluene. To this solution L-cystein ethylester hydrochloride (1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. The generated water was removed with a Dean & Stark trap.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[O:13])OC(=O)[NH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[NH2:9][C:8]1[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[C:12]([NH:23][NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Reactant: NNc1ccccc1
Solvent: CCO
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)NNc1ccccc1

Procedure:
Into a 1000-mL 3-necked round-bottom flask, was placed a solution of 7-nitro-1H-benzo[d][1,3]oxazine-2,4-dione (56 g, 269.23 mmol, 1.00 equiv) in ethanol (500 mL), 1-phenylhydrazine (31.98 g, 296.11 mmol, 1.10 equiv). The resulting solution was heated to reflux for 5 min. The resulting mixture was then concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/petroleum ether (1:2˜1:0) and ethyl acetate/petroleum ether (1:1) to yield 2-amino-4-nitro-N′-phenylbenzohydrazide as a yellow solid. MS: 273 (MH+).