Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]([F:33])([F:32])[C:25]1([C:29]([OH:31])=O)[CH2:28][CH2:27][CH2:26]1.[Cl:34][C:35]1[C:42]([NH:43][C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][CH2:58][CH:57]([C:61]([F:64])([F:63])[F:62])[CH2:56]4)[C:52]([Cl:54])=[CH:53][C:46]=3[N:45]=2)=[C:41]([Cl:65])[CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>CN(C=O)C>[Cl:34][C:35]1[C:42]([NH:43][C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][CH2:58][CH:57]([C:61]([F:64])([F:63])[F:62])[CH2:56]4)[C:52]([Cl:54])=[CH:53][C:46]=3[N:45]=2)=[C:41]([Cl:65])[CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:29]([C:25]1([C:24]([F:23])([F:33])[F:32])[CH2:26][CH2:27][CH2:28]1)=[O:31]
Reactant: O=C(O)C1(C(F)(F)F)CCC1
Reactant: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C3(C(F)(F)F)CCC3)c2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21

Procedure:
The title compound was prepared from TBTU (35 mg, 0.11 mmol), TEA (50 μL, 0.36 mmol), 1-trifluormethyl-cyclobutanecarboxylic acid (57 mg, 0.4 mmol) and 2,4-dichloro-3-[5-chloro-1-methyl-6-(3-(trifluoromethyl)piperidin-1-yl)-1H-benzimidazol-2-ylamino]benzylamine (45.3 mg, 0.1 mmol) in DMF (3 mL) analogy to example 1 step (i).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=[O:17].C(=O)([O-])O.[Na+]>C(OCC)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]([C:4]2[S:3][CH:2]=[N:6][CH:5]=2)[OH:17])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Brc1nccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: OC(c1ccc(Cl)c(Cl)c1)c1cncs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Bromothiazole (5 g) in dry diethyl ether (20 ml) was added dropwise to a stirred solution of n-butyllithium (1.6M in hexanes, 21 ml) in diethyl ether (20 ml) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, trimethylsilylchlorlde (3.9 ml) was added and the mixture was allowed to warm to 0° C. The mixture was then cooled to -70° C. and further n-butyllithium (21 ml) was added. The mixture was warmed to 0° C. and after 30 minutes was cooled again to -70° C. and 3,4-dichlorobenzaldehyde (5.8 g) in diethyl ether (40 ml) was added. The mixture was then allowed to warm to room temperature and after 30 minutes saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with dichloromethane and the material thus obtained was purified by chromatography on silica gel to give the title compound. The hydrochloride salt was prepared. M.p. 167°-170° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]1[N:9]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[N:13]=[C:10]2[S:11][CH:12]=1.[CH2:19](O)[CH3:20]>C(Cl)Cl.O>[CH3:7][C:8]1[N:9]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]=[C:10]2[S:11][CH:12]=1
Reactant: Cc1csc2nc(C(=O)O)cn12
Reactant: CCO
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(C)csc2n1

Procedure:
To a solution of 6.3 g of phosphorus pentachloride in 120 ml of dry methylene chloride, 5 g of 3-methyl-imidazo-(2,1-b)thiazole-6-carboxylic acid (prepared as described in Example 10) is added and the suspension obtained is refluxed for 3 hours. After vacuum evaporation of the solvent the residue obtained being 3-methyl-imidazo-(2,1-b)thiazole-6-carboxylchloride chlorohydrate is dissolved in 100 ml of abs. ethanol and the solution is refluxed for 4 hours. The solvent is removed and the residue obtained is dissolved in water. The solution obtained is neutralised to pH 7.5 to yield 5 g of 3-methyl-6-carboethoxy-imidazo-(2,1-b)thiazole; m.p. 117°-119°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:33])[CH2:11][N:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13](=[O:26])[CH2:14][N:15]2C(=O)C3=CC=CC=C3[C:16]2=[O:25])=[CH:5][CH:4]=1.O.NN.[CH3:37][C:38]1[CH:39]=[C:40]([N:44]=C=O)[CH:41]=[CH:42][CH:43]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:33])[CH2:11][N:12]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:13](=[O:26])[CH2:14][NH:15][C:16]([NH:44][C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([CH3:37])[CH:39]=2)=[O:25])=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(=O)CN(C(=O)CN2C(=O)c3ccccc3C2=O)c2ccccc2)cc1
Reactant: Cc1cccc(N=C=O)c1
Agent: NN
Solvent: O
Product: COc1ccc(NC(=O)CN(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)cc1
Yield: 9.9 %

Procedure:
The procedure is analogous to that described in Example 23, but 1.2 g of N-(4-methoxyphenyl)-2-(N-phenyl-2-phthalimidoacetamido)acetamide, 0.28 g of hydrazine hydrate and 0.38 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 25 g of silica (0.065-0.200 mm) contained in a column 1.7 cm in diameter [eluent: methylene chloride/ethyl acetate (80-20 by volume)], collecting 25 cm3 fractions. Fractions 2 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from acetonitrile, 0.12 g of N-(4-methoxyphenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 194° C. is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH2:6][OH:7].[C:20](OC(=O)C)(=[O:22])C>C(O)=O>[CH:20]([NH:1][CH2:2][C:3]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH2:6][OH:7])=[O:22]
Reactant: CC(=O)OC(C)=O
Reactant: NCC(CCCO)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=CNCC(CCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In formic acid (80 ml) was dissolved 5-amino-4,4-diphenylpentanol (10 g) followed by addition of acetic anhydride (13 ml) and the mixture was stirred at room temperature for 4 hours. This reaction mixture was concentrated to dryness and the group was partitioned into chloroform and water. The water layer was made basic by aqueous ammonia and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated to dryness. The group was dissolved in ethanol (30 ml) and the solution was stirred in 1N-aqueous sodium hydroxide (20 ml) at room temperature for 20 minutes. This reaction mixture was diluted with water and the crystals that separated out were harvested by filtration. This crystal crop was washed serially with water and ethyl acetate to provide the title compound (9 g) as colorless powder.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])[CH3:13].Cl>CCOCC>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[O:14]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1cccs1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1cccs1
Temperature: 25 °C
Reaction time: 15.67 h
Yield: 49.7 %

Procedure:
Ethyl difluoroacetate (1.84 g, 14.8 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (5 mL). To the stirred solution was added 25 weight % sodium methoxide (3.39 g, 15.7 mmol) followed by 2-acetylthiophene (1.72 g, 13.6 mmol). The reaction was stirred at room temperature overnight (15.67 hours), then treated with 3N HCl (8 mL). The organic layer was collected and washed with brine, dried over MgSO4, concentrated in vacuo, and recrystallized from methylene chloride/isooctane to give a brown solid (1.38 g, mp 78°-80° C., 50%). 1H NMR (CDCl3) 300 MHz 14.90 (br s, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.71 (d, J=3.8 Hz, 1H), 7.19 (m, 1H), 6.41 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); 19F NMR (CDCl3) 300 MHz: -126 98 (d); M+204.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.OS(O)(=O)=O.[CH3:14]O>>[NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:14])=[O:7])[N:3]=[CH:2]1
Reactant: O=C(O)c1c[nH]cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c[nH]cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1H-Imidazole-4-carboxylic acid (5 g, 44.6 mmol) was dissolved in MeOH (100 ml). Into the solution, H2SO4 (10 ml) was added at 0° C. The resulting mixture was stirred at 80° C. for overnight. The solvent was concentrated under reduced pressure. The pH was adjusted to 9 with aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was concentrated to give the product. Yield 5.2 g. 1H-NMR (400 MHz; DMSO-d6): δ 3.74 (s, 3H), 7.79 (bs, 2H), 12.75 (bs, 1H). LC-MS: [M+1]=127.23.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[CH3:16][C:15]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1
Reactant: Fc1cccc(-c2ccc(Cl)nn2)c1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cccc(F)c3)nn12

Procedure:
As in Example 36, a mixture of 3.0 g. of 3-chloro-6-(m-fluorophenyl)pyridazine, 2.14 g. of acetylhydrazine and 50 ml. of n-butanol is refluxed 48 hrs. to give 2.0 g. of the product as crystals, m.p. 184°-186° C.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][O:14][CH3:15])[CH:3]=1.CS(C)=O.[CH2:20]([S-:22])[CH3:21].[Na+]>O>[CH2:20]([S:22][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][O:14][CH3:15])[CH:3]=1)[CH3:21]
Reactant: CC[S-]
Reactant: COCOc1cc(F)ccc1C(=O)OC
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1ccc(C(=O)OC)c(OCOC)c1
Reaction time: 19 h

Procedure:
To a solution of methyl 4-fluoro-2-(methoxymethoxy)-benzoate (10.6 g, 50 mmol) and DMSO (20 mL), under nitrogen, was added sodium ethanethiolate (5.8 g, 55 mmol) in portions. The exothermic reaction was stirred for 19 h, diluted with water, and extracted with ethyl acetate. The organic layer was concentrated; and the residue was dissolved in ether, filtered through diatomaceus earth, and concentrated to give intermediate methyl 4-(ethylthio)-2-(methoxymethoxy)benzoate.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:25]=1.N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C>[CH3:31][O:30][C:28]1[CH:29]=[C:24]([O:23][CH3:22])[N:25]=[C:26]([NH:32][C:33]([NH:1][S:2]([C:5]2[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:19])([F:20])[F:21])[CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:3])=[O:4])=[O:34])[N:27]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(N)(=O)=O
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At room temperature, 166 mg (0.5 mmol) of methyl 2-(aminosulfonyl)-4-[(2,2,2-trifluoroethlidene)hydrazino]-benzoate and 137.5 mg (0.5 mmol) of phenyl (4,6-dimethoxy-pyrimidin-2-yl)carbamate were dissolved in 1.5 ml of N,N-dimethylacetamide. Then, 86.1 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene were added, followed by stirring for 5 minutes. The resultant mixture was allowed to stand for 15 hours. Thereafter, 0.2 ml of 35% hydrochloric acid was added to 20 ml of ice water, followed by the addition of the reaction mixture in 0.2 ml portions under stirring. After the reaction mixture was stirred for 20 minutes, the resulting precipitate was collected by filtration and dried in air. Using dichloromethane as an eluent, the crude product was purified by chromatography on a column of silica gel ("WAKO GEL C-300", trade name; product of Wako Pure Chemical Industries, Ltd.). The title compound was obtained as a white solid. Yield: 162 mg (64%). Melting point: 201°-202° C. Its physicochemical properties are shown in Table 4.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[OH:40][CH2:39][CH2:38][N:35]1[CH2:34][CH2:33][N:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:2]3[N:24]=[C:5]4[C:6]([NH:10][CH2:11][C:12]5[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:27][CH:28]=2)[CH2:37][CH2:36]1
Reactant: Nc1ccc(N2CCN(CCO)CC2)cc1
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ncccc1CNc1cccn2nc(Nc3ccc(N4CCN(CCO)CC4)cc3)nc12)S(C)(=O)=O

Procedure:
N-{3-[(2-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 2-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanol (50.0 mg, 0.226 mmol) with 2,2′-Bis-dicyclohexylphosphanyl-biphenyl (26.0 mg, 0.0476 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.052 g, 46%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=4.5 Hz, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.81 (d, J=6.7 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.30-7.25 (m, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.64 (t, J=7.3 Hz, 1H), 6.56 (s, 1H), 6.29 (d, J=7.7 Hz, 1H), 5.33-5.28 (m, 1H), 4.17 (d, J=6.1 Hz, 2H), 3.67 (t, J=5.3 Hz, 2H), 3.32 (s, 3H), 3.18-3.13 (m, 4H), 3.09 (s, 3H), 2.72-2.67 (m, 4H), 2.62 (t, J=5.4 Hz, 2H). MS=552 (MH)+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[CH:12]2.[F:20][CH:21]([F:24])[CH2:22]I>O>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:22][CH:21]([F:24])[F:20])[CH:13]=[CH:12]2
Reactant: FC(F)CI
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccc(Br)cc2ccn1CC(F)F
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
Under nitrogen atmosphere, 44 mg of 60% sodium hydride was added at room temperature to 2 ml solution of dimethylformamide with 49 mg of 6-bromo-2H-isoquinoline-1-one and the mixture was stirred for 30 min. Then, 169 mg of 2,2-difluoroethyliodide was added and stirred at room temperature for 6 hours. Cold water was added to the reaction solution, the products were extracted with chloroform. Chloroform layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by thin-layer chromatography (chloroform/methyl alcohol=10/1) to obtain 41 mg of the above compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:31]=[CH:32][C:27]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)[CH2:34][CH2:35]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: CCCCc1ccc(N2CCNCC2)cc1
Product: CCCCc1ccc(N2CCN(C(=O)Nc3nc4ccccc4nc3OC)CC2)cc1
Yield: 65.4 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(4-butylphenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>CO.[Pd]>[NH2:12][C:11]1[C:2]([OH:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1O
Yield: 95.7 %

Procedure:
A solution of methyl 2-hydroxy-3-nitrobenzoate (2 g, 0.010 mol) in methanol (30 mL), was hydrogenated with a hydrogen balloon in the presence of 10% palladium on chacoal (600 mg) for 7 h. After the reaction is completed, the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to obtain 1.6 g of the above required compound (72%) as a grey coloured solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[Cl:27])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][C:19]=1[Cl:27])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (5 ml) and dimethylformamide (1 drop) were added to a solution of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzoic acid (680 mg) in dichloromethane (7 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzoyl chloride as crystals. Then, the crystals were dissolved in dichloromethane (12 ml). The solution was dropwise added to a solution of 4-aminopyridine (187 mg) and diispropylethylamine (267 mg) in dichloromethane (5 ml) at room temperature, and the mixture was stirred for 1 hour. After the reaction, water was added to the reaction mixture. The mixture was extracted with chloroform, washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 650 mg of (R)-4-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].O.C1C=C(Cl)C=C(C(OO)=O)C=1>CO>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 96.4 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of methanol in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature without irradiation by lamps. After completion, methanol was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.9 g of 1-benzyl-3,4-epoxypyrrolidine (yield 96.7%) was obtained.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:7]([CH:21]=[CH:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:26]([CH3:28])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=2)[C:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:26]([CH3:27])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(C(C)C)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-isopropylphenyl)-5-(pent-1-enyl)pyridine (Example 133) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl 3): δ 0.74 (t, J=7.0 Hz, 3 H), 1.0-1.40 (m, 25 H), 2.25 (m, 2 H), 2.95 (m, 1 H), 3.25 (m, 1 H), 3.40 (m, 1 H), 4.35 (d, J=6.0 Hz, 2 H), 7.1, (d, J=8.5 Hz, 2 H), 7.25 (d, J=8.5 Hz, 2 H). FAB-MS: calculated for C26H39NO 382; found 382 (M+H, 100%). Rf=0.40 (10% ethyl acetate/n-hexane). mp 42-44° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]([C:14]3([CH3:17])[CH2:16][CH2:15]3)O)=[CH:4][C:3]=2[O:2]1.P(Br)(Br)[Br:19].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH3:17][C:14](=[CH:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH2:15][CH2:16][Br:19]
Reactant: CC1(C(O)CCc2ccc3c(c2)OCO3)CC1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: CC(=CCCc1ccc2c(c1)OCO2)CCBr

Procedure:
3-Methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-methylenedioxyphenyl, R is CH3 ] was prepared from 17.6 g. of 2-(3,4-methylenedioxyphenyl)ethyl 1-methylcyclopropyl carbinol (Preparation B3), 20.3 g. of phosphorus tribromide, 18.5 g. of lithium bromide and 21 g. of zinc bromide according to the procedure given above the Preparation C1, affording 19 g. of product as an oil.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(O[Cl:15])(C)(C)C>CO>[Cl:15][N:4]1[C:3]([CH2:2][F:1])([CH3:9])[CH2:7][O:6][C:5]1=[O:8]
Reactant: CC1(CF)COC(=O)N1
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CC1(CF)COC(=O)N1Cl
Reaction time: 2 h
Yield: 99.4 %

Procedure:
A solution of 4-(fluoromethyl)-4-methyloxazolidin-2-one (245 mg, 1.82 mmol) in MeOH (5 ml) was cooled to 0° C. and tert-butylhypochlorite (251 mg, 2.3 mmol) was added dropwise. The solution was stirred for 2 h, concentrated in vacuo, and the residue purified by flash chromatography (0% to 10% MeOH in DCM) to afford the title compound as a white solid (303 mg, 100%). 1H NMR (CDCl3, 400 MHz) δ 1.38 (d, J=2.4 Hz, 3H), 4.22 (dd, J=1.2, 8.8 Hz), 1H), 4.24 (d, J=11.2 Hz, 0.5H), 4.35 (d, J=10.4 Hz, 0.5H), 4.53 (d, J=10.4 Hz, 0.5H), 4.54 (dd, J=0.8, 8.8 Hz, 1H), 4.64 (d, J=10.4 Hz, 0.5H). 19F NMR (CDCl3, 376 MHz) δ −228.4 (t, J=84 Hz). 13C NMR (CDCl3, 100 MHz) δ 17.7 (d, J=3.7 Hz), 63.5 (d, J=18 Hz), 70.7 (d, J=4 Hz), 82 (d, J=179 Hz), 155.8 (s). LRMS (ESI/APCI): 168 [M+H]+, 209 [M+H+CH3CN]+.
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:38]([OH:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[H-].[Na+]>CN(C=O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:21]=1
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(OCc3ccccc3)nc(N)nc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 500 mL of dry round-bottomed flask were added (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (4, 8.0 g, 15.2 mmol) and anhydrous benzyl alcohol (128 mL). To another 250 mL of dry round-bottomed flask were charged NaH (60% in mineral oil, 2.44 g, 60.8 mmol) and anhydrous DMF (40 mL). The suspension was stirred at 0° C. in an ice-water bath. Benzyl alcohol (27 mL) was added drop-wise via a syringe. A solution was slowly formed and it was transferred to the nucleoside suspension quickly under a nitrogen atmosphere at room temperature. The mixture was heated to 50° C. and stirred. The reaction was complete after 3 h and cooled to ambient temperature. It was neutralized by the addition of 4 NHCl to ca. pH=7 (12 mL). The solution was concentrated under reduced pressure (4 mbar, 90° C. bath). The cloudy residue was diluted with dichloromethane (100 mL) and washed with water (3×30 mL), brine (30 mL) and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated under reduced pressure to an oily residue. This was purified by column chromatography (Analogix, 0 to 8% gradient of MeOH in DCM). The product eluted at 4% MeOH in DCM. The product containing fractions were combined, concentrated under reduced pressure and dried (50° C., 0.2 mmHg, 17 h) to a white foam solid (4.57 g, 11.7 mmol, 77.2%).