Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:24])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[C:6]([Cl:24])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(I)cc(C(=O)O)cc1C#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(I)cc(C(=O)Cl)cc1C#N
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To 3-cyano-5-iodo-4-methoxybenzoic acid (512 mg), toluene (5 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.15 mL) were added, and the mixture was stirred at 60° C. for 15 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (527 mg) as a pale yellow solid.
Reaction SMILES: C[O:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=[CH:6][N:5]=1.COCC1C(C)=C(N2CCCCC2)N=CN=1>>[OH:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=[CH:6][N:5]=1
Reactant: COCc1ncnc(N2CCOCC2)c1C
Agent: COCc1ncnc(N2CCCCC2)c1C
Product: Cc1c(CO)ncnc1N1CCOCC1

Procedure:
Substituting 4-methoxymethyl-5-methyl-6-morpholinopyrimidine, (5.77 g), for 4-methoxymethyl-5-methyl-6-piperidinopyrimidine and using corresponding molar proportions of the other reagents in the method of Example 10(iv), gave 4-hydroxymethyl-5-methyl-6-morpholinopyrimidine, 3.46 g, m.p. 66°-68°, from petroleum ether (40/60).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[CH2:19][C:20]([CH3:22])=[CH2:21].[In]>C1COCC1.O.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH2:21][C:20]([CH3:22])=[CH2:19])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: C=C(C)CBr
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: [In]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C=C(C)CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (609 mg) in THF (4 mL) and H2O (12 mL) at room temperature were added 3-bromo-2-methyl-propene (0.31 mL), followed by indium powder (279 mg, −100 mesh). The resulting mixture was then stirred at room temperature for 18 hr. The resulting mixture was filtered through a pad of Celite®, rinsed with EtOAc, the layers separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield an orange gum. The orange gum was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as an orange solid.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:22]([C@@:23]4([CH3:29])[CH2:24][CH2:25][C@H:26]([OH:28])[CH2:27][C:2]124)[CH2:21][CH2:20][C@@:19]1([CH3:30])[C@H:6]3[CH2:7][CH2:8][C@:9]1([OH:31])[C@H:10]([CH3:18])[CH2:11][CH2:12][C@@H:13]([CH3:17])[CH:14]([CH3:16])[CH3:15].[NH2:32][CH2:33][CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1.C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:27][C@@H:26]([OH:28])[CH2:25][CH2:24][C@:23]1([CH3:29])[C@@H:22]1[C@H:5]([C@H:6]3[C@:19]([CH3:30])([CH2:20][CH2:21]1)[C@@:9]([OH:31])([C@H:10]([CH3:18])[CH2:11][CH2:12][C@@H:13]([CH3:17])[CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:32][CH2:33][CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)[C@H](C)CC[C@@H](C)[C@@]1(O)CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@@]21C
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)[C@H](C)CC[C@@H](C)[C@@]1(O)CC[C@H]2[C@@H]3C[C@@H](NCCc4c[nH]cn4)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Yield: 13 %

Procedure:
5,6α-epoxicampestane-3β,17-diol (6.8 g, 22.1 mmol, 1 eq) and histamine (4.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give (5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)-ethylamino]-campestane-3β,17-diol) as a white solid (5.7 g, 49%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 13% yield.
Reaction SMILES: [CH3:1][N:2]([C@@H:12]1[C@H:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl.N1C=CC=CC=1>[CH3:18][C@@H:17]1[CH2:16][CH2:15][N:14]([C:19](=[O:21])[CH3:20])[CH2:13][C@@H:12]1[N:2]([CH3:1])[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CC[C@@H](C)[C@@H](N(C)c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.3 %

Procedure:
To a stirred solution of the product from Method B (0.03 grams, 0.114 mmol) dissolved in 5 mL of 10:1 dichloromethane/pyridine was added (0.018 grams, 0.228 mmol) of acetylchloride and the resulting mixture stirred at room temperature for 18 hours. The reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate (NaHCO3). The organic layer was washed again with saturated NaHCO3, dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by preparative thin layer chromatography (PTLC) (silica; 4% methanol in dichloromethane) affording 0.005 g (15%) of the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:25][CH3:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C:16]1[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=1)=[CH:10][CH:9]=2)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH3:26])[C:6]([CH2:4][OH:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Oc3nc4ccccc4s3)ccc2n1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(CO)cc2cc(Oc3nc4ccccc4s3)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a cooled (−78° C.) solution of [5-(benzothiazol-2-yloxy)-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (1.05 g, 3.1 mmol) in THF (30 mL) was added LAH (1 M in THF, 0.8 mL, 0.72 g, 7.8 mmol) and the reaction mixture was stirred (−78° C., 1 h) and allowed to warm (rt, 12 h). The reaction mixture was treated with H2O (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×30 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH:DCM (5-15%) to provide the title compound as a colorless foam (0.5 g, 49%). MS (ESI): mass calcd. for C18H16N2O2S, 324.0; m/z found, 325.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 7.85 (d, J=7.2, 1H), 7.68 (d, J=7.6, 1H), 7.56 (s, 1H), 7.55 (d, J=6.4, 1H), 7.45-7.37 (m, 1H), 7.32-7.25 (m, 1H), 7.16 (dd, J=8.8, 2.4, 1H), 6.44 (s, 1H), 5.32 (s, 1H), 4.67 (s, 2H), 4.29 (q, J=7.1, 2H), 1.33 (t, J=7.1, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][C:9]=1[N+:25]([O-:27])=[O:26].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.CN(C)C=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:22][CH:23]=2)(=[O:16])=[O:17])=[CH:10][C:9]=1[N+:25]([O-:27])=[O:26]
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(O)cc2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OS(=O)(=O)c2ccc(OCc3ccccc3)cc2)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A solution of cesium carbonate (156 mg) in water (0.3 ml) was added to a solution of 4-hydroxy-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (150 mg) and benzyl bromide (58 μl) in dimethylformamide (3 ml). The reaction mixture was heated at 80° C. for 3 hours then allowed to cool to ambient temperature, poured into water (25 ml) and extracted three times with ethyl acetate (30 ml). The combined extracts were dried over magnesium sulfate then evaporated to give 189 mg of crude 4-benzyloxy-benzenesulfonic acid 4-amino-3-nitrophenyl ester.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].N1C2C(=CC=CN=2)C(=O)C1=O.Cl.[F:25][CH2:26][CH2:27][O:28][NH2:29]>CS(C)=O>[F:25][CH2:26][CH2:27][O:28][N:29]=[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: O=C1Nc2ncccc2C1(Br)Br
Reactant: NOCCF
Agent: Cl
Agent: O=C1Nc2ncccc2C1=O
Solvent: CS(C)=O
Product: O=C1Nc2ncccc2C1=NOCCF
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A solution of 3,3-dibromo 7-aza oxindole (300 mg, 1.03 mmol) in DMSO (25 mL) was heated at 95° C. under house vacuum for 6.5 hours. The solution containing the corresponding 7-aza isatin was cooled to room temperature, followed by the addition O-(2-fluoro-ethyl)-hydroxylamine hydrochloride (prepared as described by Ishikawa et al J. Antibiot., 2000, 53, 1071) (131 mg, 1.13 mmol). After stirring for 1 hour at room temperature the mixture was quenched with water and extracted with ethyl acetate (6×25 mL). The combined organic phases were washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue purified by flash column chromatography (gradient, 2% MeOH in methylene chloride to 3%) to give 1H-pyrrolo[2,3-b]pyridine-2,3-dione 3-[O-(2-fluoro-ethyl)-oxime] (200 mg, 93%) as an orange solid that was further purified by trituration from diethyl ether-DCM (1:1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[N:31]=[C:32]=[O:33]>>[CH2:1]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)[C:32]([NH:31][C:25]1[C:24]([CH3:23])=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:30])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2ccccc2)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccccc2)C(=O)Nc2c(C)cccc2C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 2 using benzyl(4-octylphenyl)amine (1.0 g) and 2,6-dimethylphenyl isocyanate (6.4 mL) as starting materials, N-benzyl-N′-(2,6-dimethylphenyl)-N-(4-octylphenyl)urea (0.5 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(F)c3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,3-difluorobenzoyl chloride (28 μL, 0.229 mmol) and mixing for 24 h, 43.5 mg (>100%) of the title compound were recovered.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([CH2:24][N:25]3[C:37]4[C:36]5[N:35]=[CH:34][CH:33]=[CH:32][C:31]=5[N:30]=[CH:29][C:28]=4[N:27]=[CH:26]3)[O:21][N:20]=2)=[CH:15][CH:14]=1.[OH-].[NH4+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.C1C=C(Cl)C=C(C(OO)=O)C=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([CH2:24][N:25]3[C:37]4[C:36]5[N:35]=[CH:34][CH:33]=[CH:32][C:31]=5[N+:30]([O-:6])=[CH:29][C:28]=4[N:27]=[CH:26]3)[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(-c2cc(Cn3cnc4cnc5cccnc5c43)on2)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: [O-][n+]1cc2ncn(Cc3cc(-c4ccc(F)cc4)no3)c2c2ncccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
3-Chloroperoxybenzoic acid (mCPBA) (2.4 g of 75% pure material) was added to a suspension of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridine (2.76 g, 7.99 mmol) in dichloromethane (100 mL). The reaction was stirred at room temperature for 30 minutes; an analysis by TLC then indicated the presence of starting material. Additional mCPBA (0.065 g of 75%) was added, and the reaction was stirred for another 30 minutes and found to be complete by TLC analysis. Concentrated ammonium hydroxide (50 mL) and p-toluenesulfonyl chloride (1.68 g, 8.79 mmol) were sequentially added. The mixture was stirred for 30 minutes. The volatiles were removed under reduced pressure, and 1 N aqueous sodium hydroxide and water were added to the resulting mixture, which was filtered to isolate a solid. The solid was washed with diethyl ether. Additional solid precipitated from the aqueous filtrate, and was isolated by filtration and combined with the first solid to provide 2.48 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine, which was dissolved in a mixture of methanol (80 mL) and dichloromethane (80 mL). The resulting mixture was heated to 50° C., and concentrated ammonium hydroxide (20 mL) and benzenesulfonyl chloride (1.2 mL, 7.6 mmol) were added. The reaction was heated under a nitrogen atmosphere for one hour, and additional benzenesulfonyl chloride (0.5 mL) was added. The solvents were removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with 2% to 10% CMA in chloroform) followed by recrystallization from acetonitrile to provide 0.612 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a white solid, mp 265.0-266.0° C.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:25][C:24]([CH3:27])([CH3:26])[O:23][C@@H:22]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH2:19][C@H:20]1[O:25][C:24]([CH3:26])([CH3:27])[O:23][C@@H:22]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:21]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OC(C)(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: -15 °C
Yield: 87 %

Procedure:
To a solution of 100 ml of anhydrous tetrahydrofuran containing 12.13 g (0.0243 mol) of tert-butyl [(4R,6S)-6-[(tert-butyldiphenylsilyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate was added 26.75 ml (0.0268 mol) of the 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran with stirring at -15° C. and reacted for 2.5 hours at 0° to 5° C. The reaction solution was subjected to 120 g of silica gel column chromatography and eluted with ethyl acetate, and the eluate was collected and distilled away under reduced pressure. Again the residue was subjected to silica gel column chromatography and eluted [eluent: methylene chloride-acetonitrile (4:1)]. The first fraction was discarded and successive elution gave 5.52 g of tert-butyl [(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-4-yl]acetate as syrups (yield: 87%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Br[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc(CCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCCCc1ccc(C#Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 85 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
To a solution of 1-butyl-4-ethynylbenzene (Aldrich, 25.0 g, 0.157 mol) and methyl 4-bromobenzoate (Aldrich, 30.9 g, 0.143 mol) in dry acetonitrile (300 mL) under nitrogen was added cuprous iodide (1.36 g, 7.18 mmol), TEA (43.6 g, 0.431 mol) followed by Pd(PPh3)2Cl2 (5.0 g, 7.18 mmol) and the reaction mixture was stirred at 85° C. for 20 hrs. The solvent was removed under reduced pressure. The residue was taken up with Et2O (300 ml) and washed with water and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (PetEther) gave 23.0 g (55%) of the.title compound.
Reaction SMILES: NC(CC)CC.[CH3:7][O:8][N:9]([CH:24]1[CH2:29][CH2:28]C[CH2:26][CH2:25]1)[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([CH3:19])=[C:12]([CH3:20])[C:11]=1[N+:21]([O-:23])=[O:22]>>[CH3:7][O:8][N:9]([CH:24]([CH2:29][CH3:28])[CH2:25][CH3:26])[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([CH3:19])=[C:12]([CH3:20])[C:11]=1[N+:21]([O-:23])=[O:22]
Reactant: CON(c1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-])C1CCCCC1
Agent: CCC(N)CC
Product: CCC(CC)N(OC)c1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
By the above procedure, but substituting cyclohexylamine for 3-aminopentane, α4 -methoxy-N-cyclohexyl-2,6-dinitro-3,4-xylidine is obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)=[N:12][N:13]([CH3:16])[C:14]=3[NH2:15])=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C1C=CC=CN=1)C.Cl[S:32]([C:35]1[CH:40]=[CH:39][C:38]([C:41]([CH3:48])([CH3:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)=[N:12][N:13]([CH3:16])[C:14]=3[NH:15][S:32]([C:35]3[CH:36]=[CH:37][C:38]([C:41]([CH3:47])([CH3:48])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:39][CH:40]=3)(=[O:34])=[O:33])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cn1nc(OCC2CC2)c(-c2ccc3c(c2)OCO3)c1N
Reactant: CCOC(=O)C(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCC3CC3)nn2C)cc1
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To 4-(1,3-benzodioxol-5-yl)-3-(cyclopropylmethoxy)-1-methyl-1H-pyrazol-5-ylamine (Preparation 50) (230 mg) in anhydrous pyridine (8 ml) at room temperature under an atmosphere of nitrogen was added dimethylaminopyridine (108 mg) and ethyl 2-[4-(chlorosulfonyl)phenyl]-2-methylpropanoate (512 mg). The mixture was stirred overnight and then concentrated under reduced pressure. HCl 0.01N (100 ml) was poured on the resulting yellow syrup and the resulting mixture was extracted with dichloromethane (3×50 ml). The organic fraction was concentrated under reduced pressure and the residue was dissolved in methanol (8 ml). An aqueous solution of sodium hydroxyde (2M, 2 ml) was added and the reaction was stirred overnight. Water (10 ml) was then added, the mixture was acidified with an aqueous solution of HCl (1N) and extracted with dichloromethane (3×10 ml). The combined organic fractions were dried on sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 35 g) eluted with hexane:ethyl acetate (2:1) to yield the title as a pale yellow oil (281 mg).
Reaction SMILES: Cl.CO[CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].Cl.[NH2:12][CH2:13][CH2:14][SH:15]>C(O)(=O)C>[NH2:12][CH2:13][CH2:14][S:15][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10]
Reactant: NCCS
Reactant: COCc1scnc1C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ncsc1CSCCN

Procedure:
5-Methoxymethyl-4-methylthiazole hydrochloride (1.04 g.) and 0.66 g. of cysteamine hydrochoride in 5.5 ml. of acetic acid was refluxed for 24 hours. The mixture was concentrated and the residue was dissolved in water. The aqueous solution was neutralized with sodium hydroxide and extracted with chloroform. The extract was dried (MgSO4) and evaporated to dryness to give 5-(2-aminoethyl)thiomethyl-4-methylthiazole.
Reaction SMILES: [CH3:1][N:2]([CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:7]=1>C(O)C.O1CCCC1.[C].[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:7]=[C:3]([N:2]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=3)[CH3:1])[S:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(CN(C)c2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(N)cc3)cs2)cc1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a suspension of methyl 4-(N-methyl-N-(4-(4-nitrophenyl)-2-thiazolyl)aminomethyl)benzoate (200.0 g, 0.522 mol) obtained in Example 1(3) in a mixture of ethanol (800 ml, 4.0 v/w) and tetrahydrofuran (800 ml, 4.0 v/w) was added 10% palladium carbon (20.0 g) and the mixture was stirred overnight under a hydrogen atmosphere at 3 atm. The reaction mixture was filtered through celite and 10% palladium carbon (20.0 g) was added to the filtrate. The mixture was stirred under a hydrogen atmosphere at 3 atm for 3 hr. After celite filtration and solvent evaporation, toluene (800 ml) was added to the residue and the solvent was evaporated to give the title compound (182.5 g, yield 99.0%) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:20][Si:21]([CH3:36])([CH3:35])[CH2:22][CH2:23][O:24][C:25](ON1C(=O)CCC1=O)=[O:26]>O1CCOCC1.O>[CH3:20][Si:21]([CH3:36])([CH3:35])[CH2:22][CH2:23][O:24][C:25]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:26]
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](NC(=O)OCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl trans-4-aminocyclohexanecarboxylate (J. Med. Chem., 1971, 14, 600-614) (29.5 g, 143 mmol) was dissolved in 1,4-dioxane (290 ml) and water (290 ml), triethylamine (30.0 ml, 215 mmol) and 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (40.8 g, 157 mmol) were added under ice cooling and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated and then the residue was diluted with ethyl acetate and washed with 10% aqueous citric acid solution, saturated sodium bicarbonate solution, and brine in that order. The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure to give 44.3 g (98%) of the title compound as colorless needle-like crystals.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:12]([OH:14])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[OH-].[Pd+2].CCOC(C)=O.C(O)C>[C:2]1([CH2:1][CH2:9][CH2:10][C@H:11]([NH:15][C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[C:12]([OH:14])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC[C@H](NC(=O)C(F)(F)F)C(=O)O)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](CCCc1ccccc1)NC(=O)C(F)(F)F
Yield: 84.3 %

Procedure:
Reduce the product of Step 1 (9.7 g) with Pearlman's catalyst (3.5 g) in EtOAc (75 ml) and ethanol (25 ml) at 50 psi H2 for 3 hours. Filter, concentrate and wash the resultant residue with 3:1 hexane:diethyl ether to give the title compound (7.8 g).