Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.[BH4-].[Na+]>C(Cl)Cl.CO>[C:18]([Si:21]([CH3:23])([CH3:22])[O:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Oc1ccc(O)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxyphenyl benzoate (9.0 mmol) was dissolved in CH2Cl2 (9 mL/mmol), TBDMS-Cl (1.5 eq., 13.5 mmol) and imidazole (2.0 eq., 18.0 mmol) were added and the mixture was stirred at r.t. overnight. The mixture was diluted with MeOH (4.5 mL/mmol), and NaBH4 (2.5 eq., 22.5 mmol) was added slowly over 5 min (attention: vigorous gas evolution). The mixture was concentrated by removing CH2Cl2 under reduced pressure and the suspension was heated to 65° C. for 15 h.
Reaction SMILES: [OH-].[Na+].O.[NH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.C(Cl)(=O)OCC.[C:22](=S)=[S:23]>>[N:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10]1)=[C:22]=[S:23]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: S=C=S
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCC(N=C=S)CC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred and cooled mixture of 4 parts of sodium hydroxide in 60 parts of water were added successively 7.9 parts of carbon disulfide and 17.2 parts of ethyl 4-amino-1-piperidinecarboxylate at a temperature below 10° C. Stirring was continued for 30 minutes at this temperature. Then there were added dropwise 10.9 parts of ethyl carbonochloridate (exothermic reaction: temp. rises to about 35° C.). Upon completion, stirring was continued for 2 hours at 60° C. The reaction mixture was cooled and the product was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 22 parts (100%) of ethyl 4-isothiocyanato-1-piperidinecarboxylate as a residue (14).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH:13][CH3:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1ccc2cc[nH]c2c1
Reaction time: 3 h
Yield: 98.7 %

Procedure:
Indole-6-carboxaldehyde (90 mg, 0.62 mmol) was dissolved in anhydrous methanol (3 mL). Methylamine (0.95 mL of 2M solution in methanol, 1.86 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (3 mL). Sodium borohydride (24 mg, 0.62 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated. Sodium hydroxide (2 mL, 1N) was added and the indole was extracted with ethyl acetate (3×10 mL), dried over MgSO4 and concentrated to afford the title compound as a yellow oil (98 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 9.02 (s, 1H), 7.57(d, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.12 (d, J=3.1 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 3.81 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[NH:4][C:5]1[O:6][C:7]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[C:8]=2[N:9]=1>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3](=[O:19])[NH:4][C:5]1[O:6][C:7]2[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc([N+](=O)[O-])c2o1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1nc2c(OC)ccc(N)c2o1
Reaction time: 18 h
Yield: 58.6 %

Procedure:
To a stirred solution of 220 mg (0.82 mmol) (4-methoxy-7-nitro-benzooxazol-2-yl)-carbamic acid methyl ester in 25 ml methanol and 45 ml dichloromethane was added a spatula end of 10% palladium on charcoal and stirring continued for 18 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered and the filtrate concentrated in vacuo. Flash chromatography (2/98 methanol/dichloromethane) afforded 114 mg (58%) (7-amino-4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester as a white crystalline solid. ES-MS m/e (%): 238 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].FC(F)(F)C(O)=O.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:23][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1c(C)ccc2ccccc12
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)c1c(C)ccc2cccc(Br)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
Methyl 2-methylnaphthalene-1-carboxylate (5.6 g) was dissolved in acetic acid (12 ml) and trifluoroacetic acid (12 ml) and cooled in an ice bath. 1,3-Dibromo-5,5-dimethylhydantoin (4.8 g) was added in one portion then concentrated sulphuric acid was added dropwise. The mixture was then stirred at 0° C. for 30 minutes. Sodium acetate (6.12 g) was added and the mixture was partitioned between DCM and water. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and pentane with a gradient of 20-70% to give methyl 8-bromo-2-methylnaphthalene-1-carboxylate (3.27 g) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:60])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:57])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:56])[CH2:21][CH2:22][C@@:23]3([C@@H:40]4[O:44][C:43](=[O:45])[N:42]([C:46]5([C:49]6[N:54]=[CH:53][C:52]([Cl:55])=[CH:51][N:50]=6)[CH2:48][CH2:47]5)[CH2:41]4)[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:59])[CH3:58])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:55][C:52]1[CH:51]=[N:50][C:49]([C:46]2([N:42]3[CH2:41][C@H:40]([C@:23]45[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]4[C@@H:25]4[C@@:20]([CH3:56])([CH2:21][CH2:22]5)[C@@:19]5([CH3:57])[C@@H:28]([C@:29]6([CH3:32])[C@@H:16]([CH2:17][CH2:18]5)[C:15]([CH3:58])([CH3:59])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:60])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]6)[CH2:27][CH2:26]4)[O:44][C:43]3=[O:45])[CH2:48][CH2:47]2)=[N:54][CH:53]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2([C@H]2CN(C3(c4ncc(Cl)cn4)CC3)C(=O)O2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2([C@H]2CN(C3(c4ncc(Cl)cn4)CC3)C(=O)O2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (109) (80 mg, 0.094 mmol) in DCM (10 mL) was added TFA (1 mL, 0.094 mmol). The reaction mixture was stirred at rt overnight, then diluted with DCM (20 ml) and washed with water (2×15 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml), dried over sodium sulfate, filtered and concentrated to get a residue. The residue was purified on silica gel using petroleum ether/EtOAc (4:1 to 1:1) as eluent to give the product 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (111) (50 mg, 67%) as a white solid. This material was lyophilized to give a white powder. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.58 (s, 2H), 5.04 (t, J=8.5 Hz, 1H), 4.51 (dd, J=4.6, 10.9 Hz, 1H), 3.41-3.04 (m, 4H), 2.75-2.44 (m, 3H), 2.36 (d, J=13.3 Hz, 1H), 2.12-0.72 (m, 49H); LC/MS: m/z calculated 791.4. found 792.3 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:53][O:54][Si:55]([CH:62]([CH3:64])[CH3:63])([CH:59]([CH3:61])[CH3:60])[CH:56]([CH3:58])[CH3:57])=[N:43][N:44]([CH2:46][CH2:47]OS(C)(=O)=O)[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:65][NH:66][CH3:67]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:53][O:54][Si:55]([CH:56]([CH3:57])[CH3:58])([CH:62]([CH3:63])[CH3:64])[CH:59]([CH3:60])[CH3:61])=[N:43][N:44]([CH2:46][CH2:47][N:66]([CH3:67])[CH3:65])[CH:45]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[Si](OCc1nn(CCOS(C)(=O)=O)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Reactant: CNC
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1nn(CCN(C)C)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 82.9 %

Procedure:
A solution of Intermediate 74j (104 mg, 0.11 mmol) in THF (0.5 mL) was treated with dimethylamine (2M in THF, 0.57 mL, 1.1 mmol) and the mixture was stirred at RT over the weekend. The mixture was evaporated in vacuo and the residue was partitioned between DCM and water. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7% [2M NH3 in MeOH] in DCM, to give the title compound (79 mg, 81%). LCMS (Method 3): Rt 3.46 min, m/z 866.6 [MH+].
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:12][N:11]=1)=[O:9])([CH3:6])[CH3:5].[Li+].[OH-].O>C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]([C:13]2[CH:14]=[C:15]([OH:16])[C:10]([C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:24])=[O:2])=[O:9])=[N:11][CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1ncc(-c2cccc(Cl)c2)cc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ncc(-c2cccc(Cl)c2)cc1O)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
To a solution of 2-{[5-(3-chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester, 20, (0.082 g, 0.24 mmol) in THF (4 mL) is added LiOH (0.024 g, 0.98 mmol) and H2O (1 mL) and the resulting solution stirred for 3 days at room temperature. The solvent is removed under reduced pressure and the pale yellow solid that remains is then acidified with 1M HCl to until the pH is approximately 1 and the solution extracted twice with EtOAc. The combined organic layers are combined, dried (Na2SO4), filtered and concentrated under reduced pressure to afford 0.064 g (81% yield) of the desired compound as a white solid. 1H NMR (250 MHz, DMSO-d6) δ ppm 12.99 (1H, br s), 12.25 (1H, s), 9.05 (1H, s), 8.53 (1H, d, J=2.0 Hz), 7.91 (1H, s), 7.74-7.83 (2H, m), 7.51-7.58 (2H, m), 1.58 (6H, s). HPLC-MS: m/z 335 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][S:16](=[O:32])(=[O:31])[NH:17]C(C2C=CC=CC=2)C2C=CC=CC=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([OH:14])([CH2:15][S:16](=[O:32])(=[O:31])[NH2:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CS(=O)(=O)NC(c2ccccc2)c2ccccc2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)(CS(N)(=O)=O)CC1

Procedure:
5.19 g of 4-[(benzhydryl-sulfamoyl)-methyl]-4-hydroxy-piperidine-1-carboxylic acid tert.-butyl ester in 150 ml of MeOH are treated with 100 μl of triethylamine and the mixture obtained is hydrogenated overnight at RT with 10% Pd/C as a catalyst. From the mixture obtained the catalyst is filtrated off, solvent is evaporated and the evaporation residue is subjected to chromatography on silica gel. 4-Hydroxy-4-sulfamoylmethyl-piperidine-1-carboxylic acid tert.-butyl ester are obtained. m.p. 176-180°.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:15])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].C1(O)C=CC=CC=1.I[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][C:29]=1[Cl:39]>>[Cl:39][C:29]1[CH:30]=[C:31]([O:34][C:35]([F:36])([F:38])[F:37])[CH:32]=[CH:33][C:28]=1[O:27][CH2:26][CH2:25][CH2:24][O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([CH3:15])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=2[CH:10]=1
Reactant: FC(F)(F)Oc1ccc(OCCCI)c(Cl)c1
Reactant: COC(=O)C1(C)Cc2cc(O)ccc2O1
Solvent: Oc1ccccc1
Product: CC1(C(=O)O)Cc2cc(OCCCOc3ccc(OC(F)(F)F)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, using the the intermediate prepared in Example 1, Step 1 as the phenol and the iodide prepared in Step 2.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9](O)=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.C1C=CC2N(O)[N:20]=[N:19]C=2C=1.CCN=C=NCCCN(C)C.Cl.NN.C1CCCCC=1>C(#N)C>[OH:12][C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[CH:8]/[C:9]([NH:19][NH2:20])=[O:10])=[CH:1][CH:2]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CC#N
Solvent: C1=CCCCC1
Product: NNC(=O)/C=C/c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a stirred solution of p-coumaric acid (3.28 g, 20 mmol) in anhydrous acetonitrile (40 mL) was added HOBt (3.24 g, 24 mmol) and EDC.HCl (4.6 g, 24 mmol) at room temperature, and the mixture was stirred at room temperature for 2 h. The resulting yellow suspension was cooled with an ice-bath, and an ice-cold solution of hydrazine (1.25 mL, 40 mmol) and cyclohexene (0.61 mL, 6 mmol) in acetonitrile (30 mL) was added in one portion. The mixture was stirred at 0° C. for 20 min and followed by an additional 1 h at room temperature. The resulting yellow suspension was filtered off, and the solid was washed with MeOH (3×30 mL), H2O (2×30 mL), saturated NaHCO3 (2×30 mL), H2O (2×20 mL) and EtOAc (2×20 mL) successively, and finally air-dried, obtaining 133 (1.3 g, 36% yield), with its identity verified by 1H NMR (300 MHz, DMSO-d6).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.[NH4+:12].C(O)C.O>C(O)C>[NH2:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Solvent: O
Solvent: CCO
Product: Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a suspension of 2,6-dibromo-3-nitropyridine (5.00 g) in ethanol (10 ml) was added a solution (6.8 M, 15 ml) of ammonium/ethanol at room temperature, and the mixture was stirred at room temperature for 19 hr in a sealed container. Water (25 ml) was added to the reaction mixture, and the precipitate was collected by filtration and washed with ethanol. This was suspended in ethanol (55 ml), heated, and allowed to cool. The precipitate was collected by filtration to give 2-amino-6-bromo-3-nitropyridine as a yellow powder (3.19 g).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][NH:13][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[CH2:17][CH2:18]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCCN1CCOCC1
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNCCN1CCOCC1

Procedure:
The product was made from D-glucose and N-(β-aminoethyl)-morpholine comparable as in Example A. A resin-like, colorless product was obtained.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Br:37][C:38]1[C:46]2[O:45][C:44]([C:47](=O)[CH3:48])=[CH:43][C:42]=2[CH:41]=[C:40]([O:50][CH3:51])[CH:39]=1.[OH-].[K+]>C(O)C>[Br:37][C:38]1[C:46]2[O:45][C:44]([C:47]3[CH:48]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)=[CH:43][C:42]=2[CH:41]=[C:40]([O:50][CH3:51])[CH:39]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: COc1cc(Br)c2oc(C(C)=O)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Br)c2oc(-c3ccc4cc(-c5nc6cc(C(=O)O)ccc6n5C5CCCCC5)ccc4n3)cc2c1
Yield: 17 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(7-bromo-5-methoxy-benzofuran-2-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound, 17% yield).
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17](=[O:25])(=[O:24])[CH2:16]2)=[O:14])=[CH:11][C:10]=1[C:28]([F:31])([F:30])[F:29])C1C=CC=CC=1>O1CCCC1.CO.[OH-].[Pd+2].[OH-].[C]>[OH:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17](=[O:25])(=[O:24])[CH2:16]2)=[O:14])=[CH:11][C:10]=1[C:28]([F:30])([F:31])[F:29]
Reactant: O=C(c1ccc(OCc2ccccc2)c(C(F)(F)F)c1)N1CS(=O)(=O)c2ccccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ccc(O)c(C(F)(F)F)c1)N1CS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.5 %

Procedure:
3-(4-benzyloxy-3-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (490 mg) was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), and 20% palladium hydroxide-carbon (100 mg) was added to the solution, and then the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. After the reaction solution was filtered, the solvent was distilled off under reduced pressure and then the obtained residue was crystallized from diethylether to obtain the title compound (397 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:15]=2[N:16]=1.[Cl:27][C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:37]=[CH:38][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH2:19][CH2:18]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][CH:26]=[C:3]([O:2][CH3:1])[CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: COc1cccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)c1
Reactant: O=C(O)COc1ccc(Cl)cc1
Product: COc1cccc(CCc2nc3c(N4CCN(C(=O)COc5ccc(Cl)cc5)CC4)nc(N)nc3s2)c1
Yield: 48 %

Procedure:
This compound was prepared from 2-(3-methoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 48%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[CH:12]([NH:15][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])([CH3:14])[CH3:13]
Reactant: CC(C)N
Reactant: O=C(Cl)c1ccc(F)cc1F
Product: CC(C)NC(=O)c1ccc(F)cc1F
Yield: 95.5 %

Procedure:
The title compound (0.3804 g; 95%) was prepared by the same method as that described in Example 1, using 2,4-difluorobenzoyl chloride (0.3532 g, 2.00 mmol) and isopropylamine (0.26 ml, 3.05 mmol).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:14][C:9]=2[S:8][C:7]=1C(O)=O)([OH:3])=[O:2].N1C2C(=CC=CC=2)C=CC=1>CCOC(C)=O.[Cu]>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:10]2[C:6]([O:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][S:8][C:9]=2[CH:14]=1
Reactant: O=C(O)COc1c(C(=O)O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: O=C(O)COc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 190 °C
Yield: 77.4 %

Procedure:
The mixture of 3-(carboxymethoxy)-6-((2,4-dichlorobenzyl)oxy)-1-benzothiophene-2-carboxylic acid (92.0 mg), copper (13.7 mg) and quinoline (1.5 mL) was heated at 190° C. for 10 min. The mixture was diluted with EtOAc. The mixture was washed successively with 1N HCl and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane), and washed with hexane to give the title compound (63.9 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH2:4][CH2:5][N:6]=1.Cl[CH2:8][C:9](=[O:11])[CH3:10]>CC(C)=O>[O:11]=[C:9]([CH3:10])[CH2:8][N:6]1[CH2:5][CH2:4][N:3]=[C:2]1[CH3:1]
Reactant: CC(=O)CCl
Reactant: CC1=NCCN1
Solvent: CC(C)=O
Product: CC(=O)CN1CCN=C1C

Procedure:
A mixture of 8.4 g. of 2-methyl-2-imidazoline and 9.25 g. of chloroacetone is refluxed in 100 ml. of acetone for two hours. The solvent is removed in vacuo, and the residue is taken up in water and neutralized with 1N sodium hydroxide. Extracting with chloroform, drying and removing the solvent in vacuo gives 1-(2-oxopropyl)-2-methyl-2-imidazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1)=[O:16]>C1COCC1.C(N(CC)CC)C>[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[O:11][N:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[CH:25]=2)[CH:19]=1)=[O:16]
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: C#Cc1cccc(NC(=O)C(Cl)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (2.72 g, 95.6 mmol) and 2,2-dichloro-N-(3-ethynylphenyl) acetamide (2.5 g, 110 mmol) were dissolved in anhydrous THF (40 mL) and triethylamine (1.8 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 5 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(3-ethynylphenyl) acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined and then crystallized from hexanes-ethyl acetate to give 2,2-dichloro-N-[3-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl] acetamide as a white crystalline solid, 1.80 g (m.p. 167° C.). NMR (300 MHz, CDCl3): 8.21 (broad s, 1H, NH), 8.08 (m, 1H), 7.71 (m, 2H), 7.52 (t, 1H), 7.42–7.46 (m, 2H), 7.32–7.38 (m, 1H), 6.69 (s, 1H), 6.07 ppm (s, 1H). MW=416 confirmed by LC-MS, tr=36.9 min (Method W) MH+=415–419.