Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17]CC)=O)[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:22][NH2:23].BrBr.C([O-])(O)=O.[Na+]>CCO.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[C:15]([OH:17])[N:23]=[N:22][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CCN(Cc2ccccc2)CC1=O
Reactant: NN
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc2c(nn1)CN(Cc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl (1-benzyl-3-oxopiperidin-4-yl)acetate (11.4 g, 41.4 mmol) and hydrazine monohydrate (3.1 g, 62 mmol) in EtOH (50 mL) is stirred at 80° C. for one hour. The resulting solution is cooled, and concentrated in vacuo to give a white solid. The white solid is dissolved in acetic acid (120 mL) and the mixture is heated at 85° C. To the reaction mixture is added bromine (6.62 g, 41.4 mmol) dropwise. The resulting mixture is heated for another 30 min. The solvent is removed in vacuo to give a residue. A saturated NaHCO3 solution is added until pH ˜8 while stirring. The formed solid is filtered and dried in air to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc(C)o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc(CBr)o1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To a stirred solution of ethyl 5-methyloxazole-2-carboxylate (5.1 g, 32.87 mmol) and NBS (8.19 g, 46.02 mmol) in carbon tetrachloride (50.0 mL), is added benzoyl peroxide (0.79 g, 3.29 mmol) and the reaction mixture is refluxed for 16 hours. The mixture is cooled to room temperature and filtered through diatomaceous earth. The filtrate is concentrated in vacuum and the crude is purified by silica gel chromatography, eluting with hexane:ethyl acetate (9.2:0.8) to give (4.8 g, 62.33%) of the title compound as a light brown oil. ESI/MS m/z (79Br/81Br) 234.1/236.1 [M+H]+.
Reaction SMILES: [NH:1]([C:3](=[O:15])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]1)[NH2:2].C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>ClCCl>[O:15]=[C:3]([NH:1][NH:2][C:28]([C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=1)=[O:29])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(CC(=O)NN)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnn(CC(=O)NNC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
The compound (6.0 g) obtained in Example 123a and triethylamine (8.33 g) were dissolved in dichloromethane (100 mL), and a solution of 3-(trifluoromethyl)benzoylchloride (10.0 g) in dichloromethane (20 ml) was added. The reaction mixture was stirred at room temperature overnight, an insoluble material was removed by filtration, and the filtrate was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether/ethyl acetate/triethylamine=5/1/0.001) to give the title compound (4.1 g) as an oil.
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.O>[CH3:19][N:20]1[CH:24]=[C:23]([C:2]2[C:3]([NH2:18])=[N:4][C:5]([N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)=[N:6][C:7]=2[N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:22]=[N:21]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1nc(-n2cccn2)nc(-n2cccn2)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2c(N)nc(-n3cccn3)nc2-n2cccn2)cn1
Yield: 44.9 %

Procedure:
A mixture of 0.1 g (0.33 mmol) of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4-amine (Example 1), 0.10 g (0.49 mmol) of 1-methylpyrazole-4-boronic acid pinacol ester, 0.23 (0.72 mmol) of cesium carbonate and 5 mg (6.5 μmol) of [1,1′-Bis(diphenylphosphino) ferrocene]dichloropaladium (II) dichloromethane complex in 3 ml dioxane and 0.5 ml of water were irradiated with microwaves at 140° C. for 30 min. After cooling to room temperature ethyl acetate was added and filtered by celite. The solution was extracted two times with 10 ml of saturated solution of NaHCO3 and Brine. The organic layer was separated, dried with MgSO4 and concentrated. The residue was purified by column chromatography with silica gel and methylene chloride and methanol as eluent to give 45.5 mg (45.3%) of the desired product.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]3[CH:25]=[C:24]([CH2:26][CH2:27][C:28]4[S:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[N:32]=4)[CH:23]=[CH:22][N:12]3[C:13](=[O:21])[C:14]=2[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH2:4]1)=[O:2].O.[OH-].[Li+].Cl>CO.O1CCCC1.O>[CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]3[CH:25]=[C:24]([CH2:26][CH2:27][C:28]4[S:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[N:32]=4)[CH:23]=[CH:22][N:12]3[C:13](=[O:21])[C:14]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:4]1)=[O:2]
Reactant: COC(=O)CCc1c(N2CCCC(C=O)C2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)c1csc(CCc2ccn3c(=O)c(CCC(=O)O)c(N4CCCC(C=O)C4)nc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
The methyl 3-{2-(3-formylpiperidino)-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}propanoate (23.1 mg, 0.0451 mmol) obtained in (B) was dissolved in a mixed solution of methanol, tetrahydrofuran and water (1:1:1, 3 ml), added with lithium hydroxide monohydrate (3.8 mg, 0.0901 mmol), and stirred overnight at room temperature. The reaction mixture was added with 1 N hydrochloric acid (0.091 ml) to neutralize the system, and then the solvent was evaporated. The resulting residue was purified by preparative TLC (chloroform:methanol=10:1) to obtain the title compound (15.0 mg, 71%) as lyophilized product.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.[N:12]([O-])=[O:13].[Na+]>O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[N:12]=[O:13]
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cn1c(N)c(N=O)c(=O)n(C)c1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Commercially available 6-amino-1,3-dimethyl-1H-pyrimidine-2,4-dione (10 mmol) was dissolved in 1:1 water/glacial acetic acid (50 mL total volume) at 80° C. and sodium nitrite (20 mmol) added in portions. After the addition was complete the reaction mixture was stirred at 80° C. for 1 hr. Cooled in ice for 30 mins then filtered and washed with water. The precipitate was dried in vacuo to give crude 6-amino-1,3-dimethyl-5-nitroso-1H-pyrimidine-2,4-dione as a red-violet colored solid which was of sufficient purity for subsequent use without additional purification (89%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:19][CH2:20][C:21]1[C:22]([CH3:44])=[N:23][O:24][C:25]=1[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3([C:41]([OH:43])=[O:42])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:44][C:22]1[C:21]([CH2:20][S:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[C:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:33]=[CH:34][C:35]([C:38]4([C:41]([OH:43])=[O:42])[CH2:40][CH2:39]4)=[CH:36][CH:37]=3)=[CH:28][CH:27]=2)[O:24][N:23]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CSCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CS(=O)Cc1ccccc1
Reaction time: 0.25 h

Procedure:
m-Chloroperbenzoic acid (0.024 g, 0.11 mmol) was added to a solution of 1-[4′-(4-benzylsulfanylmethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (0.050 g, 0.11 mmol) in CH2Cl2. After stirring for 15 minutes the mixture was concentrated and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].CCCCCO.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][C:14]2[C:13](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:21])=[O:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: O=C(O)c1ccccc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
In a 3 liter, three necked round bottom flask, provided with a mechanical stirrer, reflux condenser and thermometer (to 200° C.) was placed 300 g. (1.25 m.) 1-bromo-4-chloronitrobenzene, 140 g. (1.02 m.) anthranilic acid, and 130 ml. n-amyl alcohol. The mixture was heated in an oil bath. After most of the chemicals were dissolved (80°-90° C.) the stirrer was started. Then, 1.3 gm. copper powder and 140 gm. (1.02 m.) potassium carbonate were added all at once. A yellow voluminous froth formed but no heat of reaction. As the reaction temperature rose from 80° to 120°, a red reaction mixture became more solid and hindered further stirring. The reflux condenser was replaced to distill off the formed water and amyl alcohol. Meanwhile, the temperature of the oil bath was steadily increased and finally kept at 200°-210° for 3 hours. The oil bath was replaced by a steam bath and the excess bromochloronitrobenzene was removed by steam distillation. After removal of bromochloronitrobenzene was completed, the solution was filtered and water added making the total volume of dark red solution about 2.5 liters. The solution was cooled to room temperature overnight, and filtered. Dilute HCl (1:1) was carefully added to the filtrate until it was just acid to Congo red litmus paper. The ochre-colored precipitate was removed by filtration and washed with water (750 ml.). The product was dried in vacuo at 70°. The original dark-red filter cake was digested with hot water several times and then treated as described above to extract all the desired product. Obtained: 247 grams (83% yield) of crude N-(4-chloro-2-nitrophenyl)anthranilic acid; orange granular powder; m.p. 235°-247° C.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=O.C1COCC1.CO.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[NH2:5][C:6]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(COc2cc(Cl)ccc2NC(=O)C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2N)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of methyl 4-(2-trifluoroacetylamino-5-chlorophenoxymethyl)benzoate (300 mg; prepared in Reference Example 6.) in mixture of THF-MeOH (4 ml+10 ml), a solution of sodium carbonate (440 mg) in water (2 ml) was added. The solution was stirred for 8 hours at 60° C. and overnight at room temperature. The reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-benzene) to give the title compound (194 mg) having the following physical data.
Reaction SMILES: [C:1]([Si:5]([CH3:40])([CH3:39])[O:6][CH2:7][C@H:8]1[O:13][C@:12]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH2:23][C:24]3[S:25][C:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[CH:27][CH:28]=3)[CH:17]=2)([O:14][CH3:15])[C@H:11]([OH:36])[C@@H:10]([OH:37])[C@@H:9]1[OH:38])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[CH2:43]([O:38][C@H:9]1[C@H:10]([O:37][CH2:26][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:11]([O:36][CH2:12][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@:12]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH2:23][C:24]3[S:25][C:26]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)[CH:17]=2)([O:14][CH3:15])[O:13][C@@H:8]1[CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:39])[CH3:40])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 198.5 %

Procedure:
(2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 9e (2.0 g, 3.4 mmol) was dissolved in 20 mL DMF and cooled to 0° C., followed by addition of 60% NaH (680 mg, 17 mmol). The reaction mixture was warmed to room temperature and stirred for 30 minutes. Thereafter, benzyl bromide (2.0 mL, 17 mmol) was added before the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure after 10 mL methanol were added and was partitioned after 30 mL ethyl acetate and 30 mL water were added. The aqueous phase was extracted with ethyl acetate (20 mL×3) and the organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 9f (2.9 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])[CH2:14]2)[C:3]=1[C:4]([O-:6])=[O:5].Cl>C(O)(C)(C)C.[OH-].[K+]>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=4)[O:24][C:25]=3[CH3:26])[CH2:14]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(CO[C@@H]2CCC[C@H](OCc3nc(-c4ccc(C(C)C)cc4)oc3C)C2)c1C(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1cccc(CO[C@@H]2CCC[C@H](OCc3nc(-c4ccc(C(C)C)cc4)oc3C)C2)c1C(=O)O
Reaction time: 48 h

Procedure:
90 mg of Methyl [2-methyl-6-[(1R,3S)-3-(5-methyl-2-(4-(2-propyl)-phenyl)-oxazol-4-ylmethoxy)-cyclohexyloxymethyl]benzoate are stirred at 90° C. in a mixture of 10 ml of tert-butanol and 1 ml of 10 N potassium hydroxide solution. The reaction is monitored by TLC. After two days, the mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvents are removed under reduced pressure and the residue is purified by RP-HPLC. This gives 69 mg of 2-methyl-6-[(1R,3S)-3-(5-methyl-2-(4-(2-propyl)-phenyl)-oxazole-4-ylmethoxy)-cyclohexyloxymethyl]-benzoic acid as an amorphous solid. C29H35NO5 (477.61), MS(ESI): 478 (M+H+).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][CH2:8][CH3:9])=[O:6])C.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15]>CC(O)C>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:4](=[O:3])[C:5]([NH:7][CH2:8][CH3:9])=[O:6]
Reactant: CCNC(=O)C(=O)OCC
Reactant: COC(CN)OC
Solvent: CC(C)O
Product: CCNC(=O)C(=O)NCC(OC)OC
Yield: 80.5 %

Procedure:
59.9 g (412.6 mM) of ethyl(ethylamino)(oxo)acetate and 45 ml (412.6 mM) of (2,2-dimethoxyethyl)amine in 480 ml of 2-propanol were stirred at room temperature for 16 h. A white precipitate was filtered, washed with 2-propanol and dried under vacuum, to give 67.8 g of N-(2,2-dimethoxyethyl)-N′-ethylethanediamide. Yield: 80.5%.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OC1CCCNC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: OC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
943 mg of 3-hydroxypiperidine was dissolved in 15 mL of toluene, to which, under ice cooling, 1.13 mL of benzaldehyde, 2.97 g of sodium triacetoxyborohydride and 0.3 mL of acetic acid were sequentially added, and stirred at room temperature for 24 hours. To the reaction mixture, saturated sodium bicarbonate was added, extracted with ethyl acetate, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (chloroform to chloroform:methanol-ammonia=60:1) to obtain 866.3 mg (49%) of 1-benzyl-3-hydroxypiperidine crude product as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]([C:14]1[C:18]([CH3:19])=[CH:17][S:16][C:15]=1[C:20](OC)=[O:21])=[C:12]=[S:13]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:20](=[O:21])[C:15]4[S:16][CH:17]=[C:18]([CH3:19])[C:14]=4[NH:11][C:12]3=[S:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: COC(=O)c1scc(C)c1N=C=S
Solvent: C1CCOC1
Product: Cc1csc2c(=O)n(-c3ccc4[nH]cnc4c3)c(=S)[nH]c12

Procedure:
1H-benzo[d]imidazol-5-amine (0.13 g, 0.98 mmol) and methyl 3-isothiocyanato-4-methylthiophene-2-carboxylate (0.21 g, 0.98 mmol) were dissolved in 10 mL of THF. The mixture was stirred by heating under reflux over night. The solvent was removed and the product was purified by means of semi-preparative HPLC.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Br:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Br:14])[CH:8]=1
Reactant: NC(CC(=O)O)c1cc(F)cc(Br)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
1.59 g (6.05 mmol) 3-amino-3-(3-bromo-5-fluorophenyl)propionic acid were suspended in 24.5 ml methanol and the mixture cooled to 0° C. 0.66 ml (9.08 mmol) thionyl chloride were slowly added. The mixture was stirred at room temperature for 20 hours and concentrated. The residue was treated with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic part was dried with sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 1.55 g (93%) 3-amino-3-(3-bromo-5-fluorophenyl)propionic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[N:19]=[CH:18][CH:17]=[CH:16][C:13]=3[C:14]#[N:15])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl>CO.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:13]([CH2:14][NH2:15])=[CH:16][CH:17]=[CH:18][N:19]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(Oc3ncccc3C#N)ccc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cn1ncc2cc(Oc3ncccc3CN)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
2-(1-Methyl-1H-indazol-5-yloxy)-nicotinonitrile (3n) (0.132 g, 0.528 mmol) was suspended in MeOH (6 mL). Pd(OH)2 (0.060 mg, 0.427 mmol) was added under a nitrogen atmosphere followed by concentrated aqueous HCl (0.6 mL). The system was purged with H2 gas and the reaction stirred at room temperature for 3 hours under an H2(g) atmosphere. The reaction mixture was filtered through a pad of celite, washed through with MeOH. The organics were concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography (MeOH/Et3N/EtOAc) to provide the desired product (4n) (0.047 g, 35% yield). 1H NMR (400 mHz, CD3OD) δ 7.96 (s, 1H), 7.90 (d, J=4.7 Hz, 1H), 7.82 (d, J=7.0 Hz, 1H), 7.56 (d, J=9.4 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.23-7.21 (m, 1H), 7.09-7.06 (m, 1H), 4.07 (s, 3H), 3.95 (s, 2H).
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:17][CH2:18][CH2:19]CC>>[C:1]([N:5]=[N:6][C:18]([CH3:19])=[CH2:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NN
Reactant: CCCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C)N=NC(C)(C)C
Reaction time: 0.75 h

Procedure:
To a solution of 6.75 g. (0.077 m.) tert.-butylhydrazine in 50 ml. of methylene chloride containing 2 g. of anhydrous sodium sulfate, was added 3.0 g. (0.0326 m.) chloroacatone. The addition was carried out dropwise holding the reaction temperature below 10° C. with an ice bath. The reaction was stirred an additional 45 minutes and filtered. The filtrate was washed with cold water (10° C.), dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated off using a rotating evaporator and a 20° C. water bath. A yellow oil containing some solids suspended in it was obtained. The crude material was slurried in cold pentane and filtered. The pentane was then evaporated off from the filtrate on the rotating evaporator. The yield was 1.9 g. (47%) of a yellow oil. The infra-red spectrum was consistent with the structure of the proposed compound. 2-tert.-butylazopropene is a thermally unstable compound and evolves nitrogen at room temperature and is therefore a very low temperature blowing agent.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]>C(O)(=O)C.[Zn]>[NH2:14][C:11]1[CH:12]=[CH:13][C:2]([F:1])=[C:3]([CH:10]=1)[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)OC(=O)c1cc(N)ccc1F
Yield: 100 %

Procedure:
Isopropyl 2-fluoro-5-nitrobenzoate (2.86 g, 12.6 mmol) was dissolved in glacial acetic acid (40 ml), and zinc dust (8.12 g, 126 mmol)was added as a solid with stirring under nitrogen. The mixture was stirred for 1 hour at room temperature, then the zinc filtered off and discarded. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (0 to 75% ethyl acetate in hexanes) to afford isopropyl 5-amino-2-fluorobenzoate. (2.48 g, 12.6 mmol). 100% yield. 199 (M+1).