Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:10]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=[C:7]([C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccncc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 127.8 %

Procedure:
Under an argon atmosphere, to a mixture of tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (1.82 g), pyridin-4-yl boronic acid (473 mg), and DME (35 ml) were added tetrakis(triphenylphosphine)palladium (317 mg), cesium carbonate (5.37 g), and water (9 ml), followed by stirring at 80° C. overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 3,6-dihydro-4,4′-bipyridine-1(2H)-carboxylate (1.28 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][N:21]=1>CO>[CH3:18][O:19][C:20]1[N:21]=[CH:22][C:23]([CH:24]=[N:2][C:3]2[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=2[OH:10])=[CH:26][CH:27]=1
Reactant: Nc1ccc(O)cc1O
Reactant: COc1ccc(C=O)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C=Nc2ccc(O)cc2O)cn1
Reaction time: 8 h

Procedure:
4-Aminoresorcinol hydrochloride (3.09 mmol) and triethylamine (3.25 mmol) were dissolved in dry methanol (20 mL). 6-Methoxynicotinaldehyde (3.09) was added and the mixture was stirred overnight. The solvents were removed under reduced pressure, the mixture diluted with EtOAc, washed with brine (2×), dried (Na2SO4), filtered and evaporated to give 1.31 g as a dark solid. The crude product was taken to the next step without further purification. MS m/z (M+H) 245.
Reaction SMILES: Cl[C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[OH:21][CH2:22][C:23]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>>[C:32]([O:31][C:30](=[O:36])[NH:29][C:23]([CH3:28])([CH2:24][CH:25]([CH3:26])[CH3:27])[CH2:22][O:21][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: COc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1Cl
Reactant: CC(C)CC(C)(CO)NC(=O)OC(C)(C)C
Product: COc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OCC(C)(CC(C)C)NC(=O)OC(C)(C)C
Yield: 20.9 %

Procedure:
8-Chloro-9-methoxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.04 g, 0.139 mmol) was subjected to Buchwald coupling (Example 16, Part H) with tert-butyl (1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (0.048 g, 0.208 mmol) which afforded tert-butyl(1-((9-methoxy-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate as white solid (15 mg, 0.029 mmol, 21% yield). LC/MS (ESI) m/e 484.2 [(M+H)+, calcd for C22H38N3O5, 484.3]; LC/MS retention time (Method C): tR=2.42 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].[CH3:10][C:11](=[CH:13][CH2:14][CH2:15][C@H:16]([CH2:18][CH:19]=O)[CH3:17])[CH3:12]>C(O)C>[CH3:17][C@H:16]([CH2:15][CH2:14][CH:13]=[C:11]([CH3:12])[CH3:10])[CH2:18][CH:19]=[N:9][NH:8][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: NNC(=O)c1ccco1
Reactant: CC(C)=CCC[C@@H](C)CC=O
Solvent: CCO
Product: CC(C)=CCC[C@@H](C)CC=NNC(=O)c1ccco1
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 2a (1.50 g, 11.9 mmol) and (R)-citronellal (2.74 g, 17.7 mmol) in ethanol (30 ml) was heated under reflux for 2 h. After cooling to room temperature, the product was concentrated and the excess of citronellal removed by Kugelrohr distillation (120° C., 0.39 mbar) to give 2.03 g (55%) of a yellow solid as a mixture of two isomers (ca. 7:1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1OC
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(C)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:14][C:15]1[CH:16]=[C:17](B(O)O)[C:18]([F:21])=[N:19][CH:20]=1>O1CCOCC1>[Br:14][C:15]1[CH:16]=[C:17]([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:18]([F:21])=[N:19][CH:20]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ncc(Br)cc1-c1ncccn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Bromopyrimidine (5.42 g, 34.1 mmol), sodium carbonate (22.75 mL, 45.5 mmol), 5-bromo-2-fluoropyridine-3-boronic acid (5 g, 22.75 mmol, commercially available from Frontier Scientific, Inc., Logan Utah), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (1.858 g, 2.275 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) were combined in dioxane (32.5 mL) and stirred at 100° C. overnight. LC-MS indicated good conversion to desired product. The material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 10% MeOH in DCM, to provide 2-(5-bromo-2-fluoropyridin-3-yl)pyrimidine (4.37 g, 17.20 mmol, 76% yield) as yellow solid. m/z (ESI) 253.8.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:35][CH2:36][CH:37]([CH2:42][Br:43])[CH2:38][C:39](Cl)=[O:40]>C1COCC1>[Br:35][CH2:36][CH:37]([CH2:42][Br:43])[CH2:38][C:39]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]3[N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[N:8]=[N:9][N:10]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:21][C:22]1=[O:27])=[O:40]
Reactant: O=C(Cl)CC(CBr)CBr
Reactant: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1C(=O)CC(CBr)CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydroquinolin-2(1H)-one (cilostazol, 1, A=H, 2.0 g, 3.50 mmol), N,N-dimethylaminopyridine (0.043 g, 0.35 mmol) and triethylamine (0.5 ml, 0.35 mmol) in THF (100 mL) at 0° C. and under nitrogen, a solution of 4-bromo-3-(bromomethyl)butanoyl chloride (0.97 g, 3.50 mmol) in THF (5 mL) is slowly added and the reaction mixture stirred at room temperature for 2 hours. Then it is partitioned between ethyl acetate and phosphate buffer (pH=3) and extracted with ethyl acetate (3×25 mL). The organic phase is dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography (CH2Cl2/acetone 7:3).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][C:25]([NH:24][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:23])([CH3:29])[CH3:28]
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)nn1
Reactant: CC(C)(N)CO
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)NC(C)(C)CO)nn1
Yield: 77 %

Procedure:
As described for example 114k, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (38 mg, 0.12 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of ethanolamine, to the title compound (36 mg, 77%) which was obtained as an off white foam. MS: m/e=385.5 [M+H]+.
Reaction SMILES: CC1C=CC=CC=1C.[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH2:12].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32]>N1C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH:12][S:27]([C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:31]([F:34])([F:32])[F:33])[CH:23]=1)(=[O:29])=[O:28]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
In a 400 ml flask, 200 ml of o-xylene, 1 ml of pyridine and 1.7 g (0.01 mole) of 2-chloro-4-nitroaniline were charged. While stirring the contents at room temperature, 2.8 g (0.01 mole) of 4-chloro-3-trifluoromethylbenzenesulfonylchloride was added dropwise at room temperature over 30 minutes. Thereafter, the reaction mixture was heated and stirred for 10 hours under reflux (140°-145° C.). After cooling the reaction mixture to room temperature, it was thoroughly washed first with dilute hydrochloric acid and then with water. Subsequent to its dehydration with anhydrous sodium sulfate, o-xylene was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: benzene) to isolate the intended Compound 3. m.p. 156°-158° C., yield 2.3 g (55%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C@@H:11]([NH:24]C(=O)OCC1C=CC=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:10]>CO.[Pd]>[NH2:24][C@H:11]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH2:1])=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Agent: [Pd]
Solvent: CO
Product: Cn1ncc(NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)c1N

Procedure:
To a solution of the crude product of 1-benzyl 5-tert-butyl (1S)-{1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]pentamethylene}biscarbamate in methanol (350 ml) was treated with 10% palladium on carbon (2.0 g) under a hydrogen atmosphere at room temperature for 6 days. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate and dried in vacuo to give tert-butyl (5S)-5-amino-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-6-oxohexylcarbamate (12.1 g) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:15](OCC)(OCC)OCC.CS(O)(=O)=O.O1CCCC1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[O:12][CH:15]=[N:14][N:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(OCC)OCC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cc2nnco2)cc1

Procedure:
A mixture of 2-(4-nitrophenyl)acetohydrazide (2.50 g), triethyl orthoformate (5.69 g), methanesulfonic acid (0.25 g) and tetrahydrofuran (50 mL) was heated under reflux for 1 hr. The reaction mixture was diluted with ethyl acetate. The mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 2-(4-nitrobenzyl)-1,3,4-oxadiazole was obtained as pale-yellow crystals (1.92 g, yield 73%) from a fraction eluted with hexane-ethyl acetate (3:1-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 104-105° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:27][C:28]([CH3:31])=[N:29][N:30]=3)=[CH:22][CH:21]=2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[O:27][C:28]([CH3:31])=[N:29][N:30]=3)=[CH:24][CH:25]=2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Yield: 82 %

Procedure:
To a solution of Methyl 3-(benzyloxy)-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (28 g) (Intermediate 8) in glacial acetic acid, suspension of 10% Pd/C in glacial acetic acid was added in Parr hydrogenation apparatus. The reaction was subjected under 60 PSI of hydrogen for 6 h. After completion, the reaction mixture was filtered to remove catalyst. Filtrate was poured into ice, the solid obtained was filtered, washed with water, saturated sodium bicarbonate solution, water, petroleum ether, air dried to obtain desired product (18 g, 70%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13])([O-:3])=[O:2].[F:17]F>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([F:17])[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13])([O-:3])=[O:2]
Reactant: FF
Reactant: COC(=O)C(=O)Cc1ccccc1[N+](=O)[O-]
Solvent: CC#N
Product: COC(=O)C(=O)C(F)c1ccccc1[N+](=O)[O-]

Procedure:
In the same manner as in Example 1, methyl 3-(2-nitrophenyl)pyruvate (2.23 g; 10 mmol) is dissolved in acetonitrile (50 g) and reacted with fluorine. By distilling off the solvent under reduced pressure, there is obtained a crude product, whicch is rectified to give methyl 3-(2-nitrophenyl)-3-fluoropyruvate.
Reaction SMILES: [CH3:1][C:2]1([C:7]([OH:9])=O)[NH:6][CH2:5][CH2:4][S:3]1.[CH3:10][N:11]=[C:12]=[O:13]>>[CH3:10][N:11]1[C:7](=[O:9])[C:2]2([CH3:1])[S:3][CH2:4][CH2:5][N:6]2[C:12]1=[O:13]
Reactant: CN=C=O
Reactant: CC1(C(=O)O)NCCS1
Product: CN1C(=O)N2CCSC2(C)C1=O

Procedure:
By operating in like manner as is described in Example 1 and by starting from 2-methyl-thiazolidin-2-carboxylic acid and methyl isocyanate, the desired product was obtained as a white solid having a melting point of 67°-68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[C:11](=[CH:20]N(C)C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH:25]([C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1)[C:26]([NH2:28])=[NH:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[N:27]=[C:26]([NH:25][C@@H:29]4[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]4)[N:28]=[CH:20][C:11]=3[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=N)N)C1
Reactant: CN(C)C=C1C[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncc3c(n2)-c2ccccc2[C@@H](c2ccc(Cl)c(Cl)c2)C3)C1
Yield: 57 %

Procedure:
This product was prepared by using (R)-4-(3,4-dichlorophenyl)-2-((dimethylamino)methylene)-3,4-dihydronaphthalen-1(2H)-one and (R)-tert-butyl 3-guanidinopiperidine-1-carboxylate hydrochloride salt under the condition described in the general procedure 1 to afford the desired product in 57% yield as a light yellow solid. M.p.=85-87° C. 1H NMR 400 MHz (DMSO-d6) δ 8.29 (bs, 1 H), 8.12 (s, 1 H), 7.50-7.35 (m, 4 H), 7.08 (s, 1 H), 7.02-6.98 (m, 2 H), 4.39 (t, J=5.2 Hz, 1 H), 3.74 (bs, 2 H), 3.12-3.04 (m, 2 H), 2.90-2.84 (m, 2 H), 1.89-1.51 (m, 3 H), 1.38-1.24 (m, 11 H). LCMS m/e 525 (M+H).
Reaction SMILES: [OH-].[K+].Br[C:4]([CH3:11])([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[OH:20]>>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:20][C:4]([CH3:11])([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C(C)(C)Oc1cccc(Cl)c1Cl

Procedure:
Potassium hydroxide-mediated reaction of ethyl 2-bromo-2-methylpropanoate with 2,3-dichlorophenol provided ethyl 2-(2,3-dichlorophenoxy)-2-methylpropanoate. After reduction to the corresponding aldehyde with diisobutylaluminum hydride, reductive amination with 2-aminoethanol provided the requisite 2-aminoethanol derivative.
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC([NH:15][CH:16]1[CH2:19][N:18]([C:20]2[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=2)[CH2:17]1)=O)(C)(C)C>O1CCOCC1>[NH2:15][CH:16]1[CH2:19][N:18]([C:20]2[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=2)[CH2:17]1
Reactant: CCOC(=O)c1sc(N2CC(NC(=O)OC(C)(C)C)C2)nc1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(N2CC(N)C2)nc1C
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 79.6 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (0.96 mL, 3.82 mmol) was added to a solution of ethyl 2-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (218a) (261 mg, 0.76 mmol) in 1,4-dioxane (8 mL) at 0° C., and the mixture was stirred at room temperature for 7.5 hours. Then, a 4 N hydrochloric acid/ethyl acetate solution (0.96 mL, 3.82 mmol) was added, and the mixture was further stirred for 45 hours. The reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution was added to the resulting residue. Thereafter, the mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure to obtain 146 mg of the title compound as a pale yellow oily substance (79%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[NH2:18]
Reactant: CS(=O)(=O)c1nccc(-c2ccccc2)n1
Reactant: NN
Solvent: CCO
Product: NNc1nccc(-c2ccccc2)n1

Procedure:
A solution of 1.0 g. of 2-methylsulfonyl-4-phenylpyrimidine in 25 ml. of absolute ethanol is treated with 0.34 g. of 95% hydrazine. The reaction mixture is refluxed for 6 hours and then cooled and the desired product is obtained by filtration, m.p. 116°-118° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH:14]=[O:15])=[CH:8][C:7]=1[O:16][CH3:17].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:15][CH2:14][C:9]1[CH:10]=[C:11]([O:12][CH3:13])[C:6]([O:5][CH2:4][CH2:3][OH:2])=[C:7]([O:16][CH3:17])[CH:8]=1
Reactant: COC(=O)COc1c(OC)cc(C=O)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)cc(OC)c1OCCO
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of (4-formyl-2,6-dimethoxyphenoxy)-acetate methyl ester (1.5 g, 5.9 mmol) in THF (30 mL, 0.2 M) was added LiAlH4 (403 mg, 10.6 mmol) at water temperature. The reaction mixture was stirred for 6 hours at room temperature, followed by addition of H2O, and then subjected to celite filtration. Evaporation of the resultant mixture under diminished pressure gave a white solid. Recrystallization of this solid from chloroform/hexane gave a colorless needle-like crystal (1.346 g, 100%, m.p. 26 to 28° C.).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N([O-])=O.[Na+].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>Cl.O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: Nc1ccccc1CO
Reactant: c1ccncc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: OCc1ccccc1-c1ccccn1

Procedure:
2-Aminobenzylalcohol (10 g) was dissolved in concentrated hydrochloric acid (25 ml) and the solution diluted with water (20 ml). The solution was stirred at 0° and a solution of sodium nitrite (5.9 g) in water (20 ml) added dropwise. The mixture was stirred at 0° for 40 minutes. The solution was added dropwise to pyridine (92 ml) stirred at 80°. After stirring at 80° for 90 minutes the mixture was concentrated in vacuo and the residue heated with 880 ammonia (100 ml). The mixture was concentrated in vacuo and the residue slurried with water and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried and evaporated. Flash chromatography produced the sub-title compound as a red oil (3.8 g). M.S. m/e 185 Base Peak 80.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH:27]1[CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH2:17][CH2:16][C@@:13]2([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[CH3:9])[CH2:15][CH2:14]2)[CH2:30][CH2:29][CH2:28]1
Reactant: C1CNC1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CCC2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and azetidine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.15 min, m/z=463; 1H NMR (CDCl3) 1.43 (d, 4H), 2.05-2.27 (m, 7H), 2.56-2.74 (m, 2H), 2.86 (m, 1H), 3.20 (m, 1H), 3.50 (m, 1H), 3.71 (m, 1H), 4.17-4.39 (d, 2H), 5.52 (m, 1H), 6.80 (d, 2H), 6.95-7.02 (m, 2H), 7.13-7.24 (m, 4H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>S(=O)(=O)(O)O>[N+:1]([C:13]1[CH:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:10][CH:14]=1)([O-:4])=[O:2]
Reactant: CCOC(=O)c1cccs1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])cs1
Temperature: 0 °C
Yield: 96 %

Procedure:
A solution of nitric acid/sulfuric acid (1:2.5) was added dropwise to a stirred solution (2.7 M) of ethyl 2-thiophene carboxylate in sulfuric acid at −10° C. After stirring for an additional half an hour, the reaction mixture was poured into ice-water. The resulting precipitate was filtered, washed with water and dried to give the title compound (96%) as a mixture 1:1 of 4-nitro and 5-nitro regioisomers.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([OH:13])[CH3:12].Cl>ClCCl>[Cl:1][C:2]1[C:7]([CH2:8][C:9](=[NH:10])[O:13][CH2:11][CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCO
Reactant: N#CCc1cccnc1Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)Cc1cccnc1Cl
Reaction time: 24 h

Procedure:
Through a cooled solution of 2-(2-chloropyridin-3-yl)acetonitrile (Synthesis (6), 528-30, 1992) (1.7 g, 11.1 mmol), ethanol (1.0 mL, 16.7 mmol), and dichloromethane (25 mL) was bubbled HCl gas at 0° C. for 30 minutes. After standing at 4° C. for 24 hours, the reaction mixture was concentrated, and the residue was triturated with diethyl ether. The precipitate was collected and dried to obtain the titled compound. MS (ESI+) m/z 199 (M+H)+.