Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:21]#[N:22])=[N:5][C:6]([C:11]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][CH3:20])=[CH:7][C:8]=1[O:9][CH3:10].C([O-])([O-])=O.[K+].[K+].[CH3:29][NH:30][C@@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1.CCCCCC>CC#N.O>[CH2:19]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][CH3:18])[C:11]=1[C:6]1[N:5]=[C:4]([C:21]#[N:22])[C:3]([CH2:2][N:30]([CH3:29])[C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33][CH2:32]2)=[C:8]([O:9][CH3:10])[CH:7]=1)[CH3:20]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(CBr)c(C#N)n1
Reactant: CN[C@H]1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CC#N
Product: CCc1cccc(CC)c1-c1cc(OC)c(CN(C)[C@H]2CCCc3ccccc32)c(C#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromomethyl-6-(2,6-diethyl-phenyl)-4-methoxy-pyridine-2-carbonitrile (40 mg), K2CO3 (50 mg) and (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (40 mg) in CH3CN (2 mL) is stirred at room temperature overnight. Hexane (5 mL) and water (5 mL) are added to the mixture. The organic layer is separated, washed, once with brine, dried (Na2SO4), and concentrated. The crude is purified by PTLC (4:1 hexane/EtOAc) to give (S)-6-(2,6-diethyl-phenyl)-4-methoxy-3-{[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amino]-methyl}-pyridine-2-carbonitrile. 1H NMR (CDCl3) 7.72 (d, 1H), 7.35 (t, 1H), 7.07-7.17 (m, 5H), 6.92 (s, 1H), 4.05 (m, 1H), 3.97 (d, 2H), 3.89 (s, 3H), 2.75 (m, 2H), 2.32 (m, 4H), 2.22 (s, 3H), 2.09 (m, 2H), 2.70-2.95 (m, 2H), 1.08 (t, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([S:22][CH3:23])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6].[OH:24]OS([O-])=O.[K+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([S:22]([CH3:23])=[O:24])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6]
Reactant: CSc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(Cl)c1O
Reactant: O=S([O-])OO
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
3-(3-chloro-4-hydroxy-5-methylsulfanylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (51 mg) was dissolved in tetrahydrofuran (0.5 mL) and water (0.5 mL), and oxone (43 mg) was added to the solution, and then the mixture was stirred at room temperature for 1 hour. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-diethylether to obtain the title compound (45 mg) as a brown crystal.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)=[C:15]([CH:19]=1)[C:16]([O:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)=[O:17]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc(F)cc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Neat 1-(bromomethyl)-4-fluorobenzene (1533 mg, 8.11 mmol) was added over 1 min to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (800 mg, 3.69 mmol) and potassium carbonate (1274 mg, 9.22 mmol) in acetone (60 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After filtering, the filtrate was evaporated to give a solid, which was dried in vacuo to yield the title compound as a white solid. 1.56 g.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C1C(C(OOOC(=O)C2C=CC=CC=2)=O)=CC=CC=1>[Br:13][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)OC)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(C)Br)cc1
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
To a solution of methyl 4-ethylbenzoate (5.12 g) in carbon tetrachloride (50 ml) were added perbenzoic anhydride (0.20 g) and N-bromosuccinimide (6.07 g) in turn, and the mixture was heated and refluxed. After 30 minutes, the mixture was allowed to cool, and the precipitate was separated by filtration, and washed with carbon tetrachloride. The filtrate and the washings were combined, and concentrated under reduced pressure to give the title compound (8.28 g)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCCl>[NH:10]1[CH2:11][CH:8]([O:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccncc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: c1cc(OC2CNC2)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
tert-Butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (494 mg) was mixed with DCE (5 ml), and TFA (2 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 4-(azetidin-3-yloxy)pyridine (268 mg).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[C:19]([F:20])=[C:18]3[C:13]([C:14](=[O:27])[C:15]([C:24]([OH:26])=[O:25])=[CH:16][N:17]3[CH2:21][CH2:22][F:23])=[CH:12][C:11]=2[F:28])[N:9]=1)C.NCC1SC=C(C2C(F)=CC3C(=O)C(C(O)=O)=CN4C(C)COC=2C=34)N=1>>[F:28][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([F:20])[C:10]=1[C:8]1[N:9]=[C:5]([CH2:4][NH:3][CH3:1])[S:6][CH:7]=1)[N:17]([CH2:21][CH2:22][F:23])[CH:16]=[C:15]([C:24]([OH:26])=[O:25])[C:14]2=[O:27]
Reactant: CCNCc1nc(-c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)cs1
Agent: CC1COc2c(-c3csc(CN)n3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Product: CNCc1nc(-c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)cs1

Procedure:
7-[2-[(ethylamino)methyl]-4-thiazolyl]-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 197°-201° C. (35e), and 10-[2-(aminomethyl)-4-thiazolyl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, mp 229°-231° C. (35f).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.FC1C=CC(C(C2C=CC(C(F)(F)F)=CC=2)O)=CC=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]([C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[OH:16])=[C:3]([CH3:9])[CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1cc(Cl)ccc1Br
Agent: OC(c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(Cl)ccc1C(O)c1ccc(F)cc1

Procedure:
The title compound was prepared starting from 1.00 g (4.87 mmol) of 2-bromo-5-chlorotoluene and 0.72 g (5.84 mmol) of 4-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 80A. 0.64 g (52% of theory) of the title compound was obtained.
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[OH:17])=[O:15])=[CH:10][CH:9]=1>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[O:17])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(C(O)C(=O)c2ccc(Br)cc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)C(=O)c2ccc(Br)cc2)cc1

Procedure:
Cupric sulfate, 90 g. (0.36 mole), is stirred and heated on the steam-bath with 110 ml. of pyridine and 45 ml. of water until complete solution is obtained. 4-Bromo-4'-methylbenzoin, 55 g. (0.18 mole), is added and the mixture is stirred and heated on the steam-bath for 3 hours. During this period, the yellow crystalline product separates. After cooling and dilution with water, the product is collected, washed with water, 1 N hydrochloric acid, and water, and dried; m.p. 132°-135° C. The analytical sample is obtained as yellow needles, m.p. 136°-137° C, after repeated recrystallizations from 95% ethanol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:30][O:31][CH2:32][CH:33]([NH:35][C:36]([C:38]1[CH:39]=[C:40]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[CH:41]=[C:42](I)[CH:43]=1)=[O:37])[CH3:34]>O1CCOCC1.O.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:30][O:31][CH2:32][CH:33]([NH:35][C:36]([C:38]1[CH:39]=[C:40]([C:45]2[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=2)[CH:41]=[C:42]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH:43]=1)=[O:37])[CH3:34]
Reactant: COCC(C)NC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-c2ncc[nH]2)c1
Temperature: 150 °C
Yield: 64.4 %

Procedure:
Imidazole (200 mg, 2.9 mmol) and MgO (60 mg, 2.9 mmol) were suspended in 0.5 ml dry dioxane and 2.5 ml dry DMF in a reaction bottle and stirred at room temperature for 5 minutes to form a homogeneous suspension. CuI (300 mg, 1.5 mmol), Pd(OAc)2 (18 mg, 0.0734 mmol), PPh3 (60 mg, 0.22 mmol) and 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (300 mg, 0.7335 mmol) were added to the above solution and reaction mixture were heated to 150° C. under microwave irradiation for 45 minutes. The reaction mixture was cooled, diluted with water, extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 165 mg of 5-(1H-Imidazol-2-yl)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (65%), MS (M+H)=350.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][CH:12]1[C:36](=[O:37])[N:14]2[CH:15]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:16]([OH:19])[CH2:17][S:18][C@H:13]12.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([NH:11][CH:12]1[C:36](=[O:37])[N:14]2[CH:15]([C:20]([O:22][CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:16]([OH:19])[CH2:17][S:18][C@H:13]12)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Temperature: 3 °C
Reaction time: 0.17 h

Procedure:
Formic acid (0.4 ml) and acetic anhydride (1 ml) were stirred at 40° C. for 30 minutes. The reaction mixture was cooled in an ice-water bath and added dropwise to a mixture of benzhydryl 7-amino-3-hydroxycepham-4-carboxylate (1.0 g) in methylene chloride (30 ml) at 3° C. The mixture was stirred at 3° C. for 10 minutes and adjusted to pH 7.0 with 5% aqueous solution of sodium bicarbonate, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give benzhydryl 7-formamido-3-hydroxycepham-4-carboxylate (1.05 g) as powder.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[C:19]([NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN1C(=O)CCC1>[C:6]([C:5]1[CH:14]=[CH:15][C:2]([N:29]2[CH2:30][CH2:31][CH2:32][CH:27]([NH:26][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:28]2)=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C(=O)c3ccccc3)cc2[N+](=O)[O-])C1
Yield: 90 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrobenzophenone (1.0 eq), 3-(N-Boc-amino) piperidine (1.1 eq), and TEA (2.0 eq) in NMP yielding tert-butyl 1-(4-benzoyl-2-nitro phenyl)piperidin-3-ylcarbamate (90%). LCMS (m/z): 426.2 (MH+); LC Rt=3.49 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1C=CC=CC=1.[Cl-].[Cd+2].[Cl-]>[C:1]1([CH2:7][CH2:8][C:9]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cd+2]
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: O=C(CCc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
Phenylpropionyl chloride (33.7 g) in benzene was added dropwise to a stirred mixture of 4-chlorophenyl magnesium bromide (derived from 38 g of 4-chlorobromobenzene) and cadmium chloride (37 g) in benzene at 0°. The mixture was stirred at room temperature for 6 hours and aqueous ammonium chloride solution then added. Ether extraction yielded p-chlorophenyl phenylethyl ketone (25 g) m.p. 78°-79°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:36][C:35]1[CH:34]=[CH:33][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=2)=[O:19])=[CH:16][C:15]=1[NH:14][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:12]
Reactant: O=C(Cl)c1ccc2ncccc2c1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1N
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc2ncccc2c1

Procedure:
Using an analogous procedure to that described in Example 1, 6-quinolylcarbonyl chloride was reacted with 3-amino-4-methyl-N-(3-morpholinophenyl)benzamide to give the title compound; NMR Spectrum: (DMSOd6) 2.35 (s, 3H), 3.0-3.1 (m, 4H), 3.65-3.75 (m, 4H), 6.65-6.7 (m, 1H), 7.17 (t, 1H), 7.3-7.35 (m, 1H), 7.38-7.48 (m, 2H), 7.6-7.7 (m, 1H), 7.8-7.85 (m, 1H), 8.0 (s, 1H), 8.1-8.15 (m, 1H), 8.3-8.35 (m, 1H), 8.5-8.55 (m, 1H), 8.7 (s, 1H), 8.98-9.02 (m, 1H), 10.0-10.1 (br s, 1H), 10.25-10.35 (br s, 1H); Mass Spectrum: M+H+ 467.
Reaction SMILES: Cl[O-].[Na+].[OH-].[NH4+:5].[NH2:6][C:7]1[NH:8][C:9](=[S:24])[C:10]2[CH:15]=[CH:14][N:13]([C@@H:16]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[CH2:17]3)[C:11]=2[N:12]=1>[OH-].[K+]>[NH2:6][C:7]1[N:8]=[C:9]([S:24][NH2:5])[C:10]2[CH:15]=[CH:14][N:13]([C@@H:16]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[CH2:17]3)[C:11]=2[N:12]=1
Reactant: [NH4+]
Reactant: Nc1nc2c(ccn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=S)[nH]1
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Product: NSc1nc(N)nc2c1ccn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Four mL of 5.25% aqueous sodium hypochlorite (2.8 mmol) was cooled and added to 10 mL of 1.4N ammonium hydroxide. After stirring for 30 min at 0° C., 2-amino-7-(2-deoxy-β-D-erythro-pentofuranosyl) pyrrolo[2,3-d]pyrimidine-4-thione 37 (0.78 g, 2.8 mmol) in 1.3 mL of 2N potassium hydroxide was added and stirred for 1 h at 0° C. The precipitate was collected by filtration, washed with EtOH and dried at 25° C. over P2O5 in vacuo to obtain 670 mg (81%) of the title compound 38. m.p. 162°-164° C. (dec): UV: λmax (pH 1) 238 nm (ε28,500): 347 (5,600): λmax (pH 7) 234 nm (ε35,400), 317 (10,400): λmax (pH 11) 234 nm (ε30,900), 318 (10,300): 1H NMR (DMSO-d6): δ4.11 (s, 2, exchangeable in D2O, SNH2), 6.18 (s, 2, exchangeable in D2O, NH2), 6.44 (dd, 1, J =8.3 and 5.9 Hz, C1'H), 6.61 (d, 1, J =3.8 Hz, C5H), 6.18 (d, 1, J =3.8 Hz, C6H). Anal. Calcd for C11H15N5O3S.1/4H2O: (301.83): C, 43.77: H, 5.17: N, 23.20: S, 10.62. Found: C, 43.59: H, 4.95: N, 23.13: S, 10.32.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)=[O:11])[CH:17]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CN
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)nn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-chloro-2-(pyrimidin-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 491 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:4]=1[C:5](N)=[O:6].C(O)(=[O:19])C>Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:4]=1[C:5]([OH:19])=[O:6]
Reactant: CC(=O)O
Reactant: COc1cccc(-n2cncn2)c1C(N)=O
Agent: Cl
Product: COc1cccc(-n2cncn2)c1C(=O)O

Procedure:
0.116 mol of the above crude 2-methoxy-6-(1,2,4-triazol-1-yl)-benzamide are stirred in a mixture of 120 ml of concentrated hydrochloric acid and 60 ml of glacial acetic acid for 5 h at 100° C. The mixture is evaporated down under reduced pressure and the process is repeated with the residue. After further evaporation of the mixture, the residue is dissolved in a little water and the solution is brought to pH 3 with sodium hydroxide solution. 30-40 ml of ethanol are added, after which the precipitate is filtered off under suction and dissolved in methanol. After the solution has been dried and evaporated down, 14.7 g of the above acid of melting point 200°-202° C. (decomposition) are isolated.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:8]([OH:10])=[O:9])[N:6]=1.[C:17](OC(=O)C)(=[O:19])C>C(O)=O>[CH:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:19]
Reactant: CC(C)CON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(C)CON=C(C(=O)O)c1csc(NC=O)n1
Yield: 86.9 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-iso-butoxyiminoacetic acid (syn isomer, 11.5 g.) acetic anhydride (19.3 g.) and formic acid (8.7 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-iso-butoxyiminoacetic acid (syn isomer, 11.15 g.), mp 163° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:35][CH2:36][O:37][Si](C(C)(C)C)(C)C)[CH:32]([CH3:34])[CH3:33])=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O>>[CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:35][CH2:36][OH:37])[CH:32]([CH3:34])[CH3:33])=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3cccc(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-2-((1-(3-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropylpyrimidine-4-carboxamide (503) was synthesized from 5-(benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-((1-(3-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-isopropylpyrimidine-4-carboxamide (502) following the procedure described 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (246).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][C:12]2[C:13]([N+:19]([O-:21])=[O:20])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:3]=1[Cl:10]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: Oc1cc(Cl)cc(Br)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(Cl)c1Oc1cc(Cl)cc(Br)c1Cl
Reaction time: 7 h

Procedure:
3-bromo-2,5-dichlorophenol (8.0 g, 33 mmol) and 2,3-dichloronitrobenzene (6.4 g, 33 mmol) were dissolved in NMP (30 mL), followed by the addition of potassium carbonate (5.5 g, 40 mmol). The resulting suspension was placed in an oil bath at 120° C. for 7 hours, after which the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (2×00 mL). The combined organic fractions were washed with water (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (330 g) eluting with 0-20% CH2Cl2/hexanes to afford the title compound. 1H NMR (CDCl3) δ 7.98 (dd, J=8.2 Hz, J=1.6 Hz, 1H), 7.79 (dd, J=8.2 Hz, J=1.6 Hz, 1H), 7.44 (dd, J=8.2 Hz, J=8.2 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 6.54 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:18](=[O:20])[CH3:19])=[CH:5][S:6][C:7]=1[C:8]1[CH:17]=[CH:16][C:15]2CC[CH2:12][CH2:11][C:10]=2[CH:9]=1.[O:21]1C2C=CC(C3SC=C(C#N)C=3OC)=CC=2CC1>>[O:21]1[C:15]2[CH:16]=[CH:17][C:8]([C:7]3[S:6][CH:5]=[C:4]([C:18](=[O:20])[CH3:19])[C:3]=3[O:2][CH3:1])=[CH:9][C:10]=2[CH2:11][CH2:12]1
Reactant: COc1c(C#N)csc1-c1ccc2c(c1)CCO2
Reactant: COc1c(C(C)=O)csc1-c1ccc2c(c1)CCCC2
Product: COc1c(C(C)=O)csc1-c1ccc2c(c1)CCO2
Yield: 87 %

Procedure:
Synthesis was carried out in the same manner as in Synthesis Method 2 (5) in Reference Synthetic Example 3 by using 2.6 g (0.0101 mol) of 5-(2,3-dihydro-benzofuran-5-yl)-4-methoxythiophene-3-carbonitrile to obtain 2.29 g of the desired product (yield: 87%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[N+:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:11]([O-:13])=[O:12])[CH:19]=2)=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: COc1cc(Br)ccc1N
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: COc1cc(-c2cccc([N+](=O)[O-])c2)ccc1N

Procedure:
4-Amino-3-methoxy-3′-nitro-biphenyl was prepared from 4-bromo-2-methoxyaniline (Synth. Commun. 23(6), 855-9(1993)) and 3-nitrophenyl boronic acid according to the procedure of Example 5. White solid: mp 167-168° C.; 1H-NMR (CDCl3) δ 8.39 (t, 1H, J=1.97 Hz), 8.13-8.09 (m, 1H), 7.88-7.84 (m, 1H), 7.55 (t, 1H, J=8.0 Hz), 7.09 (dd, 1H, J=7.98, 1.94 Hz), 7.04 (d, 1H, J=1.89 Hz), 6.80 (d, 1H, J=8.04 Hz), 4.0 (s, 5H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[C:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C#Cc1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C(#C[C@@H]1CCCN1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
An ice-cold stirred solution (S)-N-(tert-butoxycarbonyl)-2-(2-(3-pyridyl)ethynyl)pyrrolidine (300 mg, 1.10 mmol) in ethyl acetate (25 mL) was treated with concentrated hydrochloric acid (1 mL). The mixture was stirred for 10 min at 0–5° C., then for 3 h at room temperature. The layers were separated and the pH of the aqueous portion was brought to 12 with 1N NaOH. The aqueous phase was extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine (5 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography on silica gel, eluting with chloroform/methanol (90/10, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 0.120 g of a yellow oil.