Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:35]([NH:42][C:11](=[O:13])[CH:10]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc(C(=CC(=O)O)c2ccc(OC)cc2)cc1
Reactant: NCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=CC(=O)NCc2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.84 g (0.01 M) of 3,3-bis(4-methoxyphenyl)acrylic acid was dissolved in 10 ml of dimethylformamide. To the obtained solution, 1.2 g (0.012 M) of triethylamine and 1.2 g of ethyl chlorocarbonate were added under icecooling. After on hour, 1.2 g of benzylamine was added thereto and the mixture was stirred at room temperature for one hour. After the completion of the reaction, the reaction mixture was dissolved in 50 ml of ethyl acetate, washed with 10% hydrochloric acid, a saturated aqueous solution of NaHCO3 and a saline solution successively and dried over magnesium sulfate followed by purifying by silica gel column chromategraphy. Thus 3.3 g of the title compound having the following physicochemical properties was obtained.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[CH:18]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]1([CH2:30][O:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)CCl.CN1CCOCC1.N1C2C(=NC=CC=2)N(O)N=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:11])[NH:32][O:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]([N:14]2[C@H:18]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(=O)C1CC=NN1C(=O)[C@@H](CC(=O)O)CC1CCCC1
Reactant: NOCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1CC=NN1C(=O)[C@@H](CC(=O)NOCc1ccccc1)CC1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.7 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-{5-[(dimethylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}-4-oxobutanoic acid (269 mg, 0.83 mmol) in dichloromethane (DCM) (10 ml) was added O-(phenylmethyl)hydroxylamine (133 mg, 1.08 mmol), EDC (191 mg, 1.0 mmol), 4-methylmorpholine (0.24 ml, 2.16 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (113 mg, 0.83 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 5 hours. The reaction mixture was then washed with water (15 mL) and NaHCO3 solution (15 mL×3), and concentrated to provide the crude product as a mixture of diastereomers. This mixture was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N,N-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxamide (120 mg, 33% yield). MS: 429 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[C:14](=[O:17])[NH:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:24]1([CH2:23][N:15]2[C:14](=[O:17])[C:13]([C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16]2)[CH2:26][CH2:25]1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(OC)c2)n[nH]c1=O
Reactant: ClCC1CC1
Product: COC(=O)c1cc(-c2ccc(OC)c(OC)c2)nn(CC2CC2)c1=O
Yield: 78.7 %

Procedure:
Using 6-(3,4-dimethoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 78.7%.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14]/[C:15](/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20]I.[I-]>C1COCC1>[CH3:14]/[C:15](/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCCCI
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a stirred solution of 192 mg (8.01 mmol) of NaH in 20 mL of THF at 0° C. under argon was added 1.21 mL (8.01 mmol) of diethyl malonate dropwise. The mixture was stirred at 0° C. for 0.5 hours at which time was treated with 1.0 g (2.67 mmol) of Example 4, Part A iodide in 2 mL of THF. After 1 hour at 0° C. the reaction was heated to 40° C. for 2 hours, then cooled to room temperature and stirred for 18 hours. The mixture was quenched with NH4Cl and diluted with ether. The organic layer was washed with H2O, brine, dried over MgSO4 and the solvent evaporated to provide 950 mg of a pale yellow oil. Flash chromatography was performed on 50 g of silica gel, packed, loaded and eluted with (95:5) hexane/ether. The pure product fractions were combined and evaporated to provide 580 mg (54%) of title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([C:16]2[C:20]3[N:21]=[C:22](Cl)[N:23]=[CH:24][C:19]=3[S:18][CH:17]=2)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C@@H:26]1([NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH2:32].O.ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([C:16]2[C:20]3[N:21]=[C:22]([NH:32][C@@H:27]4[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:26]4[NH2:33])[N:23]=[CH:24][C:19]=3[S:18][CH:17]=2)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: COc1cc(NC(=O)c2csc3cnc(Cl)nc23)cc(OC)c1OC
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1cc(NC(=O)c2csc3cnc(N[C@@H]4CCCC[C@@H]4N)nc23)cc(OC)c1OC
Yield: 60 %

Procedure:
To a solution of 0.0885 g (0.233 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4,5-trimethoxy-phenyl)-amide in 2.33 mL of dioxane was added 0.168 mL (1.4 mmole) of cis-cyclohexane-1,2-diamine. The mixture was heated at 100 degrees for over night. Water and dichloromethane were added, separated. The aqueous layer was washed with dichloromethane twice. The organic layer was washed with aqueous sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-0.7 N ammonia solution in methanol (gradient 100:0-90:10) gave 0.064 g of 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4,5-trimethoxy-phenyl)-amide as a light yellow solid. MH+/Z=458.
Reaction SMILES: C(OC(=O)[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:24]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:25]=1.[C:55]([O-:58])([O-])=[O:56].[K+].[K+].[OH-].[Na+]>C(O)C>[C:24]1([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=4)([CH3:14])[C:55]([OH:58])=[O:56])=[CH:12][CH:11]=3)[N:34]=2)[CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(F)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2cccc(F)c2)C(=O)O)cc1

Procedure:
A mixture of 2-(3-fluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol), toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 2, Part F) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)ethoxy]-phenyl}-2-(3-fluoro-phenoxy)-2-methyl-propionic acid 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.87 (d, 1H, J=7.8 Hz), 7.57 (d, 2H, J=7.8 Hz), 7.50–7.27 (m, 5H), 7.12 (m, 3H), 6.76 (d, 2H, J=8.6 Hz), 6.72–6.58 (m, 3H), 4.14 (t, 2H, J=6.7 Hz), 3.18 (d, 1H, J=14.1 Hz), 3.08 (d, 1H, J=14.1 Hz), 2.94 (t, 2H, J=6.7 Hz), 2.37 (s, 3H), 1.38 (s, 3H). MS (ES+) m/z mass calcd for C34H31FNO5 552.21, found 552.2.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][CH2:6][CH2:7][CH:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=1.[Cl-:17].[NH4+:18]>>[ClH:17].[C:11]1([CH2:10][CH:8]2[NH:9][C:3](=[NH:18])[CH:4]=[CH:5][CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(Cc2ccccc2)CCC=C1
Product: Cl
Product: N=C1C=CCCC(Cc2ccccc2)N1

Procedure:
The product of Example 188 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].[N:34]1([CH2:40][C:41]2[CH:42]=[C:43]([CH:50]=[CH:51][CH:52]=2)[O:44][CH2:45][CH2:46][CH2:47][CH2:48][NH2:49])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][NH:14][C:22]([NH:49][CH2:48][CH2:47][CH2:46][CH2:45][O:44][C:43]2[CH:50]=[CH:51][CH:52]=[C:41]([CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:42]=2)=[O:23])[CH3:15])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: NCCCCOc1cccc(CN2CCCCC2)c1
Solvent: ClCCl
Product: CN(CCNC(=O)NCCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.8 g (2.6 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.69 g (2.7 mmol) of 4-[3-(piperidinomethyl)phenoxy]butaneamine as starting materials. Working up by chromatography (eluant: methylene chloride) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%])=592 ([M+H]+, 2), 230 (100); IR (KBr): 1632 cm-1 (C≡O). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 124° C. with decomposition.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4](O)(=O)C.C=O.[C:10]1([C:16]2[NH:24][C:19]3=[N:20][CH:21]=[CH:22][N:23]=[C:18]3[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:4])[CH2:3][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][N:23]=2)[NH:24][C:16]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(-c2cc3nccnc3[nH]2)cc1
Reactant: CNC
Reactant: CC(=O)O
Agent: C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1c(-c2ccccc2)[nH]c2nccnc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of dimethylamine in tetrahydrofuran (0.5 mL, 2.0M) at 0° C. was treated with glacial acetic acid (15 μl) then with formaldehyde (75 μl, 40% solution). After stirring at 0° C. for 10 minutes this mixture was treated with 6-phenyl-5H-pyrrolo[2,3-b]pyrazine [0.195 g, Example 2(c)] and then with tetrahydrofuran (3 mL) to ensure complete dissolution. The reaction mixture was allowed to warm to ambient temperature, then stirred overnight, then diluted with ethyl acetate (5 mL) and then extracted three times with hydrochloric acid (5 mL, 1N). The combined acid extracts were adjusted to pH 6–7 by addition of potassium hydroxide solution (5N). The resulting pale yellow solid was filtered, then washed with water and then dried to give the title compound (0.16 g) as a pale yellow solid, m.p. 191–192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 102 mg of 4-ethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.19 (t, 3H, J=7.6 Hz), 2.62 (q, 2H, J=7.6 Hz), 7.20 (d, 2H, J=8.8 Hz, 7.38 (m, 3H), 7.65-7.72 (m, 4H), 8.81 (d, 2H, 6.4 Hz), 10.06 (s, 1H). MS: m/z 446.0 (M++1).
Reaction SMILES: O[C:2]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:4])[CH3:3].CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:2]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:4])=[CH2:3]
Reactant: CC(C)(O)c1cc2ccccc2o1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
3.10 g of 2-(1-hydroxy-1-methylethyl)benzofuran was dissolved in 100 ml of methylene chloride. Thereto were added 2.22 g of methanesulfonyl chloride and 3.92 g of triethylamine at 0° C. The mixture was stirred at room temperature for 4 hours, then washed with water, 1 N hydrochloric acid, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene) to obtain 2.44 g (yield: 88%) of 2-isopropenylbenzofuran as a colorless oily material.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].O>O1CCCC1>[CH:14]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1)([CH3:16])[CH3:15]
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C=O)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (46, 4.05 g, 27.71 mmol) in tetrahydrofuran (30.0 mL) were added sodium hydride (60% in mineral oil, 1.5 g, 38 mmol) and triisopropylsilyl chloride (8.0 mL, 38 mmol) under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give compound (47, 3.0 g, 36%). MS (ESI)[M+H+]+=303.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:5]([CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=[O:6].[C:22]([Mg]Cl)(C)(C)[CH3:23].[NH4+].[Cl-].[CH2:30]1[CH2:34]O[CH2:32][CH2:31]1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([CH:7]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:8]2)([OH:6])[C:31]([CH2:22][CH3:23])([CH2:30][CH3:34])[CH3:32])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)c2cc(F)cc(F)c2)C1
Reactant: C1CCOC1
Reactant: CC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(C)(CC)C(O)(c1cc(F)cc(F)c1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
To a solution of 3.07 g (10.34 mmol) of tert-butyl 3-(3,5-difluorobenzoyl)azetidine-1-carboxylate in 20 mL of THF, 36.19 mL (36.19 mmol) of tert-butyl magnesium chloride was added and stirred for 3.5 h at −78° C. To the solution was added 8 mL of aq. NH4Cl and the solution was filtered to remove the solid. The filtrate was washed with ether. The combined organic layer was concentrated to remove solvents and residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound; 1H-NMR(CDCl3) δ 0.897 (s, 9H), 1.425 (s, 9H), 2.234(br, 1H), 3.25 (m, 1H), 3.55 (m, 1H), 3.71 (t, J=8.9 Hz, 1H), 3.97 (t, J=8.4 Hz, 1H), 4.17(m ,1H), 6.53-6.74 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.C(O)(=O)C>O1CCOCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]2[NH:13][CH2:12][C:11]3[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:9][CH:10]=3)[NH:1]2)[CH:16]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)c1cccc(CN)c1N
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1NC(c1cccnc1)NC2
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
A mixture of methyl 2-amino-3-(aminomethyl)benzoate (5.0 g, 27.7 mmol), nicotinaldehyde (3.0 g, 27.7 mmol) and acetic acid (2.0 mL) in dioxane (50 mL) was stirred in the microwave for 20 minutes. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (10% methanol in CH2Cl2) to give methyl 2-(pyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-8-carboxylate (4.0 g, 53% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])C)[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[C:17](Cl)(=[O:19])C.COC1C=CC=C2C=1CC[C@H](C)N2.BrC1C=CC2N(C(C3CC3)=O)[C@@H](C)CCC=2C=1O.C1(C(Cl)=O)CC1>>[Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:19][CH3:17])=[O:14])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)Cl
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: COc1cccc2c1CC[C@H](C)N2
Agent: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Agent: O=C(Cl)C1CC1
Product: COC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C

Procedure:
Methyl (S)-6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized following the procedure for (5)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone substituting methyl chloroformate for acetyl chloride in Step 5 or from (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline following the procedure used for the synthesis of (2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol, substituting methyl chloroformate for cyclopropanecarbonyl chloride. MS: (ES, m/z): 300, 302 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=O.[OH-:21].[Na+].Cl>ClCCl>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[C:12]([OH:21])=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: [OH-]
Reactant: Nc1ncccc1C=O
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc2cccnc2nc1-c1ccccn1
Reaction time: 48 h
Yield: 13 %

Procedure:
2-Amino-pyridine-3-carbaldehyde (200 mg) and 2-(bromoacetyl)pyridine hydrobromide (506 mg) were suspended in a 5 N aqueous sodium hydroxide solution (1 ml), and the suspension was hermetically sealed and, in this state, was allowed to stand for 2 days. The reaction solution was neutralized with 10% hydrochloric acid, dichloromethane was then added thereto, and the mixture was extracted. The dichloromethane layer was washed with water and saturated brine and was dried over magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give 2-pyridin-2-yl-[1,8]naphthyridin-3-ol (48 mg, yield 13%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]1([CH3:20])[CH2:19][C:17](=O)[CH2:16][C:14](=[O:15])[CH2:13]1.[NH2:21]/[C:22](/[CH3:30])=[CH:23]\[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>C(O)(C)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:16]2[C:14](=[O:15])[CH2:13][C:12]([CH3:11])([CH3:20])[CH2:19][C:17]=2[NH:21][C:22]([CH3:30])=[C:23]1[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: C/C(N)=C/C(=O)OC(C)C
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CC(C)O
Product: CC1=C(C(=O)OC(C)C)C(c2cccc(Cl)c2Cl)C2=C(CC(C)(C)CC2=O)N1
Temperature: 25 °C

Procedure:
3.50 g (20 mmol) of 2,3-dichlorobenzaldehyde, 2.80 g (20 mmol) of dimedone and 2.86 g (20 mmol) of isopropyl 3-aminocrotonate are dissolved in 100 ml of isopropanol and stirred under reflux for 5 h. The product precipitates. The mixture is treated with 50 ml of water and cooled to RT. The product is filtered off with suction and washed successively with isopropanol, ethanol and ether. 6.6 g (78% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1cccc(N=C=O)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1cccc(NC(=O)Nc2ccc(OC)c(-c3c(Br)cnn3C)c2)c1
Yield: 91.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.12 mmol) was treated with 3-methoxyphenyl isocyanate (0.018 g, 16.0 μL, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 72 (0.047 g, 0.11 mmol, 94%) as a solid film. LCMS m/z (%)=431 (M+H79Br, 100), 433 (M+H81Br, 93). 1H NMR (400 MHz, acetone-d6) δ: 8.13 (s, 2H), 7.68 (d, J=8.9 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.12 (d, J=7.3 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].C[O:7][C:8](=[O:28])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](S(=O)(=O)NC2C=CC=C(Br)C=2)[CH:12]=1.Cl>>[Cl:1][S:2]([C:14]1[CH:15]=[CH:16][C:11]([CH:10]=[CH:9][C:8]([OH:28])=[O:7])=[CH:12][CH:13]=1)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc(Br)c2)c1
Agent: Cl
Product: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
To neat chlorosulfonic acid (5.3 ml, 80 mmol) at 0–5° C. temperature slowly cinnamic acid (41) (1.47 g, 10 mmol) was added. As the reaction proceeded hydrogen chloride gas evolved. The reaction mixture was stirred successively at 0° C. for 1 hour, at ambient temperature for 2 hours and at 40–42° C. for 2 hours. The dark, viscous syrup was poured onto ice, the precipitated solid was filtered and washed with water. The title compound (0.5 g, 20%) as a white solid was obtained. 1H NMR (DMSO-d6, HMDSO), δ 6.55 (1H, d, J=16 Hz); 7.58 (1H, d, J=16.0 Hz); 7.65 (4H, s); 8.15 (1H, br s).