Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH2:32]([C:34]1[O:35][CH:36]=[C:37](/[CH:39]=[CH:40]/[C:41]2[C:42]([OH:52])=[N:43][N:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:45]=2)[N:38]=1)[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:32]([C:34]1[O:35][CH:36]=[C:37](/[CH:39]=[CH:40]/[C:41]2[C:42]([O:52][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:43][N:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:45]=2)[N:38]=1)[CH3:33]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)co1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(CC)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.48 g), 4-[(E)-2-(2-ethyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol.hydrochloride (1.07 g), potassium carbonate (1.05 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4-1:3, v/v) to give ethyl {4-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (480 mg, yield 20%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 155-157° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:22]Br>C(O)(=O)C>[NH2:1][C:2]1[C:3]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:4][C:5]([Br:22])=[CH:6][N:7]=1
Reactant: Nc1nccnc1C(=O)c1cccnc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(Br)nc1C(=O)c1cccnc1
Reaction time: 1 h

Procedure:
(3-Amino-pyrazin-2-yl)-pyridin-3-yl-methanone (1.00 g, 4.99 mmol) is dissolved in glacial acetic acid (10 ml). Na2CO3 (0.583 g, 5.49 mmol) is added. After evolution of gas has finished, a solution of bromine (0.192 ml, 3.74 mmol) in acetic acid (5 ml) is added dropwise. Na2CO3 (0.583 mg, 5.49 mmol) is added, followed by a second solution of bromine (0.192 ml, 3.74 mmol) in acetic acid (5 ml). The resulting orange suspension is left to stir for 1 hour. The reaction is quenched by pouring onto ice water (150 ml), and the orange solid formed is collected by filtration, washed with water and dried in vacuo at 40° C. overnight to yield the title compound. [M+H]+ 279.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1(Cl)[N+:14]([O-])=O)[C:6]#[N:7])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:3][C:4]([C:5]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:21])[NH:14][C:6]=1[NH2:7])=[O:18])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C#N)C1C=CC=CC1(Cl)[N+](=O)[O-]
Product: CCOC(=O)c1c(N)[nH]c2cccc(Cl)c12

Procedure:
The synthesis route used to prepare analogues Is described in Scheme 3. (2-ethoxycarbonylmethyl-phenyl)-acetic acid ethyl ester 2 (71%) was obtained by hydrolysis of 1,2-phenylenediacetonitrile 1 with concentrated H2SO4. Compound 2 with sodium ethoxide in ethanol gave compound 3 (61%), which further reacted with guanidine in the presence of potassium t-butoxide under 150° C. in a microwave reaction to give compound 4 (34%). To access target compounds, first, compound 4 was tried to turn the 4-oxo to 4-chloro, which traditionally Is adopted in synthesizing 4-anilino substituted analogues. However, because of the lower aromaticity of the ring, the chlorination did not run well under known reaction conditions, Compound 4 was decomposed when refluxed with POCl3. Thus, the 4-oxo was converted to 4-sulfonate, which is a good leaving group for SNI reaction. Compound 5 was obtained when treating compound 4 with the 4-nitrobenzenesulfonyl chloride (36%). The target compound 6 with different substitution on the phenyl ring was obtained when refluxing compound 5 with corresponding aniline for 12-18 h.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[C:4]([F:13])[CH:3]=1.II.[CH3:16][C:17]([S:20](/[N:22]=[CH:23]/[C:24]1[O:28][CH:27]=[N:26][CH:25]=1)=[O:21])([CH3:19])[CH3:18]>C1COCC1.C1(C)C=CC=CC=1>[F:13][C:4]1[CH:3]=[C:2]([CH:23]([C:24]2[O:28][CH:27]=[N:26][CH:25]=2)[NH:22][S:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH:7]=[CH:6][C:5]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: CC(C)(C)S(=O)/N=C/c1cnco1
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Agent: II
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(c1ccc(OC(F)(F)F)c(F)c1)c1cnco1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene (582 g, 2247 mmol), Mg (54.6 g, 2247 mmol) and iodine in THF (10 mL) was heated at reflux for 2 h. The reaction was cooled to 0° C. and added to a solution of (E)-2-methyl-N-(oxazol-5-ylmethylene)propane-2-sulfinamide (300 g, 1498 mmol, step 1 of example 1) in toluene (10 mL) cooled to 0° C. The reaction was stirred at 0° C. for 30 min. The reaction was quenched with water and extracted with DCM. The organic layer was concentrated to afford crude N-((3-fluoro-4-(trifluoromethoxy)phenyl)(oxazol-5-yl)methyl)-2-methylpropane-2-sulfinamide (55) which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)=[CH:16][CH:15]=1)(=O)=O>>[C:29]1(/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][N:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)=[CH:19][CH:18]=3)[N:23]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1cc[nH]c1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCCn3cccc3)cc2)co1)\c1ccccc1
Yield: 57 %

Procedure:
In substantially the same manner as in Working Example 8, pyrrole was allowed to react with 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methansulfonate to give 2-[(E)-2-phenylethenyl]-4-[4-[3-(1-pyrrolyl)propyl]phenoxymethyl]oxazole. The yield was 57%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 108-109° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:3]=12.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:26]#[N:27])=[CH:20][CH:19]=1>CN(C=O)C>[C:26]([CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[N:10]=[C:9]2[CH2:11][CH2:12][CH3:13])=[CH:19][CH:20]=1)#[N:27]
Reactant: N#CC(Cc1ccc(CBr)cc1)c1ccccc1
Reactant: CCCc1nc2nccc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(CC(C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
To a solution of 7-methyl-2-propylimidazo [4,5-b]pyridine (106 mg, 0.61 mmol) in DMF (3 mL) was added NaH (0.91 mmol). The suspension was stirred at room temperature for 30 minutes, at which time a solution of the product of Step D (200 mg, 0.667 mmol) in DMF (2 mL) was added. The mixture was stirred for 2 hours at room temperature, quenched with water, and then concentrated in vacuo. The residue was partitioned between water and EtOAc, and the combined organic layers were washed with brine, dried (K2CO3), filtered, and evaporated in vacuo. The residue was chromatographed on a silica gel flash chromatography column eluted with 50% ethyl acetate/hexane to afford 46 mg (19%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:49])[N:29]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[C:43]1([S:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:32][CH2:31][N:29]([CH3:30])[C:28](=[O:49])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(=[O:42])=[O:41])[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CN(CCc1ccccc1NS(=O)(=O)c1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1NS(=O)(=O)c1ccccc1
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
At 0° C., trifluoroacetic acid (4 ml) was given to a solution of N-((1R)-1-{N-[2-(2-(phenylsulfonylamino)phenyl)ethyl]-N-methylcarbamoyl}2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (647 mg, 1.08 mmol) in dichloromethane (4 ml). The reaction mixture was stirred for 2.5 h at. 0° C. It was diluted with dichloromethane (15 ml). A saturated aqueous solution of sodium hydrogen carbonate (15 ml) was added. Solid sodium hydrogen carbonate was added until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (2×15 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (20 g), using dichloromethane/methanol/25% aqueous ammonia 200:10:1 as eluent to give 434 mg of (2R)-N-[2-(2-(phenylsulfonylamino)phenyl)ethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.Cl.[NH2:18][CH:19]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][C:23]([PH:26](=[O:28])[OH:27])=[CH:22][CH:21]=1>S(Cl)(Cl)=O.ClCCl>[OH:1][C:2]1[C:7]([C:8]([NH:18][CH:19]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:20]2[CH:25]=[CH:24][C:23]([PH:26](=[O:27])[OH:28])=[CH:22][CH:21]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: COc1ccc(C(N)c2ccc([PH](=O)O)cc2)cc1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(NC(=O)c2cnc(-c3cccnn3)nc2O)c2ccc([PH](=O)O)cc2)cc1
Reaction time: 3 h
Yield: 12 %

Procedure:
4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (545 mg, 2.5 mmol) in 5 ml of thionyl chloride was heated at reflux overnight. Then it was concentrated under vacuum and the residue was dissolved in 10 ml of dichloromethane. To the mixture was added 4-(amino(4-methoxyphenyl)methyl)phenylphosphinic acid hydrochloride (1-1-e, 782.5 mg, 2.5 mmol) and TEA (505 mg, 5 mmol) in 10 ml of dichloromethane at 0° C. The mixture was stirred for 3 hours and then it was washed with sat. NH4Cl. The organic layer was concentrated under vacuum and the residue was purified on prep-HPLC to provide the product 9-2 (150 mg, 12%). 1H NMR (CD3OD, 300 MHz,): δ 9.37 (m, 1H), 8.83 (s, 1H), 8.51 (m, 1H), 8.15 (m, 1H), 7.80 (m, 2H), 7.53 (m, 2H), 7.23 (m, 2H), 6.79 (m, 2H), 6.56 (s, 1H), 6.34 (s, 1H), 3.77 (s, 3H).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([Cl:27])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl.C(Cl)Cl>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([Cl:27])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(Cl)n3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(Cc1ccc(OCC(=O)O)cc1)N1CCOC(c2csc(Cl)n2)C1

Procedure:
0.55 g (0.0013 mol) of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-chloro-thiazol-4-yl)morpholine are stirred in 4 ml of methanol and 4 ml of 1N sodium hydroxide solution at room temperature for 10 minutes. The mixture is then neutralised with 4 ml of 1N hydrochloric acid, and the product is obtained by extraction with methylene chloride.
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.ICC>O1CCCC1>[CH2:1]([S:15][C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: Fc1ccc(S)cc1
Solvent: C1CCOC1
Solvent: CCI
Product: CCSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
Triethylamine (5.44 mL, 39 mmol) was added to a solution of 4-fluorobenzenethiol (5 g, 39 mmol) and iodoethane (3.78 mL, 46.8 mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred at ambient temperature for 2 hours and then filtered. The filtrate was concentrated, triturated with hexane, and dried under vacuum to afford the title compound (4.8 g, 76%).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:11]=2[CH:24]=1.Cl[C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[CH2:16]1[C:10]2[CH:9]=[CH:8][C:7]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:11]=2[CH2:12][CH2:13][CH2:14][N:15]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(Br)ccc2C1
Reactant: COC(=O)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCCN(C(=O)OC(C)(C)C)C2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
To a 50-mL round-bottom flask charged with THF (15 mL) cooled to −78° C. under an N2 atmosphere was slowly added tert-butyllithium (0.922 mL, 1.474 mmol, 1.6 M in pentane). At this temperature, tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (0.37 g, 1.134 mmol) in THF (4 mL) was added. The resulting solution was stirred at -78° C. for 10 min. To the reaction flask was quickly added methyl chloroformate (1.75 mL, 22.68 mmol), and the resulting mixture was stirred at −78° C. for 30 min then warmed to room temperature for 10 min. The solvent was evaporated under reduced pressure and the residue was partitioned between water (10 mL) and EtOAc (50 mL). After separation, the aqueous phase was extracted with EtOAc (2×15 mL), the combined organic phases were washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated. Flash column chromatography (EtOAc:hexanes, 0-10%) provided 2-tert-butyl 7-methyl 1,3,4,5-tetrahydro-2H-2-benzazepine-2,7-dicarboxylate (0.142 g, 41%) as a slightly yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.83-7.80 (m, 2H), 7.24 (d, J=7.6 Hz, 1H), 4.45 (br, 0.7H), 4.40 (br, 1.3 H), 3.90 (s, 3H), 3.68 (br, 2H), 3.00 (br, 2H), 1.78 (m, 2H), 1.37 (s, 9 H).
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].C(N(C(C)C)C(C)C)C.Br[CH2:22][CH:23]1[O:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25][CH2:24]1>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:22][CH:23]2[O:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][CH2:24]2)[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: COC(=O)C1=CCCNC1
Reactant: BrCC1COc2ccccc2O1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=CCCN(CC2COc3ccccc3O2)C1
Reaction time: 16 h
Yield: 74.3 %

Procedure:
First 11.1 g (50 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 22.6 g (175 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 11.45 g (50 mmol) of 2-bromomethylbenzo-1,4-dioxan (U.S. Pat. No. 2,366,102) in 100 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 50° and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The organic phases are washed with water and extracted by shaking with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 10.75 g (74.4%) of 1-(benzo-1,4-dioxan-2-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester are obtained in the form of a yellow oil. The 1-(benzo-1,4-dioxan-2-ylmethyl)-1,2,5,6-tetrahydropyridine- 3-carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and decomposes at 215°-217°.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[N:18][C:17]([C:23]([OH:25])=[O:24])=[C:16]2[OH:26]>CCOCC>[OH:26][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([NH:12][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH:14]=2)[N:19]=[N:18][C:17]=1[C:23]([OH:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc2nnc(C(=O)O)c(O)c2c1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)Nc2ccc3nnc(C(=O)O)c(O)c3c2)cc1
Reaction time: 16 h

Procedure:
A solution of p-toluenesulphonyl chloride (7.0 g.) in ether (30 ml.) was added to a stirred solution of 6-amino-4-hydroxycinnolin-3-yl carboxylic acid (1.025 g.) in N-sodium hydroxide solution (15 ml.). The heterogeneous mixture was stirred vigorously for 16 hours. The aqueous phase was separated, washed with ether (2 × 25 ml.), and acidified to pH 2 with 5N-hydrochloric acid. The solid which separated was filtered off, washed with water and dried as much as possible on the filter. The product was purified by chromatography on a silica column (30 g., Kieselgel 60), eluted with a mixture of ethanol (15 parts by volume), chloroform (85 parts by volume) and formic acid (1 parts by volume), to give 4-hydroxy-6-(p-toluenesulphonylamino)cinnolin-3-yl carboxylic acid, m.p. 272°-273° C. EXAMPLE 16
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10]C)=O)=[N:6][CH:7]=1.[CH3:12][NH2:13]>CO.O1CCCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([NH:13][CH3:12])=[O:10])=[N:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)c1ncc(Br)cn1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 5-bromopyrimidine-2-carboxylate (94 mg, 0.43 mmol) was dissolved in a mixture of methanol (1 mL) and tetrahydrofuran (2 mL). An aqueous solution of methylamine (40%, 0.5 mL) was added. The reaction was stirred at room temperature for three days, and was evaporated to dryness in vacuo. The title compound was obtained as a white solid (94 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[CH:7][CH:6]=[CH:5]2.[H-].[Na+].I[CH3:16]>CN(C=O)C>[CH3:16][O:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH2:1])=[CH:3]2
Reactant: CI
Reactant: Nc1ccc2c(O)cccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2cc(N)ccc12
Reaction time: 1 h

Procedure:
To a solution of 6-aminonaphth-1-ol (1.0 g) in DMF (50 mL), NaH (60% in mineral oil, 0.17 g) was added, and the reaction was stirred for 1 hour. Iodomethane (0.39 mL) was added, and the reaction was stirred for another 1 hour. The reaction was then partitioned between NaHCO3 (aq., 150 mL) and EtOAc (100 mL), the layers separated, and the organic layer washed with brine, dried (Na2SO4) and concentrated. The crude reaction was purified over silica gel (gradient of EtOAc in heptane) to provide the title compound (0.8 g) as an orange oil:: 1H NMR (DMSO-d6) δ 7.81 (d, 1H); 7.16 (dd, 1H), 7.04 (d, 1H), 6.85 (dd, 1H), 6.75 (d, 1H), 6.53 (dd, 1H), 5.32 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]#[N:19])=[CH:7][C:6]=1[F:20].[CH:26]([NH2:29])([CH3:28])[CH3:27]>C(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]([NH:29][CH:26]([CH3:28])[CH3:27])=[NH:19])=[CH:7][C:6]=1[F:20]
Reactant: CC(C)N
Reactant: N#Cc1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Solvent: CCO
Product: CC(C)NC(=N)c1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of 5-[4-(2,5-dichloro-phenoxy)-3-fluoro-phenylamino]-3-hydroxy-isothiazole-4-carbonitrile (0.2 g) and isopropylamine (5 ml) in 20 ml of ethanol was placed into a high-pressure reaction apparatus and heated to 100° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was chromatographed by silica gel column (chloroform/methanol, 40:1) to give the desired product as a light yellow solid. MS: 454; 1H NMR (DMSO-d6, 300 MHz): δ 10.28 (brs, ½H, NH, D2O exchangeable), 9.62 (brs, 1H, NH, D2O exchangeable), 9.31 (brs, ½H, NH, D2O exchangeable), 8.57 (s, 1H, OH, D2O exchangeable), 7.88 (brs, 1H, NH, D2O exchangeable), 7.61 (d, 1H, J=8.7 Hz, ArH), 7.22 (dd, 1H, J=2.1, 8.7 Hz, ArH), 7.16 (t, 1H, J=8.7 Hz, ArH), 6.99 (dd, 1H, J=2.1, 12.6 Hz, ArH), 6.88 (d, 1H, J=2.1 Hz, ArH), 6.83 (dd, 1H, J=2.1, 8.7 Hz, ArH), 3.85 (m, 1H, CH), 1.20 (d, 6H, J=6.3 Hz, 2×CH3).
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[C:8]([Cl:11])[CH:9]=2)[C:4](=[O:13])[O:3]1.[O:14]1CCOCC1>Cl>[Cl:11][C:8]1[C:7]([Cl:12])=[CH:6][C:5]([C:4]([OH:3])=[O:13])=[C:10]([CH:2]=[O:14])[CH:9]=1
Reactant: C1COCCO1
Reactant: O=C1OC(Br)c2cc(Cl)c(Cl)cc21
Agent: Cl
Product: O=Cc1cc(Cl)c(Cl)cc1C(=O)O
Yield: 73 %

Procedure:
A suspension of 3-bromo-5,6-dichloro-3H-isobenzofuran-1-one (2.0 g) in 5% aqueous HCl (10 mL) and 80% aqueous dioxane (25 mL) was heated to reflux for 2 hours. The solvent was removed and the resulting residue re-dissolved in ethyl acetate, dried (magnesium sulfate) and concentrated. The resultant yellow solid was recrystallized from DCM/hexane to give the sub-title compound as a white solid (1.13 g, 73%). 1H NMR (400 MHz, CDCl3) δ 6.66 (0.84H, s), 7.95 (0.16H, s), 8.05 (0.84H), 8.12 (0.16H, s), 8.14 (0.84H, s), 8.41 (0.84H,), 10.41 (0.16H, s), 11.07 (0.16H, brd s) ppm.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=[O:6])[CH2:3][CH2:2]1.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Mg]Br.[NH4+].[Cl-].O>C1COCC1>[CH:1]1([CH2:4][CH:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[OH:6])[CH2:3][CH2:2]1
Reactant: Br[Mg]c1ccccn1
Reactant: O=CCC1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: OC(CC1CC1)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyclopropylacetaldehyde (1.00 g, 11.89 mmol, purchased from Beta Pharma, Inc., Branford, Conn.) in THF (15 mL) at 0° C. under N2 was added 2-pyridylmagnesium bromide (47.6 mL×0.25 M, purchased from Rieke Metals, Inc., Lincoln, Nebr.) dropwise over 15 min. The mixture was stirred at 0° C. after 30 min, allowed to warm to rt and stirred at rt for 3.5 hr. To the reaction mixture was added saturated aqueous NH4Cl solution (5 mL) followed by water (15 mL). The mixture was extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4. After removal of organic solvents, purification of the residue by flash chromatography on silica gel with 40-70% EtOAc/hexanes the title compound was obtained as a white solid. Mass Spectrum (ESI) m/z=164.1 (M+1).