Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].O[CH2:13][CH:14]([CH2:16]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]2[C:8]=1[CH:13]=[CH:14][CH:16]=[N:7]2
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c2cccnc12
Yield: 40.7 %

Procedure:
In a similar fashion using route 10 general procedure 20, 5-fluoro-2-nitroaniline (1.0 g, 6.4 mmol), glycerol (1.83 g, 19.86 mmol), 3-nitrobenzenesulfonic acid sodium salt (1.8 g, 8.33 mmol) and H2SO4/H2O (1.2 ml, 7:5) gave the title compound (500 mg, 60%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][C:2]([NH:13][C:14]([C:16]1[C:21](=[O:22])[C:20]([O:23][CH3:24])=[CH:19][N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[N:17]=1)=O)([CH3:12])[C:3](=[O:11])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+].C(O)(=O)C>O>[CH3:1][C:2]1([CH3:12])[C:3](=[O:11])[N:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([C:16]2[C:21](=[O:22])[C:20]([O:23][CH3:24])=[CH:19][N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[N:17]=2)=[N:13]1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)NC(C)(C)C(=O)Nc2ccccc2)c1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C2=NC(C)(C)C(=O)N2c2ccccc2)c1=O
Temperature: 25 °C
Yield: 27.1 %

Procedure:
A mixture of N-[1,1-dimethyl-2-oxo-2-(phenylamino)ethyl]-5-methoxy-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (142 mg), sodium acetate (74 mg) and acetic acid (1 mL) was irradiated with microwave at 120° C. for 2 hr. After cooling to room temperature, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (37 mg).
Reaction SMILES: [Cl:1][CH:2]([Cl:8])[CH:3]1[NH:7][CH2:6][CH2:5][O:4]1.C(N(CC)CC)C.[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>C(Cl)(Cl)Cl>[Cl:1][CH:2]([Cl:8])[CH:3]1[N:7]([C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])[CH2:6][CH2:5][O:4]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: ClC(Cl)C1NCCO1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(C(Cl)Cl)N1CCOC1C(Cl)Cl
Yield: 98.4 %

Procedure:
2nd part: By operating as in the second part of Example 13, but using 23.5 g (0.15 mole) of 2-dichloromethyl-1,3-oxazolidine, 18 g (0.18 mole) of triethylamine and 24.3 g (0.165 mole) of dichloroacetyl chloride in 200 ml of chloroform, after the removal of the chloroform by distillation under vacuum, 39.4 g (yield 98%) of crude 2-dichloromethyl-3-dichloroacetyl-1,3-oxazolidine is obtained.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=429.04.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(=S)=S>[C:14]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)(=[O:16])[CH3:15]
Reactant: c1ccc2c(c1)CCO2
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CCO2
Reaction time: 1 h

Procedure:
To a stirred solution of 12 g [100 mmole) 2,3-dihydrobenzofuran in 80 ml carbon disulfide was added in portions 30 g (225 mmole) anhydrous aluminum chloride. The mixture was heated at reflux and 18.9 ml (200 mmole) acetic anhydride was slowly added. Refluxing was continued for one hour after the addition was completed. Carbon disulfide was then removed by distillation and the residue was cooled in ice. Cracked ice (100 ml) was slowly added, the reaction mixture was acidified to pH 1 and diluted with water (100 ml) and extracted with ethyl ether (2×250 ml). The extracts were dried (Na2SO4) .and the ether evaporated. The residual oil was purified pn a column of silica gel (600 ml), eluting with 9:1 (v/v) hexane/ethyl acetate, then with a 4:1 (v/v) mixture of the same solvents, and finally with a 2:1 mixture. The product fractions were combined and evaporated to obtain the desired product as an oil; 1H-NMR(CDCl3)ppm(delta): 2.4 (s, 3H), 3.2 (t, 2H), 4.6 (t, 2H), 6.7 (d, 1H), 7.7 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.CCCCCCCCCC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCCCCC
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 56 %

Procedure:
To a mixture of 306 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 825 mg (5.51 mmol) of 2-cyclopropyl-6-methylphenol were added decane (2.76 g) and 327 mg (5.55 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 282 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 56%) and 4.3 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.9%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[H-].[Na+].Br[CH:24]1[CH2:27][CH2:26][CH2:25]1.CO>CN(C=O)C>[CH:24]1([N:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:20])[C:5]([C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][CH:10]=3)=[N:6]2)[CH2:27][CH2:26][CH2:25]1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: BrC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cn(C2CCC2)nc(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 1.5 h

Procedure:
Under an argon atmosphere, to a solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (2.0 g) in DMF (40 mL) was added under ice-cooling 60% sodium hydride (596 mg), and the mixture was stirred for 1.5 hr. Then, bromocyclobutane (1.05 mL) was added, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added methanol, and the mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) and further purified by HPLC to give the title compound (0.92 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH2:27]([N:29]([CH2:39][CH3:40])[CH2:30][CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH2:39]([N:29]([CH2:27][CH3:28])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([NH:36]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:37][CH:38]=1)[CH3:40]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CCN(CC)CCc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCN(CC)CCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-diethylamino-ethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C.[CH2:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1)[CH:23]=[CH2:24].[CH2:40]([O:48][C:49]1[CH:72]=[CH:71][C:52]([C:53]([O:55][C:56]2[CH:68]=[CH:67][C:66]3[C:65]4[C:60](=[CH:61][C:62](O)=[CH:63][CH:64]=4)[CH:59]([CH3:70])[C:58]=3[CH:57]=2)=[O:54])=[CH:51][CH:50]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>O.C(Cl)Cl>[CH2:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([O:37][C:62]2[CH:63]=[CH:64][C:65]3[C:66]4[C:58](=[CH:57][C:56]([O:55][C:53](=[O:54])[C:52]5[CH:51]=[CH:50][C:49]([O:48][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:72][CH:71]=5)=[CH:68][CH:67]=4)[CH:59]([CH3:70])[C:60]=3[CH:61]=2)=[O:36])=[CH:33][CH:32]=1)[CH:23]=[CH2:24]
Reactant: C=CCOCCCCOc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)Oc2ccc3c(c2)C(C)c2cc(O)ccc2-3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C=CCOCCCCOc1ccc(C(=O)Oc2ccc3c(c2)C(C)c2cc(OC(=O)c4ccc(OCCCCCCCC)cc4)ccc2-3)cc1
Temperature: 5 °C
Reaction time: 12 h
Yield: 22 %

Procedure:
Dimethylaminopyridine 0.01 g and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 0.8 g were added to a methylene chloride (50 ml) solution of 4-(4-allyloxybutyloxy)benzoic acid 0.84 g and 2-(4-octyloxybenzoyloxy)-7-hydroxy-9-methylfluorene (J1) 1.5 g while maintaining 5° C., and the mixture was further stirred at room temperature for 12 hours. Water 50 ml was added thereto, and the resulting organic layer was dried on anhydrous magnesium sulfate. A residue obtained by distilling the solvent off was refined by silica gel column chromatography to obtain 0.5 g of 2-[4-(4-allyloxybutyloxy)benzoyloxy]-7-(4-octyloxybenzoyloxy)-9-methylfluorene (J2).
Reaction SMILES: Cl[C:2]1[C:3]([F:24])=[CH:4][C:5]2[C:6]([CH:23]=1)=[N:7][C:8]1[N:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[F:24][C:3]1[C:2]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][C:6]2=[N:7][C:8]3[N:9]([C:19]([CH3:20])([CH3:21])[CH3:22])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)cc3nc21
Yield: 64.4 %

Procedure:
7-Fluoro-4-oxo-8-(1-piperazinyl)-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 5 but starting from 1.7 g of 8-chloro-7-fluoro-4-oxo-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4.3 g of piperazine in 20 cm3 of pyridine. The pure product is obtained after a single recrystallization from 20 cm3 of dimethylformamide. 1.25 g of 7-fluoro-4-oxo-8-(1-piperazinyl)-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are isolated in the form of a yellow solid melting at 90° C., solvated by 4.5% of water.
Reaction SMILES: OC[C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](CNC)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[C:20]([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:20][C:11]1[C:16]2[C:15](=[CH:10][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: CNCc1c2ccccc2c(CO)c2ccccc12
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc2cc3ccccc3cc12
Yield: 103.4 %

Procedure:
10-(hydroxymethyl)-9-((methylamino)methyl)anthracene (0.800 g, 3.18 mmol) and K2CO3 (0.56 g, 4.05 mmol) were taken up in 15 mL acetonitrile. A solution of 2,2-dimethylpropane-1,3-diyl(o-(bromomethyl)phenyl)boronate 3 (1.00 g, 3.44 mmol) in 5 mL acetonitrile was added and the mixture was refluxed under nitrogen for 24 h. The mixture was filtered hot on a sintered-glass frit and upon cooling, a yellow solid precipitated. The resulting solid was triturated with acetonitrile/water (4:1, v/v), filtered on a sintered-glass frit and vacuum dried to yield 11 as a bright yellow solid (0.632 g, 51.6% yield): 1H NMR (300.13 MHz, CD3OD) δ2.58 (s, 3H), 4.58 (s, 2H), 5.22 (s, 2H), 5.61 (s, 2H), 7.62 (m, 6H), 7.80 (m, 2H), 8.18 (m, 2H), 8.58 (m, 2H); 13C-{1H} NMR (75.4 MHz, CD3OD) δ136.9, 136.2, 135.9, 132.9, 132.7, 131.4, 129.9, 128.3, 127.1, 126.8, 126.5, 124.9, 124.1, 63.8, 57.1, 50.9, 40.7.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O-:20])=O)[CH2:3]1.[Li+].Cl.[NH2:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)C[CH2:25]1>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C@@H:4]([C:18]([NH:23][C@H:24]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH3:25])=[O:20])[CH2:3]1
Reactant: O=C([O-])[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2C[C@@H](O)CN2Cc2cccc(C(F)(F)F)c2)cc1
Yield: 42.3 %

Procedure:
The title compound (D35) (10.3 mg) was prepared according to the general procedure for amides preparation starting from lithium (2R,4R)-4-hydroxy-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D15) (11.7 mg, 0.054 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (27.2 mg, 0.054 mmol).
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].Cl[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:8]=1.O>CN(C)C=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:9]2[N:8]=[C:7]([O:2][CH3:1])[CH:12]=[C:11]([CH3:13])[N:10]=2)=[CH:16][CH:17]=1
Reactant: Cc1cc(Cl)nc(Nc2ccc(Cl)cc2)n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)nc(Nc2ccc(Cl)cc2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A 28% methanol solution of sodium methylate (1.5 g) was added to a solution of 1.5 g of 4-chloro-2-(4-chloroanilino)-6-methylpyrimidine in 50 ml of dimethylformamide and the mixture was stirred for 2 hours at 70° C. After completion of the reaction, the reaction mixture was poured into water, extracted with 150 ml of toluene, washed with water, dried over Glauber's salt, and the toluene layer was concentrated by evaporation. The residue was purified by silica gel column chromatography to obtain 1.3 g (yield: 88%) of 2-(4-chloroanilino)-4-methoxy-6-methylpyrimidine having a melting point of 101°-103° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7]C(O)=O)=[CH:4][CH:3]=1.C1(C=CC(O)=CC=1)O.N12CCCN=C1CCCCC2>CS(C)=O>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=Cc1ccc(O)cc1
Temperature: 135 °C

Procedure:
In a 1-liter sulfonating flask equipped with mechanical stirrer, reflux condenser and nitrogen delivery line, 300 ml of dimethyl sulfoxide are added to 150 g (0.91 mol) of 4-hydroxycinnamic acid, 6 g (54 mmol) of hydroquinone and 6 g (39 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture is then heated at 135° C. for 31/2 hours. After cooling, the mixture is poured onto ice and extracted three times with 500 ml of diethyl ether, and the organic phase is washed five times with 100 ml of water, dried over magnesium sulfate and concentrated. The resulting oil is recrystallised twice from n-hexane to yield 69.07 g (0.58 mol, 63% of the theoretical yield) of 4-hydroxystyrene in the form of a white powder (m.p. 68° C.).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15].B(F)(F)F.[CH3:21]COCC>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]([O:16][CH3:21])=[O:15]
Reactant: COc1ccc2ccc(C(=O)O)c(O)c2c1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)c1ccc2ccc(OC)cc2c1O
Temperature: 0 °C
Yield: 92.3 %

Procedure:
A suspension of 6.2 g (0.028 mole) of 1-hydroxy-7-methoxy-2-naphthalenecarboxylic acid in 75 ml of methanol under a nitrogen atmosphere was treated over 15 minutes with 15.0 ml (17.3 g; 0.12 mole) of boron trifluoride etherate. The mixture was stirred at reflux for 45 hours, cooled, and added slowly to 500 ml of ice cold 5% aqueous sodium bicarbonate solution. The precipitated product was filtered, and washed with water to yield 6.0 g (92% yield) of the ester, mp 80°-83°, suitable for further synthetic use. A sample purified by chromatography (silica gel, dichloromethane elution) was analytically pure, mp 79°-81° (a mp of 81°-82° is given by M. E. Alonso, A. W. Chitty, S. Pekerar, and M. de L. Borgo, J. Chem. Soc. Chem. Comm., 1542 (1984).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O.O>O1CCOCC1>[C:18]([O:17][C:15]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:13])[N:12]=2)[CH2:6][CH2:5]1)=[O:14])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Oc1cccc(N2CCNCC2)n1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(O)n2)CC1
Temperature: 75 °C

Procedure:
To a stirring solution of 6-piperazin-1-yl-pyridin-2-ol (0.6 g, 3.30 mmol—Pavia, M. R., Taylor, C. P., Hershenson, F. M., Lobbestael, S. J. J. Med. Chem. 1987, 30(7), 1210) in 1,4-dioxane (15 ml) was added t-BOC2O (0.80 g, 3.68 mmol) and H2O (3 ml). The reaction mixture was heated at 75° C. for 8 h and cooled to RT. The heterogenous mixture was filtered and concentrated. Purification by flash silica gel chromatography afforded the title compound as a red solid, 0.90 g (97%). MS (ESI) 280.4 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](O)=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:17])=O>CN(C=O)C>[Cl:17][C:8]1[C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2c(O)ncnc2c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Yield: 70 %

Procedure:
A mixture of 7-nitroquinazolin-4-ol (3.4 g, 17.79 mmol), thionyl chloride (20 mL), and DMF (0.5 mL) was refluxed for 48 h. After the mixture was cooled, excess thionyl chloride was removed by evaporation and the residue was azeotroped with toluene to afford 2.61 g (70%) of 4-chloro-7-nitroquinazoline as a yellowish solid.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].CI.[C:10](O)(=[O:12])[CH3:11]>[Pd].C(OC=C)(=O)C>[C:1]([O:4][CH:5]([O:7][C:10](=[O:12])[CH3:11])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CI
Solvent: C=COC(C)=O
Product: CC(=O)OC(C)OC(C)=O
Reaction time: 1.5 h

Procedure:
Into an autoclave were charged 135 g of acetic anhydride, 15 g of methyl iodide and 4.5 g of palladium (5%) supported on barium sulfate (Kawaken Finechemical Co.). The reaction was effected for 90 minutes in the same way as in Example 9. GC analysis showed that 0.415 g of vinyl acetate and 14.0 g of ethylidene diacetate were formed with considerable amount of acetic acid.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:25]([O:32][C:33]([CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:25]([O:32][C:33]([CH:35]1[CH2:39][CH2:38][N:37]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])=[N:15][CH:14]=2)[CH2:36]1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: O=C(OCc1ccccc1)C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: O=C(OCc1ccccc1)C1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)C1
Yield: 49.6 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (67 mg. 0.20 mmol), pyrrolidine-3-carboxylic acid benzyl ester hydrochloride (50 mg, 0.25 mmol) and sodium triacetoxyborohydride (55 mg, 0.26 mmol) to afford 52 mg (50%) of the desired product after purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([OH:16])=O)[NH:12][N:13]=1.O.[NH2:18][NH2:19]>CO.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([NH:18][NH2:19])=[O:16])[NH:12][N:13]=1
Reactant: NN
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: NNC(=O)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Yield: 86.5 %

Procedure:
In methanol (20 ml), 5-(2,4-dichlorophenyl)-2H-pyrazole-3-carboxylic acid (1.00 g) was dissolved, and 6 drops of concentrated sulfuric acid was added thereto. The mixture was heated under reflux for 19 hours. After the mixture was allowed to cool, hydrazine monohydrate (0.97 g) was added to the mixture, and the resulting mixture was heated under reflux for 16 hours. The mixture was concentrated under a reduced pressure, and water was added thereto. The precipitated crystal was separated by filtration, washed with water, and dried to give the title compound (912 mg, 87%) as a white powder.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([N+:26]#[N:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(O)C.O>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26]/[N:27]=[C:8](\[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])/[C:9]([O:11][CH3:12])=[O:10])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: N#[N+]c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)CC(=O)/C(=N\Nc1ccc(Cl)c(Cl)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a mixture of dimethyl 3-oxopentanedioate (3.48 g, 20 mmol) in ethanol (12 mL) and water (40 mL) at room temperature was added sodium acetate (12.0 g, 146 mmol), and was followed by the addition of 3,4-dichlorobenzenediazonium solution (20 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The product was collected by filtration, then washed with water (˜50 mL) and dried overnight under reduced pressure to yield 6.776 g (93%) of (E)-dimethyl 2-(2-(3,4-dichlorophenyl)hydrazono)-3-oxopentanedioate as a yellow solid. MS (ESI) 347 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1>CO.[Pd].O>[CH3:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Cc1ncccc1CC(=O)O
Reaction time: 3 h

Procedure:
The residue including benzyl 2-(2-methyl-3-pyridyl)acetate obtained in Preparation 29-(2) was dissolved in methanol (5 ml), and 10% palladium on carbon was added thereto. The mixture was stirred under hydrogen atmosphere for 3 hours. The reaction mixture was diluted with water and washed with ethyl acetate. The solvent was removed in vacuo to give 2-(2-methyl-3-pyridyl)acetic acid (90 mg).