Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10](=[O:11])[C:9]2([CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12]2)[N:8](C(OC(C)(C)C)=O)[CH2:7][C@H:6]1[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)(O)=[O:2].[NH2:33][C:34]1[CH:35]=[C:36]2[C:49](=[CH:50][CH:51]=1)[CH2:48][C@@:38]1([C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]1=[O:47])[CH2:37]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[F:31][C:29]1[CH:30]=[C:25]([C@H:6]2[N:5]([CH2:4][C:1]([NH:33][C:34]3[CH:35]=[C:36]4[C:49](=[CH:50][CH:51]=3)[CH2:48][C@@:38]3([C:46]5[C:41](=[N:42][CH:43]=[CH:44][CH:45]=5)[NH:40][C:39]3=[O:47])[CH2:37]4)=[O:2])[C:10](=[O:11])[C:9]3([CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12]3)[NH:8][CH2:7]2)[CH:26]=[C:27]([F:32])[CH:28]=1
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C2(COCCOC2)NC[C@H]1c1cc(F)cc(F)c1)Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21

Procedure:
0.114 g (0.25 mmol) tert-butyl (R)-4-carboxymethyl-3-(3,5-difluoro-phenyl)-5-oxo-8,11-dioxa-1,4-diaza-spiro[5.6]dodecane-1-carboxylate were stirred overnight at RT with 67.9 mg (0.27 mmol) (S)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 63.3 mg (0.33 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 44.6 mg (0.33 mmol) HOBT, 35 μl (0.25 mmol) TEA and 1.5 ml DMF. The solvent was spun off and the residue was stirred with 15 ml of a methanolic hydrochloric acid (1.25N) 1 h at 50° C. The reaction mixture was concentrated by rotary evaporation and the residue was purified by PR-HPLC. The product-containing fractions were concentrated by rotary evaporation and the residue was triturated with diisopropylether. After suction filtering the solid was washed with diisopropylether and dried.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:6].[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C)C=O.C(OCC)(=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:5]([C:4]1[CH:3]=[C:2]([CH:17]=[CH:16][CH:15]=1)[O:1][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:6]
Reactant: O=C(NCc1ccccn1)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)NCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
23.8 g (0.10 mol) of 3-hydroxy-N-(pyridin-2-ylmethyl)-benzamide (stage B of Example 42) are added portionwise to the suspension of 4.5 g (0.10 mol) of sodium hydride (55% dispersion in oil) in 400 ml of N,N-di-methylformamide at 0° C. under argon, followed, after 10 minutes, by 15.4 ml (0.10 mol) of tert-butyl 2-bromo-acetate. The mixture is stirred at ambient temperature for 1 hour. The reaction medium is diluted with ethyl acetate and extracted with water. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The white solid is taken up in diisopropyl ether, filtered and dried, to give 26.3 g (74%) of a beige powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:26](O)=[O:27])=[N:22][N:23]([CH3:25])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH3:25])[N:22]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: Cn1cc(Cl)c(C(=O)O)n1
Product: Cn1cc(Cl)c(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)n1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound as a colorless amorphous material. MS (ISP): m/z=402.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH2:10]O)[C:3]=1[OH:12].ClCCl.CS(Cl)(=O)=O>C(N(CC)CC)C>[Br:1][C:2]1[C:3]2[O:12][CH2:10][CH2:9][C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OCCc1cc(Cl)cc(Br)c1O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1cc(Br)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a mixture of 2-bromo-4-chloro-6-(2-hydroxyethyl)phenol (99.8 mg, 0.397 mmol), triethylamine (0.40 mL, 2.9 mmol), and dichloromethane (4 mL) at 0° C. was added methanesulfonyl chloride (56.0 μL, 0.724 mmol). The reaction was stirred at 0° C. for 1.5 hours, at which point additional methane sulfonyl chloride (10 μL) was added and the reaction mixture warmed to room temperature. After stirring overnight, the reaction mixture was re-cooled to 0° C. and triethylamine (0.2 mL) and methanesulfonyl chloride (15 μL) were added. After two hours the reaction mixture was partitioned between ethyl acetate and water, and the organic layer washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 30% ethyl acetate in heptanes) to yield 40.0 mg (40%) of 7-bromo-5-chloro-2,3-dihydrobenzofuran. 1H NMR (400 MHz, CDCl3) δ: 7.26 (d, 1H), 7.09 (d, 1H), 4.67 (t, J=8.8, 2H), 3.30 (t, J=8.8, 2H).
Reaction SMILES: [OH-].[Li+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[C:11](=[O:13])[CH3:12].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1.Cl>C1COCC1>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:3][C:4]3[C:5]([C:11](=[O:13])[CH:12]=2)=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=3)=[CH:17][CH:16]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(Cl)cc2)oc2cccc(O)c12
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (51 mmol, 4 equivalents) is added in one portion to a well-stirred solution of 2′,6′-dihydroxyacetophenone (12.8 mmol) in dry THF (40 ml) under an argon atmosphere at −78° C. The reaction mixture is stirred at −78° C. for one hour and subsequently at −10° C. for two hours. After the mixture has been re-cooled to −78° C., a solution of 4-chlorobenzoyl chloride (13.97 mmol) in THF (20 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (400 g) and concentrated HCl (16 ml) and extracted with dichloromethane (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (100 ml) and sulfuric acid (0.5 ml) are added to the residue, and the mixture is heated at 95–100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised in methanol, giving 4′-chloro-5-hydroxyflavone. 1H NMR (250 MHz, CDCl3): δ=6.7–8.0 (m, 7H), 12.5 (s, 10 H); EI-MS (70 eV) m/e (rel. abund.)=272; UV (2-propanol): λ=213 nm, 301 nm, 275 nm, 338 nm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:27][C@@H:28]1[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]1)(=O)=O>CN(C=O)C>[CH3:33][C:30]1([CH3:34])[O:29][C@H:28]([CH2:27][O:14][C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:32][O:31]1
Reactant: CC1(C)OC[C@@H](COS(=O)(=O)C(F)(F)F)O1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)O1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
A slurry of 3-nitro-5-(trifluoromethyl)phenol (0.658 g, 3.17 mmol), cesium carbonate (3.10, 9.52 mmol) and [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl trifluoromethanesulfonate (1.00 g, 3.49 mmol) in DMF (10 mL) was heated at 60° C. for 56 h. The reaction mixture was allowed to cool to rt and filtered. The filtrate was diluted with EtOAc and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (4R)-2,2-dimethyl-4-{[3-nitro-5-(trifluoromethyl)-phenoxy]methyl}-1,3-dioxolane (770 mg, 75%) of as pale yellow oil. 1H NMR (400 MHz,CDCl3, HCl salt) δ: 8.10 (s, 1H), 7.94-7.97 (m, 1H), 7.51 (s, 1H), 4.49-4.56 (m, 1H), 4.09-4.23 (m, 3H), 3.92 (q, 1H), .1.45 (s, 3H), and 1.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][CH:11]([OH:15])[C:10]2=[O:16])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:23][CH2:24][C:25](Br)=[O:26]>ClCCl>[Br:23][CH2:24][C:25]([O:15][CH:11]1[CH2:12][C:13](=[O:14])[N:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:10]1=[O:16])=[O:26]
Reactant: O=C(Br)CBr
Reactant: O=C1CC(O)C(=O)N1Cc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CBr)OC1CC(=O)N(Cc2ccc(Cl)nc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
1.34 g (5.56 mmol) of 1-[(6-chloropyridin-3-yl)methyl]-3-hydroxypyrrolidin-2,5-dione (XI-1a) and 674 μl (8.34 mmol) of pyridine are dissolved in 15 ml of dichloromethane, and 1.12 g (5.56 mmol) of bromoacetyl bromide are added at 0° C. The mixture is stirred at room temperature for 30 minutes, and ice-water is then added. The organic is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture dichloromethane:methanol (97:3) gives 1.44 g (55% of theory) of 1-[(6-chloropyridin-3-yl)methyl]-2,5-dioxopyrrolidin-3-yl bromoacetate.
Reaction SMILES: N[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[BrH:12].N([O-])=O.[Na+]>O.[Cu]Br>[Br:12][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1cccc(C)c1N
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cccc(C)c1Br
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a solution of 1-(2-amino-3-methylphenyl)ethanone (Helv. Chim. Acta; EN; 62, 1979, 271-303) (850 mg, 5.7 mmol) in hydrobromic acid (9 ml, 5.7 mmol) and water (6 ml), at 0° C., was added aqueous sodium nitrite solution (503 mg, 7.3 mmol) and the mixture was stirred for 15 min. This mixture was added to copper (I) bromide (899 mg, 6.3 mmol) in hydrobromic acid (9 ml, 5.7 mmol) at 60° C. and the reaction mixture was heated at 95° C. for a further 30 min. After cooling, the mixture was poured into an ice/water slurry and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and concentrated in vacuo. To the residue was added ethyl acetate:cyclohexane [1:4] and the solution was filtered through silica. The filtrate was concentrated in vacuo to give the title compound (1.06 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH3:25][O:26][C:27](=[O:41])[CH:28]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30].CCCCCCC>C1C=CC=CC=1>[CH3:32][O:31][C:29](=[O:30])[CH:28]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:38][CH:39]=1)[C:27]([O:26][CH3:25])=[O:41]
Reactant: COC(=O)C(Cc1ccc(O)cc1)C(=O)OC
Reactant: OCCOCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: COC(=O)C(Cc1ccc(OCCOCc2ccccc2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.5 %

Procedure:
Under a nitrogen atmosphere, 2-benzyloxyethanol (30.4 g, 0.2 mol), tributylphosphine (50.4 g, 0.2 mol) and 2-(4-hydroxy-benzyl)-malonic acid dimethyl ester (example 1b) (42.9 g, 0.18 mol) were successively dissolved in dry benzene (1.5 L). Solid azodicarboxylic dipiperidide (ADDP) (40.4 g, 0.2 mol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (0.5 L) was added and the precipitate was filtered off. After evaporation of the solvent the product was chromatographed eluting with heptane graduated with ethyl acetate to give 64.0 g (96%) of 2-[4-(2-benzyloxy-ethoxy)-benzyl]-malonic acid dimethyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22](O)=[O:23])[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:47]([CH2:49][NH2:50])[OH:48].O>ClCCl>[OH:48][CH2:47][CH2:49][NH:50][C:22]([C:9]1[C:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:14][C:15]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=2[CH:8]=1)=[O:23]
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1nc2c3c(c(C(=O)NCCO)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Reaction time: 64 h
Yield: 15.6 %

Procedure:
To a suspension of 0.3 g (0.93 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred for 64 h at room temperature. 284 μl (4.7 mmol) Ethanolamine were added and the mixture was stirred for 24 h at room temperature. The reaction was poured into water and the precipitate filtered off. The residue was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to afford 53 mg (17%) of the title compound as a yellow solid. m.p. 228°-229° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)cc1
Reactant: c1nc[nH]n1
Product: Fc1ccc(CNc2nc(-n3cncn3)nc3sc4c(c23)CCCC4)cc1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:22].C(Cl)Cl.C([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=O)C>C(N(CC)CC)C>[C:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:22])=[C:2]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[N:11]=3)[C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)c1cn(-c2ccccc2)c2nc(Cl)c(F)cc2c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(-c2ccccc2)c2nc(N3CCNCC3)c(F)cc2c1=O

Procedure:
Alternately, the title compound is prepared as follows: To a solution of 1.6 g. of compound (III) (R1 =C2H5, R=phenyl, X=Cl) (product of 1(c) in 50 ml. of methylene chloride is added 1 ml. of triethylamine and 710 mg. of N-acetylpiperazine. After heating for 2 hours, the solvent is washed with 50 ml. of 1N HCl solution and then with water. The methylene chloride solution is dried and evaporated to dryness, yielding 2.1 g. of compound (I) ##STR14##
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8]([Cl:20])=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Solvent: c1ccccc1
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Yield: 83 %

Procedure:
A stirring mixture of 68.2 g (0.29 mole) of 3,5-diacetoxybenzoic acid and 21 ml (0.29 mole) of thionyl chloride in 150 ml of dry benzene was heated in an oil bath at 80°-90° C. for 2 hours. After cooling the benzene was removed in vacuo to leave 3,5-diacetoxybenzoyl chloride as a tan, solid which was recrystallized from cyclohexane as colorless crystals, mp 87°-89° C., 61.8 g (83% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C.O1CCCC1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:21])=[CH:13][CH:14]=1
Reactant: O=C(CCCc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(CCCC(=O)c2ccc(F)cc2)cc1
Yield: 77.7 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-(4-nitrophenyl)butan-1-one (0.5 g, 1.7 mmol) and 10% palladium on carbon (0.06 g) in ethyl acetate (15 mL) and tetrahydrofuran (5 mL) was hydrogenated at room temperature using the hydrogen balloon. The catalyst was removed by filtration, and the filtrate concentrated in vacuo. Purification by silica gel chromatography, eluting with 10% ethyl acetate/hexane gave the title compound as a white solid (0.34 g, 78%). The product was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:20][CH2:21][NH2:22])[N:3]=1.[O-:23][C:24]#[N:25].[K+]>Cl.CO>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:20][CH2:21][NH:22][C:24]([NH2:25])=[O:23])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(N)nc(SCCN)c(C#N)c1-c1ccc(O)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: N#Cc1c(N)nc(SCCNC(N)=O)c(C#N)c1-c1ccc(O)cc1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
31.1 mg (0.1 mmol) of 2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrile are suspended in 0.91 ml of 1N HCl, and 8.1 mg (0.1 mmol) of potassium cyanate are added. After the addition of a few drops of methanol, the mixture is stirred at 50° C. for a total of 10 hours. The crystals are filtered off with suction and washed with water and ether.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[H-].[Na+].Br[C:14]1[S:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1>CN(C)C=O>[CH3:8][C:7]1[CH:6]=[C:5]([O:9][C:14]2[S:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)[C:4]([CH3:10])=[CH:3][C:2]=1[NH2:1]
Reactant: Cc1cc(O)c(C)cc1N
Reactant: Brc1nc(-c2ccccc2)ns1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2nc(-c3ccccc3)ns2)c(C)cc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Amino-2,5-dimethylphenol (10.5 g) is added at room temperature to a suspension of sodium hydride (60% dispersion in mineral oil, 3 g) in anhydrous dimethylformamide (300 ml). The reaction mixture is stirred for 30 minutes and 5-bromo-3-phenyl-1,2,4-thiadiazole (18 g) prepared according to Chem. Ber. 1961, 94, 2043 is then added slowly. After stirring for 15 h, the reaction mixture is diluted in ice-water and then extracted with diethyl ether. Drying over magnesium sulphate followed by concentration of the combined organic phases gives the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:6].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27]([CH:29]4[CH2:30][CH2:31]4)=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Product: Cc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-methylphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 405.2 (M+H)+.
Reaction SMILES: [CH3:1]N(C)C=O.[NH2:6][C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(OCC)(=O)C>[NH2:6][C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:1])=[O:10]
Reactant: CN(C)C=O
Reactant: Nc1cc(Oc2ccccc2)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(Oc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To N,N-dimethylformamide 5.0 mL solution of 2-amino-4-phenoxybenzoic acid 0.40 g were added potassium carbonate 0.29 g and dimethyl sulfate 0.20 mL, and it was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, it was dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to give methyl 2-amino-4-phenoxybenzoate 0.33 g of colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CC(C)C(=O)Nc1ccc2c(c1)CCN2
Product: CC(C)C(=O)Nc1ccc2c(c1)CCN2c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cn1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate 6) and N-(indolin-5-yl)isobutyramide (intermediate 50) (0.017 g, 14%).