Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][O:40][CH2:41][CH2:42][NH:43][CH2:44][CH2:45][O:46][CH3:47]>>[CH3:39][O:40][CH2:41][CH2:42][N:43]([CH2:44][CH2:45][O:46][CH3:47])[C:32]([N:12]1[C:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)([CH3:24])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][C:7]=1[O:35][CH:36]([CH3:37])[CH3:38])=[O:33]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCCNCCOC
Product: COCCN(CCOC)C(=O)N1C(c2ccc(C(C)(C)C)cc2OC(C)C)=NC(C)(c2ccc(Cl)cc2)C1(C)c1ccc(Cl)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with bis-(2-methoxyethyl)-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H49N4O5SCl2 [(M+H)+] 668.3017, observed 668.3010.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:9][C:8]=2[CH:23]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:32])C=1.O.C(=O)([O-])O.[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]3([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])[O:32][CH:9]3[C:8]=2[CH:23]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C=C1CNC(=O)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C2OC21CNC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-2H-1-benzopyran (0.5 g, 1.52 mmol) in dichloromethane (10 ml) at 0° C. was treated with m-chloroperbenzoic acid (70%, 0.45 g, 1.52 mmol). After stirring for sixteen hours at room temperature, water and sodium hydrogen carbonate were added and the organic phase separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/acetone (95/5), to give 0.43 g of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran 1NMR (CDCl3): δ1.4 (s, 3H), 1.6 (s, 3H), 3.7 (dd,1H), 3.85 (s, 1H), 4.15 (dd, 1H), 6.70 (br.s, 1H), 6.95 (d, 1H), 8.2 (d, 1H), 8.30 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[NH2:10][NH2:11].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:9][S:8][C:4]1[N:3]=[C:2]([NH:10][NH2:11])[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(Cl)n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CSc1nccc(NN)n1
Yield: 57.6 %

Procedure:
In a 250 mL round bottom flask, 4-chloro-2-methylsulfanyl-pyrimidine (5 g, 31.1 mmol), hydrazine (4.5 g, 140 mmol) and potassium carbonate (6.45 g, 46.7 mmol) were combined with ethanol (50 mL). The mixture was refluxed for 3 hrs and filtered. The filtered solid was rinsed with ethanol (30 mL). The combined ethanol solution was evaporated to give a crude oily mixture which was purified by ISCO flash column chromatography (30% to 100% ethyl acetate in hexanes) to give N-(2-methylsulfanyl-pyrimidin-4-yl)-hydrazine as a white solid (2.8 g, 57.6% yield).
Reaction SMILES: CS(N)(=O)=O.[CH:6]1([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:40]1([C:43]2[C:44]([O:53][CH:54]3[CH2:59][CH2:58][CH2:57][C:56]([CH3:61])([CH3:60])[CH2:55]3)=[CH:45][C:46]([F:52])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[CH2:42][CH2:41]1>>[CH:40]1([C:43]2[C:44]([O:53][CH:54]3[CH2:59][CH2:58][CH2:57][C:56]([CH3:61])([CH3:60])[CH2:55]3)=[CH:45][C:46]([F:52])=[C:47]([CH:51]=2)[C:48]([NH:12][S:9]([CH:6]2[CH2:8][CH2:7]2)(=[O:11])=[O:10])=[O:49])[CH2:42][CH2:41]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CCCC(Oc2cc(F)c(C(=O)O)cc2C2CC2)C1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: CC1(C)CCCC(Oc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)C1

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methane sulfonamide with cyclopropane sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzoic acid, the title compound was obtained as a white solid (0.07 g, 31%): 1H NMR (300 MHz, DMSO-d6) δ11.79 (s, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.03 (d, J=13.3 Hz, 1H), 4.67-4.58 (m, 1H), 3.11-3.03 (m, 1H), 2.06-1.95 (m, 2H), 1.76-1.70 (m, 1H), 1.65-1.54 (m, 2H), 1.37-1.17 (m, 4H), 1.13-1.08 (m, 4H), 0.98 (s, 3H), 0.97 (s, 3H), 0.90-0.84 (m, 2H), 0.68-0.63 (m, 2H); MS (ES+) m/z 410.0 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH:17]=1)[C:10]([CH3:31])([CH3:30])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:30][C:10]1([CH3:31])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)N2CCCC2)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
A mixture of 3,3-dimethyl-2-{3-[(pyrrolidine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (842 mg, 2 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(pyrrolidine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (350 mg, 44%) as a white solid: LC/MS m/e calcd for C23H27N3O3 (M+H)+: 394.49, observed: 394.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@H:9]2[CH2:13][C@H:12]([C:14]#[N:15])[C@@H:11]([O:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:10]2)=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1.[OH2:38]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:9]2[CH2:13][C@H:12]([C:14]#[N:15])[C@@H:11]([O:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:10]2)(=[O:35])=[O:38])=[C:4]([C:23]([F:25])([F:24])[F:26])[CH:3]=1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#C[C@H]1C[C@H](Sc2ccc(Br)cc2C(F)(F)F)C[C@@H]1OC1CCOCC1
Solvent: ClCCl
Product: N#C[C@H]1C[C@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1OC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (1S,2R,4R) and (1R,2S,4S)-4-(4-bromo-2-trifluoromethyl-phenylsulfanyl)-2-(tetrahydro-pyran-4-yloxy)-cyclopentanecarbonitrile (345 mg, 0.766 mmol) and mCPBA (472 mg, 70%, 1.915 mmol) in DCM (10 ml) was stirred at room temperature overnight. The mixture was diluted with water and extracted 2 times with DCM. The combined extracts were washed with 15% Na2SO3 solution, saturated NaHCO3 solution, dried (Na2SO4) and evaporated. The remaining colorless solid (370 mg) was used in the next reaction step without further purification. MS (EI): 482.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:5]=2[O:4][CH2:3]1.CI.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:1]=[C:2]1[N:7]([CH3:16])[C:6]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(c1)OCC(=O)N2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(c1)OCC(=O)N2C
Yield: 92 %

Procedure:
Following the procedure of Example 1, 21.7 g of 3-oxo-7-methoxy-3,4-dihydro-2H-[1,4]benzoxazine and 19.88 g of methyl iodide were reacted in 600 ml of acetone in the presence of 19.32 g of solid potassium carbonate. The reaction was carried out, and the product isolated and purified by the procedure of Example 1 to yield 3-oxo-4-methyl-7-methoxy-3,4-dihydro-2H-[1,4]benzoxazine; yield=92%; molecular ion by mass spectrum=193.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]1[C:10](=[O:24])[C:11]2[C:16]([C:17](=[O:20])[C:18]=1Cl)=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=[CH:13][CH:12]=2>C(O)C>[O:20]=[C:17]1[C:18]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[C:9]=2[C:10](=[O:24])[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[C:16]1=2
Reactant: Nc1ccccn1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CCO
Product: O=C1c2nc3ccccn3c2C(=O)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Yield: 4.5 %

Procedure:
1.73 g (18 mmol, 1 eq) of 2-aminopyridine are added to a suspension of 5.00 g (18 mmol), 1 eq) of 2,3-dichloro-1,4-dihydro-1,4-dioxo-5-nitronaphthalene in 400 mL of ethanol. The mixture is brought to reflux for 5 h. After an orange precipitate appears, the reaction is allowed to cool to ambient temperature and the precipitate is filtered and purified on a flash column (support: silica 6-35 μm, h=45 cm, δ=16 cm; conditioning: heptane/ethyl acetate, 50/50; eluant: heptane/ethyl acetate, 50/50 to 70/30) to obtain 0.54 g of 6,11-dihydro-6,11-dioxo-7-nitronaphtho[2',3':4,5]imidazo[1,2-a]pyridine or 6,11-dihydro-6,11-dioxo-10-nitronaphtho[2',3':4,5]imidazo[1,2-a]pyridine, which after recrystallization in 1,2-dichlorobenzene produces 0.24 g of the expected product in the form of orange crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.[F-].[Cs+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:6]1[CH:5]=[C:4]([CH:15]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C)cc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (500 mg, 1.15 mmol), 4-methyl phenylboronic acid (0.237 g, 1.74 mmol), Palladium Tetrakis (triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)-3-cyclopropylpropanoate (375 mg) as a thick oil.
Reaction SMILES: C(N1C=CN=C1)([N:3]1[CH:7]=[CH:6]N=C1)=O.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=O)=[CH:19][CH:18]=1)(=[O:16])=[O:15].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37](CCN)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[C:27]([O:31][C:32]([N:34]1[CH2:35][CH2:36][CH:37]([N:3]([CH2:7][CH3:6])[C:24](=[O:26])[CH2:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:15])=[O:16])=[CH:22][CH:21]=2)[CH2:38][CH2:39]1)=[O:33])([CH3:28])([CH3:29])[CH3:30]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(C(=O)Cc1ccc(S(C)(=O)=O)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
A slurry of carbonyldiimidazole (1.94 g, 11.98 mmol) in THF (10 ml) was treated with a solution of 4-methylsulphonylphenylacetic acid (2.5 g, 11.68 mmol) in THF (12.5 ml) at ambient temperature and then heated to 50° C. After one hour carbonyldiimidazole (0.189 g, 1.17 mmol) was added. After a further 15 minutes a solution of N-(1-tert-butoxycarbonyl-4-piperidinyl)ethylamine (2.53 g, 11.10 mmol) in toluene (10 ml) was added dropwise over two minutes to the reaction mixture. After 30 minutes at 50° C. the reaction mixture was treated with 1M NaOH (12.5 ml) and the mixture was stired rapidly for 30 min and then allowed to cool to room temperature. The organic layer was separated and washed with aqueous citric acid (10% w/w, 10 ml) and then with water (5 ml). The organic layer was evaporated to dryness to afford N-(1-tert-butoxycarbonyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenyl-acetamide as a colourless oil (4.75 g, 100%).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5][C:4]=2[NH:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:22](I)[CH:23]=[CH2:24].CCOC(C)=O>CN(C=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5][C:4]=2[N:3]1[CH2:24][CH:23]=[CH2:22]
Reactant: C=CCI
Reactant: COC(=O)c1cnc2ccc(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCn1c(=O)ccc2ncc(C(=O)OC)cc21
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
A solution of methyl 6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (1.963 g, 5.36 mmol) in DMF (32 ml) was treated with K2CO3 (2.95 g, 21.3 mmol), stirred for 10 mins and then treated with allyl iodide (0.535 ml, 5.88 mmol), heated for 7 h at 75° C., further allyl iodide (0.15 ml, 0.89 mmol) was added and the reaction heated for a further 2 h. The reaction was treated with EtOAc, washed with water three times. The combined aqueous phases were then re-extracted with EtOAc and this washed with water twice. The combined organic phases were dried, evaporated and the residue was subjected to column chromatography on silica gel using a 1:1 EtOAc:hexane gradient to provide the desired compound (0.809 g, 62%).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:13]([O:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][O:12][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:10])[OH:8])[OH:6])=[O:4])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](O)[C@H](O)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 29.8 %

Procedure:
To a solution of D-fructose (10 g, 55.5 mmole) in pyridine (40 ML) and chloroform (25 mL) was added trityl-chloride (35 g, 126.3 mmole) and the mixture was stirred at 25° for 2 days, another 5 g of trityl chloride was added and stirring was continued for 2 days. Solvent was removed under reduced pressure and the residue was extracted with chloroform, washed with aqueous saturated cupric sulfate solution, brine, dried over anhydrous sodium sulfate and concentrated. Column chromatography [chlorofm-methanol (100:1)] gave 1,6-Di-O-trityl-D-fructose (11 g, 30%). This compound was identified by its specific rotation and by NMR and Mass spectrometry.
Reaction SMILES: Cl[CH2:2]CCl.[CH3:5][C:6]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:7]=1[OH:8]>CC1C=CC(O)=CC=1O>[CH3:2][C:10]1[CH:11]=[C:12]([OH:13])[CH:6]=[C:7]([CH:9]=1)[OH:8].[CH3:5][C:6]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:7]=1[OH:8]
Reactant: ClCCCl
Agent: Cc1c(O)cccc1O
Agent: Cc1ccc(O)cc1O
Product: Cc1cc(O)cc(O)c1

Procedure:
This product mixture is introduced into a separation vessel or series of separation vessels. This vessel or these vessels may be fractional distillation vessels. In these vessels, the mono-substituted methylresorcinol isomers are separated from unreacted resorcinol and other methylated hydroxyaromatic compounds. The boiling points of these compounds are substantially close to each other so that a good separation in a single fractional distillation vessel may be difficult. The boiling points are: m-methoxy phenol 244.3° C., 2-methylresorcinol 264° C., 4-methylresorcinol 267°-270° C., 5-methylresorcinol 287°-290° C., and resorcinol 275.9° C. and higher methylated resorcinols above 290° C. Preferably, the product mixture is fractionally distilled to obtain a fraction rich in 5-methylresorcinol and a fraction rich in 2-methylresorcinol. Also, a fraction rich in 4-methylresorcinol may be obtained. Each rich fraction is treated in a separate vessel to fractional crystallization from 1,2-dichloroethane with a varied solvent ratio. From this operation the appropriate mono-substituted resorcinol and preferably, predominantly the 5-methylresorcinol along with some 2-methylresorcinol are obtained in a pure state.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[I-:16].[K+]>CC(C)=O>[I:16][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCI
Temperature: 25 °C
Reaction time: 96 h
Yield: 85 %

Procedure:
A solution of 10.0 g (0.04 mol) of N-(3-bromopropyl)-phthalimide in 240 mL of acetone was treated with 41.7 g (0.25 mol) of potassium iodide and stirred at room temperature for 4 days. The reaction mixture was filtered and the filtrate was diluted with 800 mL of ether and filtered again through celite. The filtrate was then concentrated at reduced pressure. The resulting yellow solid was recrystallized from 550 mL of hexane (filtered hot and boiled down to 300 mL) to yield 10.71 g (91.1%) of 2 as off-white needles.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:1][NH:2][C:3](=[S:6])[NH:4][NH:5][C:17]([C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)=[O:18]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CNC(=S)NN
Solvent: c1ccncc1
Product: CNC(=S)NNC(=O)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
To a stirred room temperature solution of 4-methylthiosemicarbazide (5.91 g, 5.62×10-2 mole) and pyridine (150 ml) was added 2-naphthoyl chloride (10.7 g, 5.61×10-2 mole). After stirring overnight, the pyridine was evaporated at reduced pressure. The concentrate was treated with water and the undissolved product was collected by filtration and dried by suction. Crystallization from acetone/ethanol afforded off-white needles, Mp 211° C. (decomp).
Reaction SMILES: O[C:2]1[C:3]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:23].P(Cl)(Cl)(Cl)=O>>[Cl:23][C:2]1[C:3]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: Oc1nc(-c2ccccc2)nc2c1Cc1ccccc1O2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2ccccc2)nc2c1Cc1ccccc1O2

Procedure:
Eight and one tenth (8.1) gram 4-hydroxy-2-phenyl[1]benzopyrano[2,3-d]pyrimidine, 9.0 g phosphoruspentachloride and 36 ml phosphorusoxychloride are heated for two hours under reflux. Excess phosphorusoxychloride is then distilled off under a vacuum and the residue is partitioned to chloroform and water, a pH 6 value being adjusted by the addition of 10% sodium hydroxide. The organic phase is separated and the chloroform removed by distillation in a rotary evaporator. The residue obtained is separated by chromatography using cyclohexane/chloroform 1:1 as an eluting agent. There are obtained 4.0 g 4-chloro-2-phenyl[1]benzopyrano[2,3-d]pyrimidine, mp 168°-170° C. as colorless crystals. Thereafter 0.05 g sodium are dissolved in 10 ml anhydrous ethanol and 0.25 g 3-dimethylamino-1-propane-thiol added to the solution. The mixture obtained is added dropwise to a solution of 0.6 g 4-chloro-2-phenyl[1]benzopyrano[2,3-d]pyrimidine at reflux temperature. The reaction mixture is then kept under reflux for another two hours. After cooling the reaction mixture is filtered and the filtrate is evaporated to dryness and the residue partitioned to chloroform and water. The organic phase is separated off, the chloroform is evaporated and the residue recrystallized from ethanol. There are obtained 0.4 g colorless crystals, mp 93° C.
Reaction SMILES: Cl[C:2]([C:4]1[C:5]2[CH2:25][CH2:24][CH2:23][CH2:22][C:6]=2[S:7][C:8]=1[NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)=[O:11])=[O:3].[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH2:35][NH2:36])=[CH:34][C:29]=2[O:28][CH2:27]1.N1C=CC=CC=1>ClCCl>[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH2:35][NH:36][C:2]([C:4]3[C:5]4[CH2:25][CH2:24][CH2:23][CH2:22][C:6]=4[S:7][C:8]=3[NH:9][C:10]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)=[O:11])=[O:3])=[CH:34][C:29]=2[O:28][CH2:27]1
Reactant: COC(=O)c1ccc(C(=O)Nc2sc3c(c2C(=O)Cl)CCCC3)cc1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2sc3c(c2C(=O)NCc2ccc4c(c2)OCO4)CCCC3)cc1

Procedure:
Methyl 4-(3-chlorocarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylcarbamoyl)benzoate is added to a solution of (benzo[1,3]dioxol-5-ylmethyl)amine in dichloromethane and 1.1 equivalents of pyridine and the solution is stirred. The solvent is removed and is worked up in a customary manner. 1.3 g of methyl 4-{3[(benzo[1,3]dioxol-5-ylmethyl)carbamoyl]-4,5,6,7-tetrahydrobenzo[b]thiophene-2-ylcarbamoyl}benzoate, m.p. 165°, are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)C>[C:11]1([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:31]4[CH2:32][CH2:33][CH:28]([N:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[CH2:29][CH2:30]4)=[N:7][N:6]3[C:8]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccc2nc(-c3ccccc3)c(-c3ccncc3)n2n1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CCO
Product: c1ccc(-c2nc3ccc(N4CCC(N5CCCC5)CC4)nn3c2-c2ccncc2)cc1
Temperature: 155 °C

Procedure:
A mixture of 4.03 g (13.1 mmol) of 6-chloro-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine and 4.4 g (29 mmol) of 4-pyrrolidin-1-ylpiperidine in 50 mL of ethanol is heated at 155° C. for 4 hours. After cooling, the solvent is evaporated off under reduced pressure and the residue is chromatographed on silica gel, eluting with a mixture of dichloromethane and methanol (93:7).