Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]Br)[CH3:2].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>Cl.C(OCC)(=O)C.O>[CH2:1]([O:3][CH2:4][CH2:5][O:16][C:15]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[OH:7])[CH3:2]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCOCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 120 h
Yield: 28.4 %

Procedure:
Commercially available 2-bromoethyl ethyl ether (33.8 g, 221 mmol) was added to a solution of commercially available 3,4-dihydroxybenzaldehyde (30.5 g, 221 mmol) and sodium carbonate (35.1 g, 331 mmol) in NP-dimethylformamide (310 mL) under nitrogen atmosphere at mom temperature. The liquid mixture was stirred at room temperature for 5 days. The reaction liquid was cooled to 0° C. and diluted with 2 M hydrochloric acid, ethyl acetate, and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed serially with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The insoluble matters were separated by filtration with dichloromethane and the raw material was removed. The filtrate was purified with silica gel column chromatography (n-heptane:ethyl acetate=17:3-1:1) to obtain the title compound (13.2 g, 28%).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[O:6][C:5]1=[O:13])(=O)[CH3:2].[OH-].[Na+].O.C(=O)[C:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:2]1(/[CH:1]=[C:4]2/[C:5](=[O:13])[O:6][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:8]/2)[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCC1CC(C(C)=O)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1C/C(=C\c2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
To a mixture of 36.8 g (0.200 mole) of 3-acetyl-5-butyldihydro-2(3H)-furanone in 200 mL of toluene charged to a 500 mL flask fitted with a mechanical stirrer, Dean-Stark trap and an addition funnel was added 8.00 g (0.200 mole) of sodium hydroxide at once. The mixture was vigorously stirred for 10 mins. at room temperature and then heated under reflux for 1 hour while water was removed in the Dean-Stark trap. After the one hour period 23.9 g (0.225 mole) of benzaldehyde was added to the refluxing solution in 4-5 ml aliquats in 1 hour. The reaction was further heated under reflux for an additional 2.5 hours. The reaction mixture was then cooled to room temperature and washed with 3×80 ml of water. The water layer was extracted with 50 ml of toluene and the toluene layers combined. The toluene solution was then washed with 100 ml of saturated sodium chloride and dried over Na2SO4 and concentrated to 35.4 gms of an orange oil under rotoevaporation. 19.0 gms of this oil was subjected to simple straight takeover distillation (0.04 mm Hg: 25°-147° C.) to leave 16 g (64.5% yield) of (E)-3-(phenylmethylene)-5-butyldihydro-2 (3H)-furanone as a viscous liquid. 1HNMR (CDCl3) δ7.5 (m, 6H), 4.56 (pentet, 1H), 3.3 (ddd, 1H), 2.8 (ddd, 1H), 1.9-1.2 (m, 6H), 0.86 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])#[N:2].Cl.ON.C([N:26]([CH2:29]C)CC)C.[O:31]1CCCC1>O.CO>[O:31]1[CH:29]=[N:26][C:1]([C:3]2[NH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][C:6]=3[NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:15])=[N:2]1
Reactant: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CO
Product: O=S(=O)(Nc1cccc2cc(-c3ncon3)[nH]c12)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of N-(2-cyano-1H-indol-7-yl)thiophene-2-sulfonamide (0.50 g), hydroxyamine hydrochloride (0.17 g), triethylamine (0.83 mL), tetrahydrofuran (2 mL) and methanol (2 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. A mixture of the obtained crystals and methyl orthoformate (10 mL) was heated under reflux for 4 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography. The title compound (0.18 g, yield 33%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point>185° C. (decomposition).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH2:16][C:17]2([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:20][CH2:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.O1CCO[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[F:27][C:26]1[C:21]([C:17]2([CH2:16][N:8]([C:5]3[N:6]=[N:7][C:2]([CH:29]=[CH2:30])=[CH:3][CH:4]=3)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:20][CH2:19][CH2:18]2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C=Cc1ccc(N(CC2(c3ncccc3F)CCC2)C(=O)OC(C)(C)C)nn1
Temperature: 110 °C
Yield: 86 %

Procedure:
t-Butyl 6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (2.5 g, 6.36 mmol), triethenylboroxin pyridine complex (1.0 g, 4.13 mmol), Pd(PPh3)4 (0.3 g, 0.25 mmol), nitrogen-sparged dioxane (13.2 mL) and aq. 2 N K2CO3 (0.9 mL) were combined and heated to 110° C. for 25 min. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography provided a light yellow oil (2.1 g, 86%), (m/z [M+H]=385.2).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:13]1CCC[CH2:14]1>>[O:13]=[C:14]1[NH:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[NH:1]1
Reactant: COC(=O)c1cccc(N)c1N
Reactant: C1CCOC1
Product: COC(=O)c1cccc2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 60 h
Yield: 84 %

Procedure:
To a solution of methyl 2,3-diaminobenzoate (10.5 g, 63.2 mmol) in tetrahydrofuran (100 mL) was added N,N′carbonyldiimidazole (10.2 g, 63.2 mmol), and the mixture was stirred at room temperature for 60 hours. The resulting solid was collected by filtration and washed with ethyl acetate to give 10.2 g (53.1 mmol, 84.0%) of the title compound as a colorless crystal.
Reaction SMILES: Cl[C:2]1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=[CH:4][N:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34](C(C)C)(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[F:61][CH:62]([F:79])[CH2:63][NH:64][CH:65]1[CH2:71][CH2:70][C:69]2=[C:72]([NH2:78])[C:73]([O:76][CH3:77])=[CH:74][CH:75]=[C:68]2[CH2:67][CH2:66]1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:3]([CH3:4])[CH3:2])(=[O:35])=[O:36])=[N:26][C:21]([NH:78][C:72]2[C:69]3[CH2:70][CH2:71][CH:65]([NH:64][CH2:63][CH:62]([F:79])[F:61])[CH2:66][CH2:67][C:68]=3[CH:75]=[CH:74][C:73]=2[O:76][CH3:77])=[N:22][CH:23]=1
Reactant: COc1ccc2c(c1N)CCC(NCC(F)F)CC2
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Product: COc1ccc2c(c1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCC(NCC(F)F)CC2

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with N*7*-(2,2-Difluoro-ethyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,7-diamine to afford 2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide. LC/MS (ESI): 581.24. 1H NMR (400 MHz, DMSO, d6) δ 9.46 (s, 1H), 8.99 (m, 2H), 8.08 (m, 2H), 7.72 (m, 1H), 7.13 (m, 3H), 6.85 (m, 1H), 6.38 (td, 1H), 3.66 (s, 3H), 3.54 (m, 2H), 3.39 (m, 1H), 3.06 (m, 1H), 2.84 (m, 1H), 2.66 (s, 6H), 2.29 (m, 4H), 1.31 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][CH2:31]I)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:2]([N:9]([CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[CH2:12]1)[CH2:31][CH2:30][CH:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)CCC(CNCc1ccccc1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCC(CN(CCC(c1ccccc1)c1ccccc1)Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.2 %

Procedure:
2-(N-benzylamino)methyl-6-methoxytetralin hydrochloride (0.602 g; obtained in Reference Example 6), 3,3-diphenylpropyl iodide (0.803 g) and potassium carbonate (0.800 g) were added to DMF (20 ml). The reaction mixture was stirred at room temperature for 24 hours, and water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to obtain the entitled compound (0.335 g).
Reaction SMILES: [I:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH:19](OC)(OC)OC>CO>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[I:1]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1I
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1I

Procedure:
2-iodo-3-nitro-benzoic acid (61 g, 208 mmol, prepared as described in Org. Syn. Coll. Vol. I, 56-58, and 125-127), sulfuric acid (40.8 g, 416 mmol), and trimethyl orthoformate (88.4 g, 833 mmol) were dissolved in 500 mL dry MeOH. The reaction was refluxed under argon for 20 h. The reaction mixture was concentrated to 100 mL then partitioned between saturated NaHCO3(aq) and CH2Cl2. The layers were separated and the aqueous layer extrated three times with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The yellow solid was crystallized from CH2Cl2/hexanes yielding 2-iodo-3-nitro-benzoic acid methyl ester, 57.8 g (90%) as a yellow solid: m.p.64.0-64.5° C.; 1H NMR (300 MHz, CDCl3) δ 3.99 (s, 3H), 7.54 (app t, J=7.8 Hz, 1H), 7.70 (dd, J=8.1, 1.8 Hz, 1H), 7.77 (dd, J=7.8, 1.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.CO>[Pd].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(CCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (27 mg, 0.06 mmol) in 4:1 MeOH:DCM (2.5 mL) was added palladium on carbon (10% wt., 0.59 mg, 5.53 mol). The reaction was stirred at room temperature under a hydrogen balloon for 12 h after which the reaction was purged with nitrogen and filtered through Celite™. The remaining palldium was washed with DCM (30 mL) and the resulting solution was concentrated in vacuo to afford tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propanoate (27 mg, 0.06 mmol, 100% yield) which was used without further purification. LC/MS (m/z, MH+): 491.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:10])([CH3:9])[C:7](=[O:11])[NH:6][C:5]1=[O:12].CO.C(N(CC)C(C)C)(C)C.[CH2:24]([C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][N:39]=[C:38](Cl)[N:37]=2)=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(O)C>[CH2:24]([C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([NH:1][CH2:2][CH2:3][N:4]3[C:8]([CH3:9])([CH3:10])[C:7](=[O:11])[NH:6][C:5]3=[O:12])[N:37]=2)=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Clc1nccc(-c2ccc(Cc3ccccc3)s2)n1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CO
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(Cc3ccccc3)s2)n1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
A 10% (w/v) solution of 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione in MeOH (0.93 mL, 0.54 mmol) was added to a 5 mL microwave vessel. The MeOH was evaporated with a stream of N2 to leave an oily solid which was dissolved in 94 μl (0.54 mmol) of N,N-diisopropylethylamine and 2 mL of iPrOH, to which was added 0.15 g (0.54 mmol) of 4-(5-benzylthiophen-2-yl)-2-chloropyrimidine. The reaction solution was heated in a microwave to 170° C. for 20 min and then allowed to stand at rt for 2 h to give a precipitate which was collected by filtration and purified by C-8 prep HPLC to give the title compound. MS (M+H)+ 422.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[C:8]([C:10]2[N:14]=[CH:13][NH:12][N:11]=2)=[O:9])[CH2:3][CH2:2]1.[H-].[Na+].CI.[C:31](=O)([O-])O.[Na+]>CN(C=O)C>[CH3:31][N:12]1[CH:13]=[N:14][C:10]([C:8]([N:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:24])[F:25])[CH:17]=2)=[O:9])=[N:11]1
Reactant: O=C(c1nc[nH]n1)N(Cc1cccc(OC(F)(F)F)c1)C1CCOCC1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)n1
Reaction time: 0.17 h

Procedure:
To a solution of N-(tetrahydro-2H-pyran-4-yl)-N-[3-(trifluoromethoxy)benzyl]-1H-1,2,4-triazole-3-carboxamide (138 mg) in DMF (2 mL), sodium hydride (60%, 18 mg) was added and the resulting mixture was stirred for 10 minutes; thereafter, methyl iodide (35 μL) was added and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography (NH silica gel cartridge; hexane/ethyl acetate=1:0 to 1:3) to give the titled compound (75 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:20]=O>C(O)(=O)C.S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:20]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)NC(Cc1ccc(Cl)cc1)C(=O)OC
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)N1Cc2cc(Cl)ccc2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of methyl 3-(4-chlorophenyl)-2-(ethoxycarbonylamino)propanoate (3.55 g, 12.4 mmol) in acetic acid (12 mL) and sulfuric acid (4 mL) was treated with paraformaldehyde (0.392 g, 13.0 mmol). After stirring at room temperature overnight, the mixture was added to ice (50-60 g), diluted with water (30 mL) and extracted with ethyl acetate (3×˜50 mL). The combined organic phase was washed with saturated aqueous sodium chloride (25 mL), dried over MgSO4 and concentrated. Purification by silica gel chromatography (90 g column, 25-50% ethyl acetate in hexanes) gave 2-ethyl 3-methyl 7-chloro-3,4-dihydroisoquinoline-2,3(1 H)-dicarboxylate (2.19 g, 59%) as a clear, viscous oil. 1H NMR (CDCl3, 400 MHz) δ 7.12 (m, 3 H), 5.20 (m, ˜0.6 H), 4.98 (m, ˜0.4 H), 4.76 (m, 1 H), 4.53 (m, 1 H), 4.25 (m, 2 H), 3.65 (s, 3 H), 3.20 (m, 2 H), 1.35 (t, J=7 Hz, ˜1.8 H), 1.28 (t, J=7 Hz, ˜1.2 H) (mixture of rotamers). ESI+ MS found for C14H16ClNO4 m/z 298.0 (M+H, weak).
Reaction SMILES: [OH-].[Na+].C(O)C.[Cl:6][C:7]1[C:15]([Cl:16])=[C:14]2[C:10]([CH2:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:18][C:19]#[C:20][Si](C)(C)C)[C:13]2=[O:17])=[CH:9][C:8]=1[O:31][CH2:32][C:33]([O:35]CC)=[O:34]>O>[Cl:6][C:7]1[C:15]([Cl:16])=[C:14]2[C:10]([CH2:11][C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([CH2:18][C:19]#[CH:20])[C:13]2=[O:17])=[CH:9][C:8]=1[O:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CCC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
- A solution of 50% sodium hydroxide (2.5 g.) in 50 ml. of abs. ethanol is added to a suspension of ethyl [6,7-dichloro-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate (3.08 g., 6.3 mmol) in 100 ml. of abs. ethanol under an argon atmosphere. The mixture stirred at room temperature for a period of 5 hr. (excluding light) and mixed with water provides a clear yellow solution which is first extracted with ether and then acidified with dilute hydrochloric acid. The acidified solution is extracted with 1:1 ether-ethyl acetate which, after washing with brine and drying over magnesium sulfate, is concentrated under reduced pressure to afford 2.22 g. (91% yield) of (6,7-dichloro-1-oxo-2-phenyl-2-propargyl-5-indanyloxy)acetic acid as a tan solid, m.p. 238.5°-241.5° (corr.). Crystallization from isopropanol affords the indanyloxyacetic acid product as white needles, m.p. 237.5°-240° (corr.). This material is solvated with 0.17 mole of isopropanol, according to NMR analysis, and has the following elemental analysis.
Reaction SMILES: [CH:1]1([C:5](=[S:7])[NH2:6])[CH2:4][CH2:3][CH2:2]1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[N:6]=[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[S:7][CH:9]=1)=[O:12])[CH3:15]
Reactant: NC(=S)C1CCC1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1csc(C2CCC2)n1
Temperature: 0 °C
Yield: 39.3 %

Procedure:
A mixture composed of 9.7 g of cyclobutancarbothioamide, 16.5 g of ethyl bromopyruvate and 200 ml of ethyl alcohol was heated to reflux for 1 hr. The reaction mixture was partially condensed in vacuo and the residual materials were diluted with ice water and and excess of saturated sodium bicarbonate solution. The solids were collected to yield 7.0 g of 2-cyclobutyl-4-thiazolecarboxylic acid ethyl ester; m.p. 48°-50° C. after recrystallization from pentane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)/[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCC/C(=C/C=C/C(=O)O)c1cccc(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC/C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.7 %

Procedure:
As in Example 115, (2E,4Z)-5-(3-methoxyphenyl)-2,4-nonadienoic acid (7.37 g) and 4-nitrophenol (4.89 g) in 30 mL of dichloromethane was reacted with 1,3-dicyclohexylcarbodiimide (5.91 g). The mixture was stirred at room temperature for 3 days and the usual work up furnished 9.69 g of (2E,4Z)-5-(3-methoxyphenyl)-2,4-nonadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: [CH2:1]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C[N+]1([O-])CC[O:27]CC1.[OH2:31].S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.O>[OH:31][CH:10]([CH2:11][OH:27])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22]
Reactant: O
Reactant: C=CCCCCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCC(O)CO
Reaction time: 16 h
Yield: 71 %

Procedure:
A solution of N-(10-Undecenyl)phthalimide (4.97 g, 16.6 mmol), prepared as discribed above, 4-methylmorpholine-N-oxide (8.62 mL, 60% by wt in water, 50.0 mmol) and potassium osmate dihydrate (58 mg, 0.16 mmol) in 100 mL acetone/water (1:1 by wt) was stirred for 16 hours. Water (100 mL) and sodium sulfite (10 g) were added and the resulting solution stirred for an additional hour. The resulting reaction mixture was extracted with dichloromethane (3×80 mL) and the organic phase dried using magnesium sulfate and evaporated to obtain 3.93 g (71% yield) of N-(10,11-Dihydroxyundecyl)phthalimide (inventive compound no. 1108).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]1.[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.N1CCCCC1>C(O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:14](=[O:15])/[C:13](=[CH:23]/[C:22]2[CH:25]=[CH:26][C:19]([N:18]([CH3:27])[CH3:17])=[CH:20][CH:21]=2)/[C:12]([CH3:16])=[N:11]1
Reactant: CC1=NN(c2nc3ccccc3s2)C(=O)C1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: CC1=NN(c2nc3ccccc3s2)C(=O)/C1=C/c1ccc(N(C)C)cc1

Procedure:
1 g (4.32 mmol) of 2-(1,3-benzothiazol-2-yl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one and 1.93 g (12.96 mmol) of 4-(dimethylamino)benzaldehyde are stirred under reflux with the addition of 3 ml of piperidine in absolute ethanol for 2 hours. The mixture is then diluted with water and the bright red precipitate is filtered off, then washed with water and a small amount of cold methanol and dried under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:12]Br>CC(O)=O.C(Cl)Cl.CCOC(C)=O>[Br:12][C:11]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: Oc1ccc2cccnc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ccc2cccnc2c1Br
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a stirred solution of 7-hydroxyquinoline (59.0 g, 0.406 mol) in AcOH (120 mL) and CH2Cl2 (240 mL) was slowly added bromine (22.9 ml, 0.444 mol) in AcOH (120 ml) while keeping the internal temperature at 0-5° C. The resulting suspension was stirred for 2 h at 0-5° C., and then diluted with EtOAc (100 mL) and filtered. The solid was washed with EtOAc (2×20 mL) and dried in vacuo to give 8-bromo-7-hydroxyquinoline (65 g, 76%).