Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=1>>[NH2:31][C:29]([C:28]1[CH:32]=[CH:33][C:25]([NH:24]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:26][CH:27]=1)=[O:30]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CC/C(Nc1ccc(C(N)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-aminobenzamide
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13](Cl)=[O:14])=[C:11]([Cl:16])[N:10]=[C:9]([S:17][CH3:18])[N:8]=1.C(Cl)Cl.[CH2:27]([O:34][CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:37][CH2:36][CH2:35][O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:14])=[C:11]([Cl:16])[N:10]=[C:9]([S:17][CH3:18])[N:8]=1
Reactant: COc1ccc(CNc2nc(SC)nc(Cl)c2C(=O)Cl)cc1Cl
Reactant: OCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNc2nc(SC)nc(Cl)c2C(=O)OCCOCc2ccccc2)cc1Cl

Procedure:
A mixture of whole amount of 4-(3-chloro-4-methoxybenzylamino)-5-chloroformyl-6-chloro-2-methylthiopyrimidine (prepared in the above (1)), methylene chloride 15 ml and 2-benzyloxyethanol 224 mg is refluxed for 30 minutes. After cooling the reaction mixture is diluted with water and neutralized with an aqueous saturated sodium hydrogen carbonate solution. The solution is washed with ethyl acetate. The methylene chloride layer is diluted with ethyl acetate, washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; hexane:ethyl acetate=5:1) to give 4-(3-chloro-4-methoxybenzylamino)-5-(2-benzyloxyethoxycarbonyl)-6-chloro-2-methylthiopyrimidine as a colorless oil 655 mg.
Reaction SMILES: CC1(C)CCCC(C)(C)N1[Mg]Cl.[Cl-].[Li+].[N:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH:41]=[O:42]>C1COCC1.ClCCl>[OH:42][CH:41]([C:32]1[CH:33]=[CH:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=1)[C:23]1[CH:22]=[C:21]([C:18]2[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=2)[S:25][C:24]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1ccc(-c2ccncc2)s1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2ccncc2)cc1C(O)c1ccc2ccccc2c1
Temperature: -25 °C
Yield: 49 %

Procedure:
A dry, nitrogen flushed flask, equipped with a stirbar and septum, was charged with 2,2,6,6-tetramethylpiperidinylmagnesium chloride.lithium chloride in tetrahydrofuran (1.0M, 1.21 mL, 1.21 mmol). The flask was cooled to −25° C. and a solution of ethyl 5-pyridin-4-ylthiophene-2-carboxylate (0.257 g, 1.10 mmol) in tetrahydrofuran (1.0 mL, 12 mmol) was added dropwise with stirring. The resulting dark reddish orange solution was stirred at −25° C. for 30 minutes. 2-Naphthalenecarboxaldehyde (0.172 g, 1.10 mmol) was then added dropwise (as a solution in 1.5 ml THF)— the reaction mixture became purple. The reaction was stirred at −25° for 5 minutes, then the cooling bath was removed and the reaction was allowed to warm to room temperature with stirring. An aliquot was removed from the reaction and quenched into sat. NH4Cl solution, then extracted with ethyl acetate. A LCMS of this extract indicated that all starting material had been consumed and that the major peak had correct mass for the desired product. The reaction was quenched by the slow dropwise addition of a saturated ammonium chloride solution (5 ml). The resulting yellow-orange mixture was transferred to a reparatory funnel and diluted further with water and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The extracts were combined, washed with saline, dried, and evaporated to leave crude product as an orange oil which was dissolved in minimal dichloromethane then was purified by column chromatography on silica gel (gradient 100% DCM to 5% MeOH in ethyl acetate) to afford product 210 mg (49% yield) as a white foam. LC/MS (FA) ES+ 390. 1H NMR (400 MHz, DMSO) δ 8.63-8.58 (dd, J=4.6, 1.6 Hz, 2H), 8.04-8.00 (s, 1H), 8.00-7.96 (s, 1H), 7.87-7.81 (d, J=8.7 Hz, 3H), 7.76-7.71 (dd, J=4.6, 1.7 Hz, 2H), 7.62-7.58 (d, J=1.6 Hz, 1H), 7.50-7.45 (t, J=3.0 Hz, 2H), 6.74-6.69 (d, J=4.2 Hz, 1H), 6.33-6.28 (d, J=4.2 Hz, 1H), 4.37-4.31 (dd, J=7.1, 4.3 Hz, 2H), 1.35-1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[NH:7][C:8](=O)O[C:4]=2[CH:3]=1.C[NH2:15].CO>>[CH3:8][NH:7][C:6](=[O:11])[C:5]1[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=1[NH2:15]
Reactant: CN
Reactant: O=c1[nH]c(=O)c2ccc(Br)cc2o1
Solvent: CO
Product: CNC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30 ml of 2.0 M methylamine-methanol solution was added to 6.28 mg of 7-bromo-1H-benzo[1,3]oxazine-2,4-dion, and the mixture was stirred at room temperature for 2 hours. The reaction solution was distilled outunder reduced pressure, to obtain 6.57 mg of the above compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:29][CH2:30][N:46]4[CH2:45][CH2:44][C:43]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]4)[CH2:14][CH2:13][N:12]([C:15](=[O:28])[C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc4c(c3)OCO4)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc4c(c3)OCO4)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(benzo[1,3]dioxol-5-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:15].P(Br)(Br)(Br)(Br)Br.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: BrP(Br)(Br)(Br)Br
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]

Procedure:
The conversion of 2-methyl-3-nitrobenzoic acid (II) to a 2-methyl-3-nitrobenzoyl halide (III) may be effected by reacting II with a suitable halogenating agent, such as phosphorus pentachloride, phosphorus pentabromide, thionyl chloride, and the like, preferably thionyl chloride, in a suitable inert solvent, such as dry benzene, at a temperature from room temperature to reflux until the reaction is complete and removing the solvent under reduced pressure. Preferably, II is converted to 2-methyl-3-nitrobenzoyl chloride by simply refluxing it in pure thionyl chloride for about 2-6 hours and removing the excess thionyl chloride under reduced pressure. The preferred 2-methyl-3-nitrobenzoyl chloride is obtained in yields of 95-100% of theoretical.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28]([OH:30])=O)=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH3:31])[CH2:16][C:15]1([CH3:39])[CH3:38])(=[O:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:30])=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:31])[CH2:16][C:15]1([CH3:38])[CH3:39])(=[O:13])[CH3:12]
Reactant: CC(=O)N1c2ccc(NC(=O)CC(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CCNCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(Cc1ccccc1)C(=O)CC(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Condensation of N-ethylbenzylamine (5.2 mg) with 1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), under the agency of HATU (19 mg) and N,N-diisopropylethylamine (16 l) in tetrahydrofuran (2 ml) was performed according to the method described in example 11.
Reaction SMILES: O1CCCC1.[H-].[Na+].[Cl:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1.[F:16][CH2:17][CH2:18][OH:19]>O>[F:16][CH2:17][CH2:18][O:19][C:12]1[N:11]=[N:10][C:9]([Cl:8])=[CH:14][CH:13]=1
Reactant: OCCF
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FCCOc1ccc(Cl)nn1
Reaction time: 0.02 h
Yield: 83.1 %

Procedure:
To anhydrous tetrahydrofuran (5 mL) containing sodium hydride (NaH 60%, 121 mg, 3.02 mmol) was slowly added anhydrous tetrahydrofuran (2 mL) having 3,6-dichloropyridazine (107, 300 mg, 2.01 mmol) dissolved therein at 0° C., and added dropwise 2-fluoroethanol (194 mg, 3.02 mmol). The reaction mixture was stirred for one minutes and water was carefully added. Organic compounds were extracted with ethyl acetate, and the recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 3-(2-fluoroethoxy)-6-chloropyridazine (108b, 295 mg, 83%) as a white solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(CCc3ccccc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2CCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 45.8 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-phenethylpyrazin-2-amine (7r) (403 mg, 994 μmol) and 4-(dimethylamino)pyridine (19.6 mg, 160 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyloxy) phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11r (298 mg, 455 μmol, 45.8%) as a yellow oily substance. Rf=0.44 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 0.12 (s, 6H), 0.20 (s, 6H), 0.91 (s, 9H), 0.93 (s, 9H), 2.83 (t, 1H, J=: 8.4 Hz), 2.94 (t, 1H, J=8.4 Hz), 3.59 (s, 2H), 6.72-6.79 (AA′BB′, 2H), 6.92-7.00 (AA′BB′, 2H), 7.01-7.07 (AA′BB′, 2H), 7.07-7.15 (m, 1H), 7.16-7.24 (m, 4H), 7.97-8.05 (AA′BB′, 2H), 8.81 (s, 1H), 10.44 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.9, 18.0, 25.5 (6C), 32.8, 34.7, 41.7, 119.6 (2C), 120.3 (2C), 125.7, 128.1 (2C), 128.2 (4C), 128.5, 129.1, 130.2 (2C), 130.3, 136.6, 141.4, 143.8, 147.9, 150.6, 153.8, 156.6, 170.3; IR (KBr, cm−1) 525, 698, 781, 839, 914, 1007, 1169, 1258, 1362, 1416, 1443, 1510, 1605, 1661, 2857, 2930, 2955, 3225.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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:16][C:12]1[CH:11]=[C:10]([S:7]([N:6]2[C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:3][C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:5]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
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: [Na+]
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
Yield: 73 %

Procedure:
Using tert-butyl {{5-bromo-1-[(3-chlorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl}methylcarbamate (1 g), phenylboronic acid (526 mg), sodium carbonate (687 mg) and tetrakis(triphenylphosphine)palladium (374 mg), a procedure as in Reference Example 57 was performed to give the title compound as a pale-yellow oil (yield 726 mg, 73%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C.O>C1COCC1>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:7][N:6]=1
Reactant: COc1ccc(Br)cn1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 5-bromo-2-methoxy-pyridine (1.453 g, 7.73 mmol) in THF (50 mL) at −78° C. under N2 was added n-BuLi (3.4 mL, 2.5 M in hexanes, 8.5 mmol) dropwise. The mixture was stirred at −78° C. for 30 minutes, then 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.4 mL, 11.60 mmol) was added. The reaction mixture was warmed to room temperature for 1 hour, then poured into water and extracted with EtOAc. The combined extracts were washed with water and brine, dried (MgSO4), filtered and concentrated to give 2A (1.221 g, 67.5%) as a colorless oil.
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH:9]([CH3:11])[CH3:10])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.ClCCl>[C:12]([O:7][CH2:6]/[CH:5]=[CH:4]/[C:3](/[CH2:1][CH3:2])=[CH:8]/[CH:9]([CH3:10])[CH3:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(/C=C/CO)=C\C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(/C=C/COC(C)=O)=C\C(C)C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a solution of (E,E)-4-ethyl-6-methyl-2,4-heptadien-1-ol (23.8 g) in pyridine (61.4 g) at 0° C. was added dropwise acetic anhydride (50.9 g). After two hours, the reaction mixture was diluted with dichloromethane. The solution was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (3% ethyl acetate-hexane) to give (E,E)-1-acetoxy-4-ethyl-6-methyl-2,4-heptadiene (24.11 g) as an oil.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([C:5]([C:26]1[CH:39]=[CH:38][C:29]([O:30][CH2:31][C@@H:32]2[O:36][C:35](=[O:37])[CH2:34][CH2:33]2)=[C:28]([CH3:40])[CH:27]=1)([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([C:19]([CH2:23][CH3:24])([OH:22])[CH2:20][CH3:21])=[CH:17][CH:18]=2)=[C:10]([CH3:25])[CH:9]=1)[CH2:6][CH3:7])[CH3:4]>O1CCCC1CO>[CH2:6]([C:5]([C:26]1[CH:39]=[CH:38][C:29]([O:30][CH2:31][C@H:32]([OH:1])[CH2:33][CH2:34][C:35]([OH:36])=[O:37])=[C:28]([CH3:40])[CH:27]=1)([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([C:19]([CH2:20][CH3:21])([OH:22])[CH2:23][CH3:24])=[CH:17][CH:18]=2)=[C:10]([CH3:25])[CH:9]=1)[CH2:3][CH3:4])[CH3:7]
Reactant: CCC(O)(CC)c1ccc(-c2ccc(C(CC)(CC)c3ccc(OC[C@H]4CCC(=O)O4)c(C)c3)cc2C)o1
Reactant: [OH-]
Agent: [K+]
Solvent: OCC1CCCO1
Product: CCC(O)(CC)c1ccc(-c2ccc(C(CC)(CC)c3ccc(OC[C@H](O)CCC(=O)O)c(C)c3)cc2C)o1
Temperature: 65 °C
Yield: 89.9 %

Procedure:
A 1 N potassium hydroxide aqueous solution (0.083 mL, 0.083 mmol) was added to a solution of 5(R)-[4-(1-ethyl-1-{4-[5-(1-ethyl-1-hydroxy-propyl)-furan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one (Example 21-(1); 8.6 mg, 0.017 mmol) in tetrahydrofuran-methanol=10:1 (1.1 mL), and the mixture was stirred at 65° C. for one and half hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform/methanol=10/1, saturated with water) to give the title compound as a colorless oil (8.2 mg, 90%).
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.FC(F)(F)C([O-])=O.C([O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[O:35])=[CH:29][CH:28]=1)(=O)C.C(O)C(N)(CO)CO>C1COCC1>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: CC(=O)Oc1ccc(NC(=O)c2ccc(N3CC[NH2+]CC3)cc2)cc1
Reactant: CC(C)COC(=O)Cl
Agent: NC(CO)(CO)CO
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)COC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
2 eq of isobutyl-chloroformate and 3.5 eq of Et3N were added to a solution of 4-[4-({[4-(acetyloxy)phenyl]amino}carbonyl)phenyl]piperazin-1-ium trifluoroacetate in dry THF (0.05 M) and the solution was allowed to stir at RT for 3 h under N2. PS-trisamine resin (excess) was added and the reaction mixture was stirred for 16 h. The resin and a white precipitate were filtered off. Excess aqueous NaOH (1 M) was added to the organic solution and the reaction mixture was stirred for 2 h. The organic solvent was removed in vacuo and aqueous HCl (1 M) was added until precipitation of a white solid that was filtered off, washed and dried in vacuo to afford the title compound (90%).
Reaction SMILES: [CH3:1][C:2](C)([CH3:6])[C:3](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[Cl:12][C:13]1[CH:48]=[CH:47][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:24][CH:25]=3)[CH:20]=[C:19]2[CH2:39][C:40]([CH3:46])([CH3:45])[C:41]([O:43][CH3:44])=[O:42])=[CH:15][CH:14]=1.C(C(C(C([O-])=O)O)O)([O-])=O>C(Cl)Cl.CCOC(C)=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:24][CH:25]=3)[C:20]([C:2]([CH3:6])([CH3:3])[CH3:1])=[C:19]2[CH2:39][C:40]([CH3:45])([CH3:46])[C:41]([O:43][CH3:44])=[O:42])=[CH:47][CH:48]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1c(C(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trimethylacetyl chloride (4.23 g, 4.32 mL, 35.09 mmol) was added to a cold suspension (0° C.) of AlCl3 (11.7 g, 87.7 mmol) in dry CH2Cl2 (60 mL) under Ar. The yellow mixture was stirred at 0° C. for 15 minutes, and a solution of 9.00 g (17.54 mmol) of methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A) in CH2Cl2 (40 mL) was added dropwise (over 10 minutes) at 0° C. The reaction mixture was stirred for 10 minutes and slowly poured onto an ice-cold and vigourously stirred mixture of 0.5M aqueous Na, K tartrate (500 mL) and EtOAc (400 mL). After 20 minutes, the aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with H2O (2×), with 1N aqueous NaOH (2×), with H2O (2×) and dried (MgSO4). Filtration and removal of solvents provided a yellow oily residue which was chromatographed on silica gel using EtOAc-hexane (1:4) to give the title compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][CH:8]([CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:9](OCC)=[O:10])=O)C.[CH3:30][NH2:31]>C(O)C>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH:14]([CH:8]1[O:7][CH2:6][C:4](=[O:3])[N:31]([CH3:30])[C:9]1=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN
Reactant: CCOC(=O)COC(C(=O)OCC)C(Oc1ccccc1OC)c1ccccc1
Solvent: CCO
Product: COc1ccccc1OC(c1ccccc1)C1OCC(=O)N(C)C1=O
Yield: 64 %

Procedure:
4 g of ethyl 2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxyphenoxy)propionate dissolved in 30 ml of ethanol was heated in an autoclave at 150° C. for 20 hours with 20 ml of a 10% ethanolic solution of methylamine. Cooling was allowed to take place and the solvent was removed under reduced pressure. The residue was crystallized from ethanol to obtain 2.26 g of 2-[α-(2-methoxyphenoxy)-benzyl]-4-methyl-morpholin-3,5-dione. Yield 64%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([NH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(CC(=O)O)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCc1ccccc1
Solvent: CCO
Product: CC(CC(=O)O)C(=O)c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
4-(4-Chloro-3-nitro-phenyl)-3-methyl-4-oxo-butyric acid E-4.1′″ (800 mg; 2.95 mmol) is placed in 8 ml ethanol and heated up to 50° C. to get solved. Benzylamine (1.61 ml; 14.73 mmol) is added and the reaction mixture stirred for 3 hours at 100° C. The crude product is purified by using reversed phase chromatography