Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O.[Cl-].[Ca+2].[Cl-]>>[C:1]1([CH2:7][CH2:8][C:9]([Cl:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: O=S(Cl)Cl
Agent: [Ca+2]
Agent: [Cl-]
Product: O=C(Cl)CCc1ccccc1

Procedure:
To a 100 ml eggplant-shaped flask were added 20.0 g (133.2 mmol) 3-phenylpropionic acid and 24.5 g (205.9 mmol) thionyl chloride, a reflux condenser pipe carrying a calcium chloride drying pipe and a sodium hydroxide acidic gas absorption device was mounted, the mixture was refluxed for 1 hour under magnetic agitation, distilled under reduced pressure to remove excessive thionyl chloride to give crude 3-phenylpropionyl chloride as a pale yellow oil, which was directly used in the reaction of following step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].N([O-])=O.[Na+].[ClH:25]>CN(C)C=O.O>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:25])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(Oc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The product (10 g) from paragraph (a) was dissolved in dimethyl formamide (150 ml), cooled to 5°-10° C. and concentrated hydrochloric acid (40 ml) added dropwise, the temperature being kept at 10°-15° C. The mixture was then kept at 5° C. while sodium nitrite (5.2 g) in water (20 ml) was added dropwise with stirring over a period of 30 minutes. The solution so prepared was added dropwise to a solution of cuprous chloride (19 g) in concentrated hydrochloric acid (150 ml) kept at 10° C., giving a thick green suspension. When addition was complete, the mixture was left to stand overnight and then heated to 60° C. for 30 minutes. The white solid was filtered off, dried, and recrystallised from petroleum (100°-120° C.) to give 3(2,4-dichlorophenoxy)benzoic acid (5.1 g) with a melting point of 143°-144° C. This compound was used as starting material for compound no 19 of Table 1.
Reaction SMILES: [CH:1]1[C:6]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=[C:3]([F:12])[CH:2]=1.S(Cl)(Cl)=O.[CH3:17]O>>[NH2:11][C@H:7]([C:6]1[CH:5]=[CH:4][C:3]([F:12])=[CH:2][CH:1]=1)[C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: N[C@@H](C(=O)O)c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4 g (R)-4-fluorophenylglycine are suspended in 80 ml of methanol. While cooling with the ice bath 3.28 ml of thionyl chloride are slowly added dropwise, so that the temperature is maintained between 15° C. and 20° C. The reaction mixture is stirred for 12 hours at ambient temperature and then evaporated to dryness. 5.1 g of the product are obtained as the hydrochloride. Analytical HPLC-MS (method A): RT=0.8 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].I[CH3:17]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:17])=[CH:7][CH:6]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(C)c2c1
Reaction time: 1 h

Procedure:
A mixture of methyl-indole-6-caroxylate (3.0 g, 16.6 mmol), sodium hydride (1.0 g, 24.9 mmol), DMF (20 ml) was stirred for 1 h at room-temperature followed by addition of iodomethane (4.7 g, 33.2 mmol) and stirring at room-temperature for 15 h. The mixture was extracted with chloroform and evaporated. The product was isolated by evaporation. Yield 3.2 g (100%).
Reaction SMILES: ClCCl.[C:4]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:7])([CH3:6])[CH3:5].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:15]([NH:22][CH:11]1[CH2:12][CH2:13][N:8]([C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:9][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)N1CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)N1CCC(NCc2ccccc2)CC1

Procedure:
A dichloromethane solution (3 mL) containing 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) (120 mg, 0.77 mmol), benzyl amine (0.17 mL, 1.56 mmol), acetic acid (0.05 mL) and sodium triacetoxy borohydride (246 mg, 1.16 mmol) was stirred for several days. The solution was concentrated and the residue partitioned between aqueous potassium carbonate and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using CHCl3/MeOH/NH4OH (87/12/1) as eluent to give N-benzyl-1-tert-butylpiperidin-4-amine. Mass spectrum (ESI) 247 (M+1). 1H NMR (500 MHz, CD3OD): δ 1.09(s, 9H); 1.38-1.48(m, 2H); 1.91-1.97(m, 2H); 2.11-2.18(m, 2H); 2.40-2.48(m, 1H); 3.02-3.08(m, 2H); 3.76(s, 2H); 4.87(s, 1H); 7.21-7.26(m, 1H); 7.29-7.36(m, 4H).
Reaction SMILES: [CH3:1][Li].C[Mg]Cl.[CH3:6][C:7](=[O:28])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@H:15]([CH2:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1>O1CCCC1.C(OCOCC)C>[CH3:6][C:7]([C@@H:8]1[C@@:25]2([CH3:26])[CH2:24][CH2:23][C@@H:22]3[C@@:20]4([CH3:21])[CH2:19][CH2:18][C@:17]([OH:27])([CH3:1])[CH2:16][C@@H:15]4[CH2:14][CH2:13][C@H:12]3[C@@H:11]2[CH2:10][CH2:9]1)=[O:28]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [Li]C
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCOCC
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
A mixture of ferric chloride (anhydrous, 1.63 g, 10.06 mmol) in tetrahydrofuran (anhydrous, 35 ml) is cooled to −50° C. under nitrogen. Methyllithium (3M, 3.4 mL, 10.2 mmol) in diethoxymethane is added to the ferric chloride mixture, maintaining the temperature below −40° C. After this addition is complete methyl magnesium chloride solution (3M, 10.1 ml, 30.18 mmol) in tetrahydrofuran is added maintaining the internal temperature below −40° C. After 10 min. at −40° C., 5α-pregnane-3,20-dione (2.84 g, 9 mmol) is added in one portion with stirring. The temperature is brought to −20° C. and stirred for 3.5 hours. The reaction is quenched by addition of 3 ml of acetic acid and the tetrahydrofuran was removed in vacuo. The residue is partitioned between 100 ml of 3N HCl and 200 ml of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and brine and the solvent is removed in vacuo to afford crude ganaxolone (94.8% purity by HPLC) (Table 1, entry 5)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[C:9]1([S:15][CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClC(Cl)C>[CH3:16][S:15][C:9]1[CH:14]=[CH:13][C:12]([C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=1
Reactant: CSc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CSc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Acetyl chloride (8.2 g, 0.105 mol) is added to a suspension of AlCl3 (16 g, 0.12 mol) in dichloroethane (50 ml) cooled to 0° C.; the mixture is stirred for 15 min and a solution of thioanisole (12.4 g, 0.1 mol) in dichloroethane (20 ml) is then added dropwise; the temperature is kept below 20° C. by cooling (30 min). The mixture is stirred for a further 1 h and allowed to stand at RT overnight. The Lewis acid complex is decomposed by addition of ice water (100 ml) with cooling, the organic phase is separated in a separating funnel, and the aqueous phase is extracted a further 2 times with dichloroethane (100 ml). The combined extracts are dried over Na2SO4 sicc. and concentrated to ¼ of the starting volume. The red-brown residue (15.2 g) is washed with diethyl ether (20 ml) and hexane (20 ml): 12 g of light red (brick-red) substance result.
Reaction SMILES: O.O.O.C([O-])(=O)C.[Pb+2:8].C([O-])(=O)C.[Pb]=O.[C:15]([OH:34])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:15]([O-:34])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[Pb+2:8].[C:15]([O-:34])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: O=[Pb]
Agent: [Pb+2]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Temperature: 150 °C

Procedure:
1.421 g of lead acetate trihydrate (or lead oxide (PbO)) and 5 ml oleic acid were added into a reaction vessel containing 20 ml diphenyl ether solution and heated to a temperature of about 150° C. for 30 min to form a lead oleate. After cooling to 60° C., this solution was mixed with 12 ml TOPSe (or TOPTe) stock solution to prepare injecting precursor. Reaction was carried out at various injecting and reaction temperatures. Also various molar ratio of lead oleate to TOPSe stock solutions were tested for injecting precursor to find the optimum conditions of reaction. Typically, injecting the precursor solution at 130° C. of 30 ml diphenylether solution and keeping the reaction temperature at 110° C. for 5 min yielded approximately 5 nm sphere PbSe quantum dots. For the synthesis of larger size (>10 nm) cubic shape PbSe dots, lower injecting temperatures (<110° C.) or second injection of additional precursors at about 30% the amount of that in the first injection after the nucleation have been used were used
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][C:13]([CH3:15])=O.C(OC(=O)C)(=O)C>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[C:13](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])([CH3:15])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)=C(C)C
Yield: 41 %

Procedure:
There were placed diethyl malonate (133 g, 0.83 mol), acetone (72 g, 1.24 mol), acetic anhydride (106 g, 1.05 mol) and zinc chloride (17.0 g, 0.125 mmol in a 500 ml three neck flask. After 24 hour reflux, benzene (200 ml) was added and the reaction mixture was washed with water (100 ml×4). The aqueous layer was further extracted with benzene (50 ml×2). The organic layers were combined and concentrated. The residue was distilled under reduced pressure to give oily product, diethyl isopropylidenemalonate (68.0 g, 0.34 mol, 41.0%, b.p.: 112° C./9 mmHg). The structure was confirmed by the following data.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCOCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2sccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: BrCc1ccc2sccc2c1
Yield: 99.8 %

Procedure:
A mixture of 5-methylbenzo[b]thiophene (3.8 g, 25.6 mmol), NBS (4.7 g, 27 mmol), and benzoyl peroxide (310 mg, 1.3 mmol) were refluxed one hour in CCl4 (100 mL) while being irradiated with a sunlamp. Upon completion, the reaction was cooled, diluted with Et2O, filtered and concentrated to yield 5.8 g of 5-bromomethylbenzo[b]thiophene. The crude 5-bromomethylbenzo[b]thiophene was refluxed for 36 hours in 1:1 dioxane/2N aq. NaOH (128 mL). After cooling, extraction with EtOAc and concentration of the extracts, the residue was chromatographed on silica gel eluting 2.6 g of 5-hydroxymethylbenzo[b]thiophene with 35% EtOAc/hexane. The title compound (1.96 g) was obtained after filtration and concentration of the reaction product produced by refluxing 5-hydroxymethylbenzo[b]thiophene (2.08 g, 12.7 mmol) and 50% MnO2 /C (17.6 g, 101 mmol) for five hours in toluene while H2O was continually removed using a Dean-Stark trap.
Reaction SMILES: C1([C@H](NCC2C=CC=C(C(C)(C)C)C=2O)[C@@H](NCC2C=CC=C(C(C)(C)C)C=2[OH:27])C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[CH:46]([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2.C(OO)(C)(C)C>C1(C)C=CC=CC=1>[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[C:46]([OH:27])([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Reactant: CC(C)(C)c1cccc(CN[C@@H](c2ccccc2)[C@@H](NCc2cccc(C(C)(C)C)c2O)c2ccccc2)c1O
Agent: CC(C)(C)OO
Solvent: Cc1ccccc1
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 85 %

Procedure:
A chiral zirconium complex was prepared by rapidly stirring (forming a vortex) a mixture of zirconium(I) acetylacetonate (43.5 mg, 0.089 mmol) and 2,2′-[[(1S,2S)-1,2-diphenyl-1,2-ethanediyl]bis(iminomethylene)]bis[6-(1,1-dimethylethyl)-phenol] (Formula IIIb wherein R6 is H, 0.096 g, 0.18 mmol) in toluene (1.00 mL) at 50° C. for one hour. The resulting solution was evaporated to dryness in vacuo, then a solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (0.500 g, 2.23 mmol) (Formula IIa wherein R1 is OCH3 and R4 is Cl) in toluene (2.00 mL) was added. The reaction mixture was heated to 65° C., and then an aqueous solution of tert-butyl hydroperoxide (70%, 0.316 g, 0.340 mL, 2.46 mmol) was added. After 3.5 hours at 65° C., the reaction was quenched by adding an acetonitrile solution (7.00 mL) containing biphenyl (0.125 g) as an HPLC internal standard and cooling to ambient temperature. Analysis by quantitative and chiral HPLC showed 100% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 85% yield (85% chemoselectivity) and 94% enantiomeric excess of the S-enantiomer.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:23]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 2-butylbenzimidazole (0.52 g) in DMF (4 ml) was added, under cooling with ice, sodium hydride (60% oil, 0.13 g), and then the mixture was stirred for 20 minutes. To the resultant mixture was added methyl 2-(4-bromomethylphenyl)benzoate (1.0 g), which was stirred for 1.5 hour at room temperature. To the mixture was added water, followed by extraction with ethyl acetate. The solvent was evaporated to dryness to give an oily residue. The oil was purified by column chromatography on silica gel to obtain a colorless oil (1.2 g, quantitatively).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 91.4 %

Procedure:
A mixture of 3,5-dichlorophenylboronic acid (5 g, 26.2 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (5 g, 28.6 mmol), K2CO3 (7.24 g, 52.4 mmol) and Pd(PPh3)2Cl2 (368 mg) in THF (20 mL) and H2O (10 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether (50 mL) and H2O (50 mL). The aqueous layer was extracted with ether (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with hexanes to afford 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (5.77 g; yield 85%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.42 (t, J=2.0 Hz, 2 H), 7.34 (d, J=2.0 Hz, 1 H), 6.05 (s, 1 H), 5.82 (s, 1 H) ppm.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1>>[CH2:2]1[CH:1]2[CH:7]3[C:6](=[O:12])[O:11][C:9](=[O:10])[CH:8]3[CH:3]1[CH:4]=[CH:5]2
Reactant: O=C1C=CC(=O)O1
Reactant: C1=CCC=C1
Product: O=C1OC(=O)C2C3C=CC(C3)C12
Yield: 25 %

Procedure:
The Diels-Alder adduct from cyclopentadiene and maleic anhydride, endo-cis-5-norbornene-2,3-dicarboxylic anhydride, m.p. 165° C, was heated at 220° C. for 4 hours. On cooling, the product solidified with a melting point of 101° C. The crude reaction product was recrystallized from benzene three times to isolate exo-cis-5-norbornene-2,3-dicarboxylic anhydride, m.p. 141° C., in 25% yield.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].S(Cl)([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1O
Temperature: 10 °C
Reaction time: 16 h

Procedure:
A suspension of compound of Example 1a (1.0 eq) in DCM (approx 4.5 vol) is treated with thionyl chloride (1.0-1.2 eq, for example 1.1 eq) and catalytic amount (0.0055 eq) of DMF and the mixture is stirred for 16 h at reflux. Unreacted thionylchloride is distilled off with DCM and the residue after distillation is diluted with THF (approx 1.8 vol) and cooled to 10° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:15][C:16]#[CH:17]>CC(C)=O.C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:17][C:16]#[CH:15])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C#CCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.5 %

Procedure:
To a stirred, chilled suspension of 1-methylpiperazine (10.0 g, 100.0 mmol) and cesium carbonate (32.6 g, 100.0 mmol) in acetone (200 mL) was added 3-bromoprop-1-yne (11.0 mL, 100 mmol) (80% in toluene). The reaction was stirred for 18 hours at room temperature under N2. The suspension was diluted with diethyl ether (200 mL) and filtered, and the filtrate was concentrated in vacuo. The resulting residue was resuspended in diethyl ether (100 mL) and refiltered. The filtrate was concentrated to an orange oil (8.2 g). The product was distilled under high vacuum. The product distilled between 95-120° C. head temperature. The product was obtained as a colorless oil (5.46 g, 32%). 1H NMR (400 MHz, CDCl3) δ 3.31 (m, 2H), 2.89 (m, 1H), 2.3-2.6 (m, 8H), 2.30 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH:12]([CH3:13])[CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCC(C)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1
Yield: 82.9 %

Procedure:
4.0 g of p-hydroxybenzoic acid and 12.5 g of (-)-2-methylbutanol were refluxed for 6 hours in toluene in the presence of sulfuric acid, while removing the generated water out from the reaction system. Subsequently, the reaction solution was washed with water to remove sulfuric acid out. The reaction solution was then dried and concentrated, and the concentrate was purified by column chromatography, to obtain 5.0 g of the objective ester compound (liquid state at room temperature, [α]D23 =4.9° (CHCl3)). (Yield: 83%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:27])[CH2:23][C:22](=O)[CH2:21][C:20]([CH3:26])([CH3:25])[O:19]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:22]2[CH2:21][C:20]([CH3:26])([CH3:25])[O:19][C:18]([CH3:27])([CH3:17])[CH2:23]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)O1
Yield: 86.8 %

Procedure:
The general McMurry procedure, described for 14 was employed using (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (2.10 g, 7.58 mmol), and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (1.40 g, 8.96 g). Standard work-up followed by purification gave 2.64 g (87%) of the title compound 211 as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.37 (s, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.7 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 2.16 (s, 2H), 2.10 (s, 2H), 1.13 (s, 6H), 1.12 (s, 6H). LCMS (ESI): m/z 399 and 401 (M−H)−.
Reaction SMILES: C1(SC2C=CC=CC=2)C=CC=CC=1.[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(O)(=O)C.S(Cl)([Cl:33])(=O)=O>C(Cl)Cl>[Cl:33][C:19]1[CH:18]=[C:17]([O:16][C:15]([F:24])([F:25])[F:14])[CH:22]=[CH:21][C:20]=1[OH:23]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1ccc(OC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
0.05 part by weight of diphenyl sulfide is added to a solution of 8.9 parts by weight of 4-trifluoromethoxyphenol in 30 parts by weight of glacial acetic acid, and 6.8 parts by weight of sulfuryl chloride are then added dropwise, without cooling. The mixture is subsequently stirred at room temperature for 3 hours, the solvent is stripped off and the residue is taken up in 50 parts by weight of methylene chloride. This solution is twice washed with 50 parts by weight of saturated bicarbonate solution, and is dried and concentrated. Distillation of the residue under reduced pressure gives 9.8 parts by weight (92% of theory) of 2-chloro-4-trifluoromethoxyphenol of boiling point 70° C./13 mbar.
Reaction SMILES: [C:1]([NH2:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].I[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([NH2:8])=[O:7])[CH:18]=[CH:17][CH:16]=2
Reactant: C#CCCCC(N)=O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCC(N)=O)c21

Procedure:
Using Method C above, 5-hexynamide (46 mg, 0.4 mmol) (prepared from 5-hexynoic acid by Method G above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (113 mg, 0.31 mmol) using (Ph3P)2PdCl2 (12 mg) and CuI (6 mg) as catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70° C. for 22 h yielding (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynamide. (Yield 52 mg, 48%).