Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:16]1([CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=1)[OH:17].[OH-].[Na+]>CS(C)=O>[Cl:8][C:7]1[C:2]([O:17][C:16]2[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Oc1ccc(O)cc1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
In procedures similar to those in Example 1 above, except that a 2,3,5-trichloropyridine was used in place of the bis reactant, it was found that reaction of equimolar amounts of the pyridine reactant, hydroquinone and 50% NaOH in dimethylsulfoxide (DMSO) at 100°-116° C. for about 11/2 hours gave product yields of 33% 1,4-((bis(3,5-dichloro-2-pyridinyl)oxy))benzene and about 49% of the desired mono compound, i.e., 4-(3,5-dichloro-2-pyridinyloxy)phenol. Reaction of 0.1 mole of the pyridine reactant with 0.2 mole of the hydroquinone and 0.15 mole of the 50% NaOH (added portionwise to the reaction mixture over a period of about 20 minutes) in 80 ml of DMSO at 90°-100° C. for about 5.5 hours resulted in a product yield of about 16.6% of the bis compound named above and about 75.9% of the desired mono compound. Further operations using equimolar amounts of pyridine reactant to hydroquinone reactant (0.4 mole each) and a mole ratio of base to hydroquinone of 2:1 (0.8 mole 50% caustic, 0.4 mole hydroquinone) in 250 ml of DMSO at temperatures of 100°-113° C. for about 2.5 hours resulted in a product yield of only 4% of the bis compound and 84.4% of the desired mono compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH3:14].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][C:8]=1[CH3:14]
Reactant: Cc1cc(N)ccc1Br
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(NS(C)(=O)=O)ccc1Br
Reaction time: 2 h

Procedure:
Methanesulphonyl chloride (0.88 ml) was added dropwise to a stirred solution of 4-bromo-3-methylbenzenamine (1.02 g) in pyridine (9 ml) under nitrogen at -10° to -14° C. After 2 h, aqueous (8%) sodium bicarbonate (35.6 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The combined, dried organic extracts were evaporated and the residue crystallized from ethyl acetate to give the title compound as a white powder (100 mg). The mother liquors were evaporated onto silica gel (Merck 7734, 3 ml) and the residue applied as a plug to a flash column of silica gel (Merck 9385). Elution with hexane:ethyl acetate (85:15) afforded a further sample of the title compound as a white solid (250 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[Cl:25][CH2:26][C:27](=O)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(CC)CC)C>C(O)C>[Cl:25][CH2:26][C:27]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:4]2[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=2)[N:2]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
2-Amino-3',4,4',5-tetramethoxybenzophenone hydrochloride (36.0 g) and ethyl 4-chloroacetoacetate (21.4 g) were stirred in ethanol (350 ml) under reflux for 7 hours. After completion of the reaction, triethylamine (10.6 g) was added dropwise at a temperature not over 20° C. and the mixture was stirred at 5° C. for 1 hour. The crystals were collected by filtration, washed twice with 50 ml each of ethanol and dried under reduced pressure to provide ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (41.0 g; yield 92%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].CON(C)[C:18]([C:20]1[S:24][C:23]([CH3:25])=[N:22][C:21]=1[CH3:26])=[O:19]>C1COCC1>[CH3:25][C:23]1[S:24][C:20]([C:18]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)=[O:19])=[C:21]([CH3:26])[N:22]=1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1sc(C)nc1C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)c2cncn2C)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 5-bromo-1-methyl-1H-imidazole (390 mg, 2.42 mmol) was added THF (8 mL) and the solution was cooled to 0° C. To this clear homogeneous solution was added isopropyl magnesium chloride-LiCl complex (1.3 M in THF, 2.5 mL, 3.25 mmol) which resulted in a white suspension. The mixture was stirred at 0° C. for 30 min, then a THF solution (2 mL) of N-methoxy-N,2,4-trimethylthiazole-5-carboxamide (550 mg, 2.75 mmol, Intermediate 41, step a) was introduced and the mixture was allowed to warm to room temperature. After 3 hours at room temperature the mixture was heated to 50° C. for 18 hours, followed by quenching with NH4Cl solution. The aqueous portion was extracted with DCM (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (25-50% EtOAc-DCM increasing gradient to 5% MeOH-DCM) provided the title compound as an amber solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH3:13]/[C:14](/[C:17]([CH3:19])=O)=[N:15]\[OH:16].[ClH:20].C(OCC)C>C(O)(=O)C>[ClH:20].[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7]2[O:8][C:17]([CH3:19])=[C:14]([CH3:13])[N+:15]=2[O-:16])=[CH:5][CH:4]=1
Reactant: CC(=O)/C(C)=N/O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Temperature: 25 °C
Yield: 86 %

Procedure:
34.8 g (0.20 mol) of 4-trifluoromethylbenzaldehyde and 20.2 g (0.20 mol) of 2,3-butanedione monoxime were dissolved in 100 ml of glacial acetic acid and the mixture was stirred at room temperature while passing gaseous hydrogen chloride through the mixture until a saturated solution was obtained. The mixture was stirred at room temperature overnight and then treated with an excess of anhydrous diethyl ether. The colourless crystalline precipitate was filtered off, washed free of mother liquors using fresh anhydrous diethyl ether and dried in vacuo to give 50 g (86%) of 2-(4-trifluoromethylphenyl)-4,5-dimethyloxazole N-oxide hydrochloride of melting point 175°-177° C. (decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[C:6]([O:10][C:11](=O)[O:12]C(C)(C)C)([CH3:9])([CH3:8])[CH3:7]>>[CH3:7][C:6]([O:10][C:11](=[O:12])[NH:1][CH2:2][CH2:3][CH2:4][NH2:5])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCCN
Product: CC(C)(C)OC(=O)NCCCN

Procedure:
In Step 1, 1,3-diaminopropane (II) is reacted with a di-t-butylcarbonate (III) to give 3- aminopropyl carbamic acid 1,1-dimethylethyl ester (IV).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(O)C>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)=[CH:23][CH:22]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=Cc1ccc(F)cc1
Agent: [Na]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(F)cc2)cc1
Reaction time: 0.08 h

Procedure:
A solution of diethyl p-nitrobenzylphosphonate (2.73 g) in ethanol (10 mL) was added to a solution of sodium (0.245 g) in ethanol (20 mL). The resulting mixture was stirred for 5 min, and then a solution of 4-fluorobenzaldehyde (1.24 g) in ethanol (10 mL) was added. The reaction mixture was stirred for 1 h. a yellow precipitate (1.444 g) was isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:4]=2[N:3]=1.[CH2:19]([O:21][C:22](=O)[O:23]CC)[CH3:20].[Li+].CC([N-]C(C)C)C>C1COCC1>[C:15]([O:14][C:12]([N:5]1[C:4]2[N:3]=[C:2]([CH2:1][C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)OCC
Reactant: Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 83.6 %

Procedure:
The compound was prepared according to the procedure as described in WO 00/33838. To a solution of 2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine (1.4 g, 5.6 mmol) and diethylcarbonate (2.5 g, 20 mmol) in THF (10 ml) was added LDA (8 ml of 2M solution in hexane) at −78° C. and stirred at −78° C. for 40 minutes. The reaction was quenched with saturated NH4Cl and extracted with ethylacetate (2×100 ml). Combined organic solution was concentrated and purified on silica gel column to give 1.5 g (83%) yellow oil. NMR (CD3OD) δ 1.25 (t, 3H, J=7.10 Hz), 1.51 (s, 9H), 1.88-1.97 (m, 2H), 2.75 (t, 2H, J=6.59 Hz), 3.74-3.80 (m, 4H), 4.10-4.20 (m, 2H), 7.0 (d, 1H, J=7.61 Hz), 7.39 (d, 1H, J=7.47 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH3:11].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:10]([S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CCBr
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a stirred solution of 4-fluorobenzenethiol (80 g, 0.625 mol) and bromoethane (71.88 g, 0.666 mol) in DMF (1.25 L) under nitrogen atmosphere, Cs2CO3 (213.75 g, 0.666 mol) was added. The reaction mixture was stirred at 25° C. overnight. TLC (petroleum ether) indicated the reaction was complete. The mixture was diluted with water (800 mL), extracted with ethyl acetate (600 mL×3). The combined organic layers were washed with water (500 mL×2) and brine (500 mL), dried over Na2SO4 and concentrated in vacuum to give ethyl(4-fluorophenyl)sulfane (60 g, 61.5%) as a colorless oil. A mixture of ethyl(4-fluorophenyl)sulfane (60 g, 0.38 mol), acetic acid (1 L) and 30% H2O2 (180 mL) was stirred at reflux under N2 overnight. TLC (petroleum ether:ethyl acetate=4:1) indicated the reaction was complete. After cooled to room temperature, the reaction mixture was poured into water (500 mL). Then NaHSO3 (200 g) was add. The mixture was extracted with ethyl acetate (500 mL×3), dried over Na2SO4 and concentrated in vacuum to remove the remaining acetic acid. Then the residue was poured into saturated aq. NaOH (800 mL) and extracted with ethyl acetate (500 mL×3) again. The organic layer was dried over Na2SO4 and concentrated in vacuum to give the title compound (66 g, 92.4%) as a colorless liquid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:9][C@H:10]([OH:32])[C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:47]([S:49][CH2:50][CH3:51])[CH3:48].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:9][C@H:10]([O:32][CH:47]([S:49][CH2:50][CH3:51])[CH3:48])[C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:24]([CH3:30])=[CH:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O
Reactant: CCSCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCSC(C)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O)[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C
Yield: 61 %

Procedure:
To a solution of the compound of Example 3 (0.50 g, 0.80 mmol) and ethyl sulfide (2.1 mL) in acetonitrile (6 mL) at 0° C. was added benzoyl peroxide (1.16 g) in three portions over 3 hours. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient of 50-100% ethyl acetate in chloroform to give the title compound (0.36 g, 61% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:19][C:9]1[C:2]([F:1])=[CH:3][C:4]([O:10][CH3:11])=[C:5]([CH:8]=1)[C:6]#[N:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(F)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(Br)cc1C#N
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a 500 mL flask was added 4-fluoro-2-methoxybenzonitrile (9.00 g, 59.5 mmol), NBS (12.7 g, 71.5 mmol) and TFA (40 mL); the resulting mixture was stirred for 4 h at 65° C. Analysis of the reaction by LC indicated completion of the reaction. The reaction mixture was concentrated to dryness, treated with EtOAc (200 mL) and washed with brine and water, dried (Na2SO4), filtered and concentrated to dryness. The resulting organic residue was purified by MPLC with the solvent systems of hexanes/EtOAc=1/1 to furnish the desired product: LC/MS: [(M+2)]+=232;
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCCCCCCCCBr)OCc1ccccc1
Yield: 101.9 %

Procedure:
This compound was prepared from 11-bromoundecanoic acid (2.65 g; 10.0 mmol), benzyl alcohol (1.62 g; 15.0 mmol), and p-toluenesulphonic acid (50 mg) in toluene (100 mL) using Procedure B. 3.62 g product was obtained, which was used in 13b without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([OH:13])(=O)[CH2:8][CH2:9][C:10]#[CH:11].[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][CH3:22])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([N:21]([CH3:22])[C:7](=[O:13])[CH2:8][CH2:9][C:10]#[CH:11])[CH:18]=[CH:19][CH:20]=1
Reactant: C#CCCC(=O)O
Reactant: CNc1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C#CCCC(=O)N(C)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Oxalyl chloride (89 μL, 1.02 mmol) was added to a solution of pent-4-ynoic acid (50 mg, 0.51 mmol) in DCM (3 mL). The reaction mixture was stirred at 50° C. for 1 hour, was cooled to 0° C. and was added dropwise to a solution of (3-chloro-phenyl)-methyl-amine (62 μL, 0.51 mmol). The reaction mixture was stirred for 2 hours at room temperature. After evaporation of the solvent, the crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 100 mg (0.45 mmol, 88%) of pent-4-ynoic acid (3-chloro-phenyl)-methyl-amide.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH2:13](O)[CH3:14]>C(Cl)(Cl)Cl>[N+:1]([CH2:4][CH2:5][C:6]([O:8][CH2:13][CH3:14])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)CC[N+](=O)[O-]
Reactant: CCO
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CC[N+](=O)[O-]

Procedure:
A suspension of 116 g (0.97 mole) β-nitropropanoic acid (CAS number 504-88-1) in chloroform (1 l) is stirred and treated with 127.5 g (1.07 mole) thionyl chloride. A rapid evolution of gas takes place and the mixture is stirred one hour at room temperature. Ethanol (50 g, 1.07 mole) is added dropwise followed by rapid gas evolution. The mixture is stirred 72 hours, concentrated and distilled to yield ethyl β-nitropropanoate, bp 95°-105° C. at 15 mm. A solution of 182 g (1.84 mole) ethyl acrylate [CAS number 140-88-5] in t-butanol (150 ml) and 10 ml of Triton B is treated at 40° C. with 135.5 g (0.92 mole) of ethyl β-nitropropanoate. Additional portions of Triton B (2 ml×3) and ethyl acrylate (25 g×3) are added over a five-hour period. The mixture is cooled and poured into a solution of 100 ml of concentrated hydrochloric acid in water (1 l). The diethyl-γ-nitro-γ-carboethoxymethylpimelate is extracted using dichloromethane (4×500 ml). The combined extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated to yield an oil. The oil (160 g) is dissolved in ethanol (1.5 l) and treated with hydrogen in the presence of 7 g 20% Pd/C. The mixture is filtered through filter aid and concentrated to yield a mixture of 5-carboethoxyethyl-5carboethoxymethyl-2-pyrrolidinone (major product), 5-carboethoxymethyl-5-carboxyethyl-2-pyrrolidinone, and 5-carboethoxyethyl-5-carboxymethyl-2-pyrrolidinone as an oil. The oil dissolved in 1 l of 50% ethanol is titrated with a solution of 50% sodium hydroxide with stirring at reflux accompanied by removal of ethanol. The hydrolyzed mixture is neutralized with concentrated hydrochloric acid to yield 5-carboxyethyl-5-carboxymethyl-2-pyrrolidinone in water. The water is removed at reduced pressure and the resulting solid is added to acetic anhydride (1 kg) with stirring. The mixture is heated at 100° C. for 16 hours. The mixture is filtered through filter aid and concentrated at reduced pressure to yield tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)acetic acid anhydride with acetic acid as an oil. The oil is dissolved in a minimum amount of acetonitrile, an equivalent amount of water is added, and the mixture is stirred 16 hours. The mixture is concentrated at reduced pressure to yield a solid. The solid is recrystallized from acetonitrile to yield tetrahydro-3,5 -dioxo-1H-pyrrolizine-7a(5H)-acetic acid with a melting point of 177°-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.51 g (29.6 mmol) of 3-bromo-4-methylaniline were dissolved in 127 ml of dichloromethane, 6.18 g (29.6 mmol) of 3-(trifluoromethyl)benzoyl chloride and 4.54 ml (32.6 mmol) of triethylamine were added and the mixture was stirred at RT for 30 min. All volatile components were removed under reduced pressure and the residue was suspended in 50 ml of methanol. The solid was filtered off and the filtrate was stirred into 100 ml of 1 M hydrochloric acid. The precipitate formed was filtered off, washed with water and dried. This gave 7.05 g (90% pure, 60% of theory) of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[C:20]3[NH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].C([N+]([CH2:29][CH3:30])(CC)CC)C>CC(C)=O>[C:30]1([C:9]2[CH:10]=[CH:11][C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:19][C:20]=3[C:8]=2[C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH:29]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CC[N+](CC)(CC)CC
Reactant: Ic1cccc(-c2cccc3c2[nH]c2ccccc23)c1
Agent: [OH-]
Solvent: CC(C)=O
Product: c1ccc(-c2ccc3c([nH]c4ccccc43)c2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
91 g (242 mmol) of 3-iodophenylcarbazole 11 and 91 g (246 mmol) of phenylcarbazoleboronic ester 12 are suspended in acetone, and a 350 ml of 20% tetraethylammonium hydroxide solution (493 mmol) are added, the mixture is carefully degassed using argon. 4.6 g (4 mmol) of tetrakis-triphenylphosphinepalladium are subsequently added. The reaction is heated to 70° C. The progress of the reaction is followed by means of thin-layer chromatography. When the reaction is complete, the batch is cooled to room temperature, and the precipitated product is filtered off with suction. The crude product is recrystallised from acetonitrile, giving a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.[Cl:20][CH2:21][C:22](Cl)=[O:23].Cl>O1CCCC1>[Cl:20][CH2:21][C:22]([NH:4][C:3]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:2]=1[CH3:1])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C)c(N)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C)c(NC(=O)CCl)c1
Reaction time: 27 h

Procedure:
To a solution of 2-methyl-5-methoxyaniline (4.7 g) in tetrahydrofuran (50 ml), under nitrogen, was added diisopropylethylamine (12.6 ml) followed by dropwise addition of chloroacetyl chloride (2.7 ml) and the mixture stirred under nitrogen for 27 hours. The solution was poured into 2M aqueous hydrochloric acid (150 ml), extracted into diethyl ether (3×150 ml), washed with brine, dried (MgSO4), and concentrated to give the sub-title compound as a brown oil (5.15 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10]2)=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[CH:2].[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)[CH3:23]>C(N(CC)CC)C.[Cu]I.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>[CH2:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:29]3[CH:30]=[CH:31][C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:33])=[CH:27][CH:28]=3)=[CH:4][C:5]=2[CH2:20][CH3:21])[CH2:11][CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(CC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90, 90.0 mg, 0.33 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for minutes. Dichlorobis(triphenylphosphine)palladium(II) (77 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 100.0 mg (72%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:34][C:35]1[CH:40]=[C:39]([CH2:41]O)[CH:38]=[CH:37][N:36]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:34][C:35]1[CH:40]=[C:39]([CH2:41][O:14][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Nc1cc(CO)ccn1
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 4-nitronaphthol (5.17 g, 27.3 mmol), PPh3 (10.75 g, 41.0 mmol) and 2-aminopyridine-4-methanol (1) (5.09 g, 41.0 mmol) in THF (50 mL) was added dropwise DIAD (8.07 mL, 41.0 mmol) at −15° C. The mixture was stirred overnight at RT and the volatiles removed in vacuo. The crude product was triturated from EtOAc (150 mL), filtered off and washed with EtOAc (100 mL). A second trituration from MeOH (100 mL) gave 2-amino-4-((4-nitronaphthalen-1-yloxy)methyl)pyridine (2) (4.54 g, 56%) as a yellow solid: m/z 296 (M+H)+ (ES+).