Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Na+].Cl.[NH2:15]C1C=CC(C)=CC=1>O>[CH2:1]=[CH:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:7][CH:8]=1.[NH4+:15]
Reactant: Cc1ccc(N)cc1
Agent: C=Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [NH4+]

Procedure:
A 20.6 g sample of sodium p-styrenesulfonate was dissolved in 100 g of water. 14.4 g of p-toluidine hydrochloride was added to the resulting solution to precipitate a solid. The solid was filtered and was dissolved in 100 cc of aqueous solution containing 20 cc of 28.8% NH3 solution. As a result, ammonium p-styrenesulfonate was obtained in a conversion of 76%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][OH:14].[H-].[Na+].O>CS(C)=O>[CH3:11][C:12]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][O:14][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC(C)(CO)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(COc1ccc([N+](=O)[O-])cc1)c1ccccc1
Yield: 72 %

Procedure:
In 200 ml of dimethylsulfoxide are dissolved 23 g of 4-nitrochlorobenzene and 25 g of 2,2-dimethyl-2-phenylethylalcohol. To this solution is added 4 g of sodium hydride is added with stirring. After 24 hours stirring at room temperature and another 30 minutes stirring at 60° C, 500 ml of water is added and the mixture is extracted with ether. The extract is washed with water, dried and the solvent is evaporated. Recrystallization of the residue from 200 ml of methanol, gives 28.5 g of 4-(2,2-dimethyl-2-phenylethyloxy)nitrobenzene, melting point: 79°-80° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](I)[CH3:24].O>CN(C)C=O>[CH2:23]([N:9]([C:10]1[C:11]([F:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:24]
Reactant: COC(=O)c1cccc(NC(=O)c2ccccc2)c1F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccccc1)c1cccc(C(=O)OC)c1F
Yield: 61.2 %

Procedure:
Methyl 3-benzamido-2-fluorobenzoate (3.10 g, 11.0 mmol) was dissolved in N,N-dimethylformamide (30 ml), and the solution was cooled. 60% Sodium hydride (0.53 g, 13.2 mmol) was added thereto, and the reaction mixture was agitated without heating or cooling. 10 minutes later, ethyl iodide (2.05 g, 13.0 mmol) was added to the mixture, and the mixture was agitated overnight at room temperature. Water was added dropwise to the reaction mixture, and the reaction mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, and then the filtrate was concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (developer solvent: ethyl acetate/n-hexane=1/5), as a result of which 2.03 g (yield: 61%) of the indicated compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([F:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15].[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C>[Cl:12][CH2:13][C:14]([C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[F:11])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(F)cc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1cc(F)c(C(=O)CCl)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution consisting of 3,5-dimethoxy fluorobenzene 26 (5.0 g, 32 mmol) and chloroacetyl chloride (4.3 g, 38 mmol) in dichloroethane (100 mL) was cooled to 0° C. and treated with AlCl3 (5.1 g, 38 mmol). The reaction was allowed to rt and stirred for 1 h and then washed with 2N HCl aq, brine, dried over MgSO4, filtered, concentrated and chromatographed on silica gel (1:9 EtOAc/hexanes to 2:8 EtOAc/hexanes) to yiled th product 27 (1.2 g) as a white solid: Mp 93-96° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(OCC)(OCC)=O)=[O:5].C([Li])CCC.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[C:23]1(/[CH:22]=[CH:8]/[CH:7]=[CH:6]/[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C=C/c1ccccc1
Yield: 82.1 %

Procedure:
To a solution of 16 ml (72 mmol) of triethyl 4-phosphonocrotonate in anhydrous tetrahydrofuran (100 ml) was added 43 ml (69 mmol) of a 1.6 M n-butyllithium solution dropwise with stirring in an ice-salt bath under nitrogen, and the mixture was stirred for 30 minutes. Then, 5.0 ml (49 mmol) of benzaldehyde was added dropwise to this reaction mixture over about 5 minutes, and the resultant mixture was stirred for 10 minutes in the ice-salt bath and for an additional 3 hours at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to conduct extraction with ether. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resultant crude oil (15.9 g) was purified by chromatography on silica gel, thereby obtaining 8.14 g (yield: 82%) of ethyl 5-phenylpenta-(2E,4E)-dienoate.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10])[CH3:2].CO[C:13](=O)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[C:13]1[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[CH3:2]
Reactant: COC(=O)Cn1ccnc1-c1nccs1
Reactant: CCNc1ccncc1N
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cnccc21

Procedure:
The title compound is prepared from N4-ethyl-pyridine-3,4-diamine and (2-thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester following the procedure given in Example 8. 1H NMR (CDCl3) δ 9.08 (s, 1 H), 8.43 (d, 1 H), 7.85 (d, 1 H), 7.38 (d, 1 H), 7.38-7.26 (m, 1 H), 7.17 (s, 1 H), 7.14 (s, 1 H), 6.35 (s, 2 H), 4.25 (q, 2 H), 1.11 (t, 3 H). Electrospray MS: m/z 311 [M+1]
Reaction SMILES: O=O.[C:3](O)(=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:3]([OH:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCC(=O)O
Agent: O=O
Product: CCCCCCCCCCCO
Yield: 22 %

Procedure:
In 3 mL of acetic acid was dissolved 375 mg of 1-undecanol to give a solution, and the solution was combined with 150 mg of the catalyst B10 obtained from Example 22 and 32 mg of N-hydroxyphthalimide, followed by stirring at 100° C. in an oxygen atmosphere at normal atmospheric pressure for 4 hours. The reaction mixture was analyzed through gas chromatography to find that undecanoic acid was produced in a yield of 22% with a conversion from 1-undecanol of 44%.
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl>C1COCC1>[CH3:1][S:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)C1CCNCC1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl 4-(methylsulfonyl)piperidine-1-carboxylate (1.5 g, 5.70 mmol) and hydrogen chloride (7.12 mL, 28.5 mmol) in THF (20 mL) was stirred at 20° C. for 15 hours. TLC indicated the formation of desired product, the reaction mixture was filtered and the pale yellow solid was collected to provide desired product (1 g, 88%). LCMS: m/e 163.96 (M+H)+, 0.25 min (method 10).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([O:14]C)=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.O.C(OCC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([OH:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1c(-c2ccccc2)cc(C)cc1-c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Yield: 89 %

Procedure:
A mixed solution of 1 mL of water and 4 mL of dimethoxyethane was added into a flask into which 2,6-dibromo-4-methylanisole (400 mg, 1.43 mmol), phenylboronic acid (535 mg, 4.39 mmol), palladium acetate (14 mg, 0.062 mmol), triphenylphosphine (60 mg, 0.23 mmol), and potassium phosphate (940 mg, 4.43 mmol) were already added, and then refluxed at normal temperature for 6 hours. After cooling to normal temperature, an ammonium chloride aqueous solution (5 mL) and 10 mL of diethylether were added thereto to separate an organic layer and extract residues using diethylether. The separated organic layer was dried with magnesium sulfate and volatile materials were removed to produce 420 mg of grey 4-methyl-2,6-diphenylanisole solid. The anisole thus produced was dissolved in 5 mL of methylene chloride without separate purification, 3 mL of boron tribromide (1 M methylene chloride solution) were dropped thereonto at −78° C., and the reaction was carried out while the temperature was slowly increased to normal temperature. After the reaction, a mixed solution of water (5 mL) and diethylether (10 mL) was added to separate an organic layer and extract an aqueous solution layer using diethylether (5 mL×3), and the separated organic layer was dried. Residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and methylene chloride to produce 333 mg of white 4-methyl-2,6-diphenylphenol solid.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[S:29]1[CH2:33][CH:32]([CH2:34][OH:35])[NH:31][CH2:30]1.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:31]1[CH:32]([CH2:34][OH:35])[CH2:33][S:29][CH2:30]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CSCN1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1C(=O)N1CSCC1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
1.9 g (8.4 mmol) of o-benzoylbenzoic acid and 1.13 g (8.4 mmol) of 1-hydroxybenzotriazole hydrate were combined in 50 ml of methylene chloride and stirred for 20 minutes at room temperature. 1.0 g (8.4 mmol) of 4-thiazolidinemethanol was added, followed by 1.6 g (8.4 mmol) of ethyl-3-(3-dimethylaminopropyl)carbodiimide. The reaction mixture was stirred for 18 hours at room temperature and washed with water, first at pH 2.5 and then at pH 9.5. The organic phase was dried and evaporated to give a foam which was chromatographed on silica gel using 1:1/chloroform:ethyl acetate as the eluant to yield 1.1 g (40%) of the title compound. 1H NMR (CDCl3) δ: 7.4-7.85(m,9H); 4.65(m,1H) ; 4.20-4.40(m,2H); 3.96(m,1H); 3.60-3.70(m,2H); 3.0-3.30(m,2H). High Resolution Mass Spectrum: m/e=328.1015±0.8 ppm (calculated for C18H18NO3S).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:25][N:26]([C:34]1[N:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1)C(=O)OC(C)(C)C>>[CH3:25][NH:26][C:34]1[N:39]=[CH:38][C:37]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:36][N:35]=1
Reactant: OC1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CN(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCC(O)CC4)sc3n2)cn1
Yield: 24 %

Procedure:
1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperidin-4-ol (187 mg, 0.5 mmol) was utilized in a Suzuki coupling with tert-butyl methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)carbamate (238 mg, 0.7 mmol) according to General Procedure Suzuki to provide 381 (53 mg) after reverse phase HPLC purification. MS (Q1) 442 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[K+].Cl[CH2:12][C:13]([OH:15])=[O:14]>>[C:13]([CH2:12][N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8])([OH:15])=[O:14]
Reactant: O=C(O)CCl
Reactant: O=c1ncc(Cl)c[nH]1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cn1cc(Cl)cnc1=O
Yield: 47 %

Procedure:
A solution made from 5-chloropyrimid-2-one (0.015 mol), aqueous 0.78 M KOH (45 ml) and chloroacetic acid (0.018 mol) was heated under reflux until the pH had fallen to below 8. The solution was then concentrated to a small volume at reduced pressure. Addition of 1 N HCl (15 ml) caused the product to crystallize; yield 47%, m.p. 186°-188° C. (acetone). (Found: C, 38.35; H, 2.69. Calc. for C6H5ClN2O3 : C, 38.23; H, 2.67).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[C:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:33]>>[C:32]([C:35]1[CH:40]=[C:39]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)[CH:38]=[CH:37][CH:36]=1)(=[O:34])[CH3:33]
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: O=Cc1cccc(B(O)O)c1
Product: CC(=O)c1cccc(C2=NCC(=O)N(C)c3ccc(-c4ccccc4)cc32)c1
Yield: 31 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3-acetylphenyl boronic acid. The title compound (44 mg) was obtained as a beige solid, (yield=31%).
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[C:13]([C:17]1[O:21][C:20]([C:22]([OH:24])=O)=[N:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C@@H:30]([NH2:32])[CH3:31].C1CCN2C(=NCCC2)CC1>C1COCC1>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C@@H:30]([NH:32][C:22]([C:20]1[O:21][C:17]([C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:18][N:19]=1)=[O:24])[CH3:31]
Reactant: CC(C)(C)c1cnc(C(=O)O)o1
Reactant: C[C@H](N)c1cccs1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](NC(=O)c1ncc(C(C)(C)C)o1)c1cccs1
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of carbonyl diimidazole (CDI) (2.42 g, 15 mmol) in THF (40 ml) is added to a stirred solution of 5-tert-butyl-oxazole-2-carboxylic acid (2.3 g, 13.6 mmol) in THF (40 ml). The mixture is stirred for 30 min, then (S)-(1-thiophen-2-yl-ethyl)-amine (2.59 g, 20.4 mmol) is added, followed 10 min later by a solution of DBU (2.24 ml, 15 mmol) in THF (20 ml). The mixture is refluxed for 16 h and the THF is then removed by distillation. The residue is dissolved in ethyl acetate and the organic solution is washed with 2N hydrochloric acid and then twice with water. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate 7:3 v/v) to give (S)-5-tert-butyl-oxazole-2-carboxylic acid (1-thiophen-2-yl-ethyl)-amide (2.40 g, 63%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]3[C:21](OC)=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:17]=3I)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)[C:34](Cl)=[O:35].COC1C=C(C(I)=CC=1OC)C(O)=O.[N+](C1C=C2C(C(NCCN(C)C)=CC=N2)=CC=1)([O-])=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:24][C:20]1[C:19]([O:35][CH3:34])=[CH:18][C:17]2[C:9]3[C:8](=[C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]4=[N:11][CH:10]=3)[N:14]([CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1ccc(I)c(C(=O)N(CCN(C)C)c2ccnc3cc([N+](=O)[O-])ccc23)c1OC
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)CCNc1ccnc2cc([N+](=O)[O-])ccc12
Agent: COc1cc(I)c(C(=O)O)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(=O)n(CCN(C)C)c3c4ccc([N+](=O)[O-])cc4ncc3c2cc1OC
Yield: 53 %

Procedure:
N-(7-Nitroquinolin-4-yl)-N-(N,N-dimethylaminoethyl)-2-iodo-5,6-dimethoxybenzamide (8b). Oxalyl chloride (1.5 mg, 12.0 mmol) was added to a solution of 3,4-dimethoxy-6-iodobenzoic acid (985 mg, 3.2 mmol) in anhydrous methylene chloride (30 mL), and the stirred mixture was refluxed for 3 hours. The mixture was then concentrated to dryness under reduced pressure. The acid chloride was redissolved in 20 mL of anhydrous methylene chloride, and this solution was added to a solution of 7b (680 mg, 2.6 mmol) and triethylamine (2.0 g, 20.0 mmol) in methylene chloride (30 mL), and the resulting mixture was stirred at reflux for 2 hours. The reaction mix was cooled and washed with saturated sodium bicarbonate (3×75 mL), and extracted with 5% aqueous HCl (4×100 mL). The combined aqueous extracts were basified with 30% NaOH and then extracted with chloroform (3×100 mL). Combined organic extracts were then dried (MgSO4) and evaporated to give 760 mg of the amide, in 53% yield; 1H NMR (CDCl3) δ 2.23 (s, 6H), 2.63 (m, 2H), 3.28 (s, 3H), 3.73 (s, 3H), 3.92 (m, 1H), 4.50 (m, 1H), 6.33 (s, 1H), 7.02 (s, 1H), 7.73 (d, 1H, J=4.8), 8.41 (m, 2H), 8.98 (m, 2H); 13C NMR (CDCl3) δ 45.5, 47.5, 55.6, 56.1, 56.8, 82.9, 110.4, 120.6, 121.8, 124.1, 125.4, 126.6, 129.2, 133.3, 147.5, 148.4, 148.8, 149.9, 152.6, 153.1, 169.7; IR (CHCl3) 1345, 1536, 1655.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH2:16]([N:18](CC)CC)C.CS(Cl)(=O)=O.CN>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:18][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O[C@@H](CN1CCCC1)c1ccc(Br)cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN[C@@H](CN1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a magnetically stirred solution of (1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethanol (29.43 g, 109 mmol) in CH2Cl2 (300 mL) at 0° C. was added triethylamine (55 mL, 394 mmol). Methanesulfonylchloride (30 mL, 388 mmol) was then added dropwise. The resulting mixture was warmed to room temperature, stirred for 5 h, and then quenched by the addition of H2O (200 mL). The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give an orange oil. The crude oil was taken up in CH2Cl2 (300 mL) and methylamine (33 wt % in EtOH, 135 mL, 1.08 mol) was added at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and re-dissolved in CH2Cl2. The crude mixture was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give (1R)-1-(4-bromophenyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine as a viscous red/orange oil (25.4 g, 90 mmol, 82% yield).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH2:29][CH3:30]>CC(C)=O>[CH2:1]([N:9]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[CH2:28][CH2:29][CH3:30])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCI
Reactant: COc1ccc(CCNCCc2ccccc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(CCc1ccccc1)CCc1ccc(OC)c(OC)c1

Procedure:
A solution of 8 g of N-phenethyl-3,4-dimethoxyphenethylamine, 8 g of anhydrous potassium carbonate, 11 ml of propyl iodide and 80 ml of acetone was refluxed for 6 hours and the mixture was filtered. The filtrate was evaporated to dryness and the residue was taken up in 50 ml of water. The solution was extracted with methylene chloride and the organic extracts were washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to obtain 9.37 g of raw N-phenethyl-N-propyl-3,4-dimethoxyphenethylamine in the form of an oil which was used as is for the next step.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[C:9]1[CH3:33])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:26]([O:25][C:23]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[NH:8][C:9]=1[CH3:33])=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)c2cc(-c3cccnc3)ccc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c2ccc(-c3cccnc3)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 134.1 %

Procedure:
2-Methyl-5-pyridin-3-yl-indole-1,3-dicarboxylic acid 3-benzyl ester 1-tert-butyl ester (0.027 g, 0.061 mmol, 1 eq) was suspended in dry CH2Cl2 (5 mL) under Ar. Trifluoroacetic acid (1.0 mL) was added, and the reaction mixture was stirred at room temperature. After 4 hours, the solvent was removed in vacuo, leaving 0.028 g (40% yield) of the indole-pyridine, a brown solid: LC/MS (ESI+) 343 (M+1), Anal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:9][C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[CH:8])[CH3:2].[F:14][C:15]1[C:16](I)=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])/[C:18]/2=[CH:25]\[C:26]1[NH:30][CH:29]=[N:28][C:27]=1[CH3:31]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:9][C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[C:8][C:16]1[C:15]([F:14])=[CH:23][CH:22]=[C:21]2[C:17]=1/[C:18](=[CH:25]/[C:26]1[NH:30][CH:29]=[N:28][C:27]=1[CH3:31])/[C:19](=[O:24])[NH:20]2)[CH3:2]
Reactant: C#CCC(NC(C)=O)C(=O)OCC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2)NC(C)=O

Procedure:
Using Method C above, 2-(acetylamino)-4-pentynoic acid ethyl ester (92.6 mg, 0.51 mmol) (Bachem) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give rac-(Z)-2-(acetylamino)-5-[5-fluoro-2,3,dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid ethyl ester. (Yield 70 mg, 81%).