Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9]2)[CH:4]([OH:15])[CH2:3][CH2:2]1.Cl.Cl[CH2:18][C:19]([CH3:25])([CH3:24])[CH2:20][N:21]([CH3:23])[CH3:22]>>[CH3:18][C:19]([CH3:25])([CH2:20][N:21]([CH3:23])[CH3:22])[CH2:24][O:15][CH:4]1[CH:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9][CH:10]2[CH2:1][CH2:2][CH2:3]1
Reactant: CN(C)CC(C)(C)CCl
Reactant: OC1CCCC2Oc3ccccc3OC12
Agent: Cl
Product: CN(C)CC(C)(C)COC1CCCC2Oc3ccccc3OC12
Yield: 58.5 %

Procedure:
In an analogous manner as described in Example 5, but starting with 10 g (0.048 mole) of the alcohol of Example 1 and 8.6 g (0.046 mole) of 1-chloro-2,2-dimethyl-3-dimethylaminopropane hydrochloride, there were obtained 8.6 g of the title-compound of boiling point 135° C. at a pressure of 6.5 Pa, having the elementary analysis:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9]C=CC=1)=O.C[O-].[Na+].C([O:16][CH2:17][CH3:18])=O.Cl.O1CCO[CH2:22][CH2:21]1>O>[N:1]1[C:2]2[C:18](=[CH:9][CH:10]=[CH:5][CH:3]=2)[C:17](=[O:16])[CH2:22][CH:21]=1
Reactant: NCC(=O)c1ccccc1
Reactant: CCOC=O
Reactant: C1COCCO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1CC=Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
2-Aminoacetophenone (7.0 g, 52 mmol) was added to and dissolved in 1,4-dioxane (100 ml). To the solution obtained was added sodium methoxide (8.4 g, 156 mmol), and the mixture was stirred at room temperature for 30 minutes. Ethyl formate (21 ml, 261 mmol) was then added, and the mixture was stirred at room temperature for an additional 125 minutes. After adding water (5 ml) to the reaction solution, and stirring for 10 minutes, 10% hydrochloric acid was added to the mixture for neutralization. The reaction solution was then concentrated under reduced pressure. The residue was suspended in chloroform (100 ml), collected by filtration, washed with chloroform (100 ml), and then purified by silica gel column chromatography to give 4.5 g of the desired compound (yield 60%).
Reaction SMILES: [ClH:1].[CH2:2]([N:5]([CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2)[CH2:3][CH3:4].O1CCCC1>CO.[Ni]>[ClH:1].[ClH:1].[CH2:20]([N:5]([CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2)[CH2:21][CH3:22]
Reactant: CCCN(CCC)CCc1ccc([N+](=O)[O-])c2[nH]ncc12
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCC)CCc1ccc(N)c2[nH]ncc12
Yield: 117.7 %

Procedure:
600 mg of N,N-dipropyl-N- 2-(7-nitro-1H-indazol-4-yl)ethyl amine, hydrochloride, in 10 ml of methanol and 10 ml of tetrahydrofuran is hydrogenated in the presence of 0.5 g of Raney nickel. The mixture is filtered off from the catalyst, combined with ethereal hydrochloric acid, and concentrated. The residue is recrystallized from methanol/diethyl ether, yielding 360 mg of N,N-dipropyl-N- 2-(7-amino-1H-indazol-4-yl)ethyl amine, dihydrochloride, mp 214°-218° C.
Reaction SMILES: [C:1]([CH:3]1[C:7](=O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[NH:19][N:18]=1>C(O)C>[NH2:2][C:1]1[N:19]2[N:18]=[C:17]([CH3:16])[CH:21]=[C:20]2[N:22]=[C:7]2[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C#N)C1
Reactant: Cc1cc(N)[nH]n1
Solvent: CCO
Product: Cc1cc2nc3c(c(N)n2n1)CN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C

Procedure:
To a stirred solution of 250 mg (1.19 mmol) of tert-butyl 3-cyano-4-oxopyrrolidine-1 carboxylate in ethanol (5 mL) was added 115 mg (1.19 mmol) of 3-methyl-1H-pyrazol-5-amine. The reaction mixture was refluxed for 1 h, cooled to ambient temperature and the solvent evaporated in vacuo. The resulting residue was chromatographed on a Biotage Horizon® system (silica gel, 0 to 100% ethyl acetate/hexanes gradient) to yield the title compound as a white solid. LC/MS 290.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:26])[CH:13]1[CH2:18][CH2:17][C:16]([C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH2:14]1.C(N(CC)CC)C.O1CCOCC1>C(Cl)Cl>[ClH:8].[CH3:11][N:12]([CH3:26])[CH:13]1[CH2:18][CH2:17][C:16]([C:19]2[N:24]=[C:23]([NH:25][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH2:14]1
Reactant: CN(C)C1CC=C(c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3ccc(F)cc3)n2)CC1
Product: Cl
Temperature: 55 °C

Procedure:
Combine 4-fluoro-benzoyl chloride (127 mg, 0.80 mmol), 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine, isomer 2 (preparation 11, 145 mg, 0.67 mmol), triethylamine (81 mg, 0.80 mmol) and 1,4-dioxane (6 mL) and heat at 55° C. for 15 hr. Dilute the mixture with DCM, wash with 0.1N NaOH solution. Extract the aqueous layer twice with DCM. Combine the organic layers, dry over sodium sulfate, filter and concentrate to give a residue. Purify the residue by chromatography (silica gel, 5% 2M NH3/MeOH in DCM) to provide the free amine of the title compound as a slightly yellow oil (183 mg, 80%): MS (ES): m/z=340.1 (M+H)+; 1H NMR (CDCl3): δ 8.55 (s, br, 1H), 8.19 (d, 1H), 7.95 (m, 2H), 7.73 (t, 1H), 7.18 (m, 2H), 6.66 (m, 1H), 2.73 (m, 1H), 2.47 (m, 3H), 2.37 (s, 6H), 2.15 (m, 2H), 1.57 (m, 1H). Using a salt formation method similar to that in example 1 gives the hydrochloride salt: hydrochloride salt: Anal. cal'd for C20H22FN3O.1.5HCl0.5H2O: C, 59.59; H, 6.13; N, 10.42. Found: C, 59.71; H, 5.56; N, 10.31.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][O:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:10][CH2:11][O:12][CH3:13])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 79.1 %

Procedure:
A mixture of 3-bromophenol (5 g, 28.9 mmol), 1-chloro-2-methoxyethane (3.77 g, 40 mmol) and K2CO3 (12.63 g, 0.178 mol) in DMF (90 mL) was stirred at 100° C. for 4.5 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue is taken up in 100 ml of tert-butyl methyl ether, and the organic phase was washed once each with 50 ml of 1 N NaOH, 50 ml of water and 50 ml of brine. The organic layer was dried with sodium sulphate, filtered and concentrated to give 1-bromo-3-(2-methoxyethoxy)benzene (5.28 g, 79%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21](Cl)=[O:22])[C:12]3=[O:24])[CH:9]=[CH:10][C:2]1=2.[C:25]1(=[O:32])[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH2:26]1.C(N(CC)CC)C.CC(C)(O)C#N.[OH-].[Na+]>ClCCl.O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]([C:26]4[C:27](=[O:31])[CH2:28][CH2:29][CH2:30][C:25]=4[OH:32])=[O:22])[C:12]3=[O:24])[CH:9]=[CH:10][C:2]1=2
Reactant: O=C(Cl)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Reactant: O=C1CCCC(=O)C1
Agent: CC(C)(O)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCC(O)=C1C(=O)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Reaction time: 3 h
Yield: 40 %

Procedure:
The 1-(2,3-dihydrobenzo[b]1,4-dioxin-6-yl)-2-oxo-1,2-dihy droquinoxaline-3-carbonyl chloride thus obtained was dissolved in dichloromethane (30 mL), and this solution was added dropwise at 0° C. over 5 minutes to a solution prepared by dissolving 4.2 g (37 mmol) of 1,3-cyclohexanedione and 6.2 g (61 mmol) of triethylamine in dichloromethane (30 mL). The reaction solution was returned to room temperature and stirred for 3 hours, and then acetone cyanohydrin (1 mL) and 6.2 g (61 mmol) of triethylamine were added thereto. The mixture was stirred for 12 hours at room temperature. After confirming the completion of the reaction, water (50 mL) was added to the reaction solution, the reaction solution was adjusted to pH 12 using a 10% aqueous solution of sodium hydroxide, and the reaction solution was separated. The aqueous layer was adjusted to pH 1 by adding 6 N hydrochloric acid, and then the aqueous layer was extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was washed with methanol, to obtain 5.2 g (yield: 40%) of 1-(2,3-dihydrobenzo[b]1,4-dioxin-6-yl)-3-(2-hydroxy-6-oxo-1-cyclohexenecarbonyl)-quinoxalin-2(1H)-one as milky white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:27])[C:10](=[CH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:11](=O)[CH3:12])[CH:6]=[CH:7][CH:8]=1.[NH2:28]/[C:29](/[CH3:37])=[CH:30]\[C:31]([O:33][CH2:34][CH2:35][CH3:36])=[O:32]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:30]([C:31]([O:33][CH2:34][CH2:35][CH3:36])=[O:32])=[C:29]([CH3:37])[NH:28][C:11]=1[CH3:12])=[O:27]
Reactant: COc1cccc(C(=O)C(=Cc2cccc3c(=O)cc(C)oc23)C(C)=O)c1
Reactant: CCCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCCOC(=O)C1=C(C)NC(C)=C(C(=O)c2cccc(OC)c2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
245 mg (0.67 mmol) of 1-(3-methoxyphenyl)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-butane-1,3-dione are heated with 96 mg (0.67 mmol) of n-propyl 3-aminocrotonate in 5 ml of 2-propanol under reflux overnight. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 94 mg (28% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17]([C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:22]=[CH:23][CH:24]=1)#[CH:18]>C1COCC1.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>[Cl:1][C:2]1[N:7]=[C:6]([C:18]#[C:17][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])[CH:22]=[CH:23][CH:24]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: C#Cc1cccc(NC(=O)C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C#Cc2nc(Cl)ncc2F)c1)C(F)(F)F
Yield: 77.6 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloro-5-fluoropyrimidine (1.56 g, 9.4 mmol), anhydrous, degassed THF (100 mL), dichlorobis(triphenyl-phosphine)palladium(II) (62 mg, 0.09 mmol), copper(I) iodide (10 mg, 0.05 mmol), and triethylamine (0.164 g, 0.23 mmol). After heating the reaction at 60° C. for 30 min, N-(3-ethynylphenyl)-2,2,2-trifluoroacetamide (1.0, 4.69 mmol) was added dropwise as a solution in THF (25 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (2-10% EtOAc in hexanes) to afford the desired product (1.25 g, 78%) as an off-white solid. ESIMS (M+H)+=344.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].Cl.[CH3:24]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([C:18](=[O:22])[C:19](=[CH2:24])[CH2:20][CH3:21])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CNC
Reactant: CCCC(=O)c1ccc(OCCCCCC(=O)O)c(Cl)c1Cl
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C(CC)C(=O)c1ccc(OCCCCCC(=O)O)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
A mixture of 6-(2,3-dichloro-4-butyrylphenoxy)hexanoic acid (9.5 g, 0.026 mole), dimethylamine hydrochloride (15 g, 0.184 mole), paraformaldehyde (2.8 g, 0.09 equiv.) and acetic acid (1 ml) were united and stirred and heated on a steam bath for two hours. The reaction mixture was treated with N,N-dimethylformamide (30 ml) and stirring and heating continued for another hour. The reaction mixture was poured into ice water and the solid that separated was removed by filtration, washed with water and dried. The yield was 9.2 g after recrystallization from butyl chloride the 6-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]hexanoic acid melted at 106°-107° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]O)[CH:10]([CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][O:16][CH2:13][CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CC1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CN2CC3COCC3C2)cc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of (1-benzyl-4-hydroxymethyl-pyrrolidin-3-yl)-methanol (7.89 g, 31.2 mmol) and p-toluenesulfonic acid monohydrate (7.12 g, 37.4 mmol) in toluene (150 mL) was heated under a Dean Stark trap (120° C., 20 h). The reaction mixture was cooled (rt) and treated with 1 N NaOH (50 mL). The aqueous phase was extracted with methyl tert-butyl ether (3×50 mL). The combined organic layers were dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using MeOH (0.2 M NH3):DCM (0-5%) to afford the title compound as a yellow oil (5.08 g, 80%). 1H NMR (500 MHz, CDCl3): 7.37-7.29 (m, 4H), 7.29-7.24 (m, 1H), 3.87-3.79 (m, 2H), 3.65-3.56 (m, 4H), 2.86-2.75 (m, 2H), 2.75-2.66 (m, 2H), 2.34 (dt, J=12.2, 6.1, 2H).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:8])([CH3:7])[NH:5][C:4](=[O:9])[CH:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28]>>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[C:4](=[O:9])[NH:5][C:6]([CH3:8])([CH3:7])[C:2]=1[OH:1])=[C:22]2[CH3:28]
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: O=Cc1ccccc1
Reactant: CC1(C)NC(=O)C=C1O
Product: Cc1c(C(C2=C(O)C(C)(C)NC2=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure D, rac-4-hydroxy-5,5-dimethyl-1,5-dihydro-pyrrol-2-one (Lit. 18) was reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as a yellow solid. MS: 365.1 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>>[ClH:17].[ClH:17].[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[NH:22][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: Clc1nc2cccnc2n1Cc1ccccc1
Product: CN(C)CCNc1nc2cccnc2n1Cc1ccccc1
Product: Cl

Procedure:
Grams 5 of 3-benzyl-2-chloro-3H-imidazo[4,5-b]pyridine and 9 ml N,N-dimethylethylenediamine are refluxed for 3 hours, then the amine in excess is removed by evaporation under vacum, the oily residue taken up with absolute ethyl alcohol and 10 ml 32% hydrochloric acid are added thereto, the solid crystalline filtered and washed with absolute ethyl alcohol. It is evaporated till dryness and 2.1 g 3-benzyl-2-(2-dimethylaminoethylamino)-3-H-imidazo[4,5-b]pyridine dihydrochloride melting at 262°-264° C. (with decomposition) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=O)[CH:6]=[N:7][C:8]=1[O:9][CH3:10].[CH3:13][C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[N:15]=1.C[Si]([C:30]#[N:31])(C)C>C1COCC1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([C:16]3[N:15]=[C:14]([CH3:13])[O:18][N:17]=3)=[CH:20][CH:21]=2)[C:30]#[N:31])[CH:6]=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C=O)cnc1OC
Reactant: C[Si](C)(C)C#N
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cnc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 g of 5,6-dimethoxypyridine-3-carbaldehyde [CAS No. 52605-99-9] in 10 ml of THF there were added 1.15 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 5 g of MS3A and 371 mg of Yb(OTf)3 under a nitrogen atmosphere, and after stirring at room temperature for 2 hours, 4.5 ml of trimethylsilyl cyanide was added and the mixture was stirred at room temperature for 12 hours and 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. A dichloromethane, heptane and ethyl acetate mixed solvent was added and the mixture was filtered to give (5,6-dimethoxypyridin-3-yl)-[4-(5-methyl[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile (2.19 g) as a white solid.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([O:17][CH:18]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26](/[CH:30]=[CH:31]/[CH:32]=[CH:33]/[CH:34]([O:43][C:44](=[O:46])[CH3:45])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=1)[CH2:19][CH2:20][CH2:21][CH:22]=[O:23])(=[O:16])[CH3:15].C(O)(C)C>CC(C)=O.CCOCC>[C:14]([O:17][CH:18]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26](/[CH:30]=[CH:31]/[CH:32]=[CH:33]/[CH:34]([O:43][C:44](=[O:46])[CH3:45])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=1)[CH2:19][CH2:20][CH2:21][C:22]([OH:3])=[O:23])(=[O:16])[CH3:15]
Reactant: CC(C)=O
Reactant: CCCCCCCCC(/C=C/C=C/c1cccc(C(CCCC=O)OC(C)=O)c1)OC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOCC
Product: CCCCCCCCC(/C=C/C=C/c1cccc(C(CCCC(=O)O)OC(C)=O)c1)OC(C)=O
Temperature: -30 °C

Procedure:
0.3 ml of Jones reagent (J. Chem. Soc. 1953., 2555) is instilled in a solution of 150 mg of the above-produced aldehyde in 11 ml of acetone with stirring at -30° C. and stirred for one hour at -30° C. Then, 0.23 ml of isopropanol is added, stirred for 15 minutes, diluted with ether, filtered, washed neutral with brine, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/0-50% ethyl acetate, 52 mg of (5RS)-5-acetoxy-5-{3-[(1E,3E)-(5RS)-5-acetoxy1,3-tridecadienyl]-phenyl}-pentanoic acid is obtained as colorless oil.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17])=[CH:9][CH:8]=1.O.[NH2:22][NH2:23]>C(O)C.CN(C)C=O>[O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[NH:22][N:23]=2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(N2CCNC2=O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(N2CCNC2=O)cc1

Procedure:
4 g (0.014 mole) of the compound prepared in Example 4 are stirred with 1 ml (0.021 mole) of hydrazine hydrate in 30 ml of ethanol and 20 ml of dimethylformamide at 80° C. for 2 hours. After the mixture has been cooled, the product is filtered off with suction and recrystallised from dimethylformamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH:14]([CH3:16])[CH3:15])=[C:8]([C:17]([OH:19])=O)[CH:7]=[CH:6]2.C(Cl)(=O)C(Cl)=O.[NH4+:26].[OH-].O>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH:14]([CH3:16])[CH3:15])=[C:8]([C:17]([NH2:26])=[O:19])[CH:7]=[CH:6]2
Reactant: [NH4+]
Reactant: COc1ccc2c(OC(C)C)c(C(=O)O)ccc2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OC(C)C)c(C(N)=O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To an ice water cooled solution of 6-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxylic acid (5.0 g, 19 mmol) in 50 mL of THF is added 2 drops of DMF followed by oxalyl chloride (2.8 g, 21 mmol). The solution is stirred a room temperature for 2 hours then poured onto 150 mL of aqueous NH4OH. An additional 700 mL of water is added and the resultant precipitate collected. Recrystallization from ethyl acetate provides 6-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxamide in 74% yield; mp 183°-184° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(OCC)(=O)C>C(Cl)Cl>[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](=[O:32])[CH2:18][NH:1][C:2]2[C:10]3[C:5](=[CH:6][C:7]([Cl:12])=[CH:8][C:9]=3[Cl:11])[NH:4][C:3]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (1.09 g, 4 mmol) in methylene chloride (25 mL) and add triethylamine (0.578 mL, 4 mmol) followed by p-trifluoromethylbenzoyl chloride (0.488 mL, 4 mmol). Stir thereaction for 1 hour at room temperature. Add an additional amount of methylene chloride (25 mL) and stir overnight. Dilute the reaction with ethyl acetate (100 mL), wash with water (100 mL) and dry the organic phase. Concentrate in vacuo and recrystallize the residue from ethyl acetate/hexane to yield the title compound as a white fluffy solid (1.42 g, 80%); mp 250°-252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:24][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC(CC1C(=O)N(Cc2ccccc2)c2ccccc21)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
479 Milligrams of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate prepared in Example 3 and 70 mg of 50% sodium hydride (in oil) were admixed in 5 ml of dimethylformamide, and the mixture was stirred at a room temperature for 1 hour. Then a mixture containing of 0.17 ml of benzyl chloride in 3 ml of dimethylformamide was added dropwise slowly into the reaction mixture, and the whole reaction mixture was stirred at a room temperature for 4 hours. The reaction mixture was poured into a large volume of water, and the organic material was extracted with chloroform, then the chloroform layer was dried and chloroform was removed by evaporation. There was obtained 110 mg of 2-(4-chlorobenzoylamino)-3-(1-benzyloxindol-3-yl)propionic acid.
Reaction SMILES: F[C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:23][S-:24].[Na+]>CS(C)=O>[CH3:23][S:24][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc2nc3ccc4c(F)cccc4c3nc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1cccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Temperature: 130 °C

Procedure:
To a stirred solution of 4-fluoro-benzo[a]phenazine-11-carboxylic acid (II.3, see Reference Example 1B (58 mg) in dry DMSO (3 mL) was added sodium thiomethoxide (55 mg) and the reaction mixture heated at 100° C. for 1.5 hours and 130° C. for 1 hour. The reaction mixture was then cooled to room temperature, quenched with acetic acid, extracted with ethyl acetate, washed with water, dried and the solvent removed in vacuo to yield the title compound as a red solid (37 mg).