Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14](Cl)[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].[Cl:20][C:21]1[CH:40]=[CH:39][C:24]([C:25]([C:27]2[CH:38]=[CH:37][C:30]([CH2:31][NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>O>[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([N:32]([CH2:33][CH2:34][CH2:35][OH:36])[CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:25](=[O:26])[C:24]3[CH:39]=[CH:40][C:21]([Cl:20])=[CH:22][CH:23]=3)=[CH:38][CH:37]=2)[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CNCCCO)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)n1ncc(N(CCCO)Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1=O
Temperature: 100 °C
Reaction time: 64 h
Yield: 11.5 %

Procedure:
In a solvent mixture of dioxane (5 ml) and water (5 ml) were dissolved 2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (473 mg) and 3-[4-(4-chlorobenzoyl)benzyl-amino]-1-propanol (1.30 g) and the mixture was stirred at 100° C. for 64 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=4:1-2:1) to provide the title compound as white powder (120 mg; yield 12%). 1H-NMR (CDCl3) δ: 1.63(9H,s), 1.83-1.98(3H,m), 3.51(2H,t,J=7.2Hz), 3.70(2H,m), 4.71(2H,m), 7.40(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.60(1H,s), 7.75(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-:12].[Na+].[OH2:14]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:4][CH2:3][CH2:8][C:7]([OH:14])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S)cc1OC
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(SCCCC(=O)O)cc1OC

Procedure:
In ethanol (50 ml) is dissolved 3,4-dimethoxythiophenol (28 g), to the resulting mixture is added an ethanol solution (77 ml) of 2.5M sodium hydroxide, and the mixture is heated for 10 minutes under reflux. To the reaction mixture is then added τ-butyrolactone (18.5 g) and the mixture is heated for 3 hours under reflux. To the reaction mixture is added water (100 ml), then ethanol is distilled off under reduced pressure. The remaining aqueous solution is washed with ethyl acetate, and the aqueous layer is acidified with dilute hydrochloric acid. The mixture is extracted with ethyl acetate. The organic layer is washed with water and dried, followed by distilling off the solvent under reduced pressure. The residue is recrystallized from ether-hexane to afford 4-(3,4-dimethoxyphenylthio)butyric acid as colorless prisms (m.p. 78° C.) (20.5 g). Then, 4-(3,4dimethoxyphenylthio)butyric acid (14.5 g) is added to polyphosphoric acid (183 g), and the mixture is stirred at 100° C. for two hours. The reaction mixture is poured into ice-water (500 ml), followed by extraction with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography (eluent:hexane - ethyl acetate=5:1) to afford 7,8-dimethoxy-3,4-dihydro-1-benzothiepin-5(2H)-one (12.0 g). Recrystallization of the product from hexane - methylene chloride give colorless prisms, m.p. 128°-129° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[C:9]=2[CH2:8][CH2:7]1)C.CO.[OH-].[Na+]>O1CCCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:6]([CH2:5][C:4]([OH:19])=[O:3])[CH2:7][CH2:8][C:9]=3[C:17]=2[CH:16]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(F)cc21
Reaction time: 2.5 h

Procedure:
To a solution of 1.24 g of the ester from Step 1 in 14 mL of tetrahydrofuran (THF) at room temperature, 7 mL of MeOH followed by 7 mL of 2N NaOH were added. After 2.5 h, the reaction mixture was poured into a separatory funnel containing ethyl acetaqte (EtOAc)/1N HCl. The phases were separated and the acidic phase was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness to yield 1.08 g of a crude and unstable waxy brown oil that was used as such in the next step (>90% purity).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=O)=O.[C:6]1([N:12]2[C:16](S)=[N:15][N:14]=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[C:6]1([N:12]2[C:16]([S:1][Cl:5])=[N:15][N:14]=[N:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: ClSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sulfuryl chloride (4.5 grams, 0.056 mol) was added dropwise at 10° C. to a mixture comprised of 10 grams (0.056 mol) of 1-phenyl-5-mercaptotetrazole and 100 ml of dichloromethane: The reaction mixture was then stirred for 2 hours at room temperature, after which the low boiling point compounds were removed by distillation under reduced pressure at a temperature of from 30° C. to 40° C. and 1-phenyltetrazol-5-sulfenyl chloride was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:11][CH2:10][Br:9]
Reactant: Oc1ccccc1Br
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: BrCCOc1ccccc1Br
Temperature: 80 °C

Procedure:
A suspension of 2-bromophenol (3.50 g, 20.23 mmol), 1,2-dibromoethane (19.00 g, 101 mmol), and potassium carbonate (7.06 g, 2.92 mmol) in acetonitrile (50 mL) was heated to 80° C. After heating overnight, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to afford the title compound as a clear oil. Yield: 6.36 g, 100%. 1H NMR (400 MHz, CDCl3) δ 3.69 (dd, J=6.6, 6.4 Hz, 2H), 4.35 (dd, J=6.7, 6.4 Hz, 2H), 6.87-6.94 (m, 2H), 7.25-7.30 (m, 1H), 7.56 (dd, J=7.9, 1.6 Hz, 1H).
Reaction SMILES: C([NH:19]CC(O)CN1CCN(CC(O)CNCCCCCCCCC=CCCCCCCCC)CC1)CCCCCCCC=CCCCCCCCC.BrCCC[N:57]1[C:61](=[O:62])[C:60]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:59]2[C:58]1=[O:67].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)(Cl)Cl>[C:58]([NH2:19])(=[O:67])[C:59]1[C:60](=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:61]([NH2:57])=[O:62]
Reactant: CCCCCCCCC=CCCCCCCCCNCC(O)CN1CCN(CC(O)CNCCCCCCCCC=CCCCCCCCC)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1C(N)=O
Temperature: 100 °C

Procedure:
Compound 3 (2.5 g) was treated with N-(3-bromopropyl)phthalimide (2.19 g) and diisopropylethylamine (2 ml) in DMF (10 ml). The reaction mixture was heated at 100° C. for 3 hours and then diluted with chloroform (300 ml) and extracted with water (4×300 ml). The chloroform was removed on a rotary evaporator and the residue subjected to flash chromatography using chloroform and methanol/chloroform as eluants to obtain the desired phthlamide adduct (Compound 4). Hydrazine hydrate (0.75 ml) was added to a solution of the phthalimide compound 4 (1.7 g) in 100% reagent alcohol (100 ml). The reaction mix was refluxed overnight and cooled to room temperature for about 1 hr. The reaction mix was then cooled at 4° C. overnight and the precipitate obtained by filtration. The solid was washed with ethanol chilled to −20° C. (2×20 ml) and dried in vacuo. The residue was dissolved in chloroform (300 ml), filtered and extracted twice with water (200 ml). The chloroform was removed on a rotary evaporator to give 1,4-Bis[(3-(3-aminopropyl)-oleoylamino)-2-hydroxypropyl]piperazine (Compound 5) in a quantitative yield. This material was acidified with HCL in dioxane and purified on reverse phase (C-18) flash chromatography using aqueous methanol as eluant and characterized by TLC and mass spectrometry.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][NH:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[Cl:12][CH2:13][C:14](Cl)=[O:15].C.C(OC)(C)(C)C>C1C=CC=CC=1>[Cl:12][CH2:13][C:14]([N:6]1[CH2:7][C@@H:3]([OH:2])[CH2:4][C@@H:5]1[C:8]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@H]1C[C@H](O)CN1
Agent: Cl
Solvent: c1ccccc1
Solvent: COC(C)(C)C
Product: COC(=O)[C@H]1C[C@H](O)CN1C(=O)CCl
Reaction time: 0.5 h

Procedure:
To a suspension of Example 65A (100 g, 0.55 mol, 1 equivalent) in benzene (2.5 L), chloroacetylchloride (62.4 g, 0.50 mol, 1 equivalent) was added dropwise at 20-25° C. The reaction mixture was refluxed for 3 hours. Then charcoal (2 g) was added, and the mixture was hot filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to get a solid. To this crude material, methyl tert-butyl ether (500 mL) was added and stirred for 30 minutes. The solid was collected by filtration, and the wet cake was dried in a vacuum tray dryer for 5 hours at about 50° C. to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.06-2.15 (m, 1H), 2.31-2.39 (m, 1H), 3.64 (d, 1H, J=11.1 Hz), 3.76 (s, 3H), 3.76-3.86 (m, 2H), 4.09 (s, 2H), 4.6-4.65 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][CH:7]=1.CCCCCCC.C([N-]C(C)C)(C)C.[Li+].O1CCCC1.C(C1C=CC=CC=1)C.[C:37](=[O:39])=[O:38]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:37]([OH:39])=[O:38]
Reactant: Clc1cccc(Br)c1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: O=C(O)c1c(Cl)cccc1Br
Temperature: -78 °C
Reaction time: 2 h

Procedure:
The mixture of 500 mg of 3-bromochlorobenzen and 3 ml of tetrahydrofuran was cooled down to −78° C. and 1.3 ml of 2.0M lithium diisopropylamide heptane/tetrahydrofuran/ethylbenzene was added. After stirring it for 2 hours, the mixture was put into dry ice and washed and extracted as described in Referencial Example 1 to obtain a crude material. The crude material was washed with a mixed solvent of hexane-ethyl acetate to obtain the said compound.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][S:5][N:4]=1)[CH3:2].C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:20][CH:1]([C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][S:5][N:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csnc1CC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1csnc1C(C)Br

Procedure:
Following generally the procedure of Example 28, ethyl 3-ethyl-4-isothiazolecarboxylate is reacted with NBS and benzoyl peroxide to give ethyl 3-(1-bromoethyl)-4-isothiazolecarboxylate, which is then reacted with sodium bicarbonate and DMSO and the resulting ethyl 3-acetyl-4-isothiazolecarboxy-late is treated with lithium hydroxide monohydrate to yield 3-acetyl-4-iso-thiazole-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][Si:32]([CH3:37])([CH3:36])[CH2:33][CH2:34]O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:34][CH2:33][Si:32]([CH3:37])([CH3:36])[CH3:31])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: C[Si](C)(C)CCO
Product: C[Si](C)(C)CCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1

Procedure:
The title compound was prepared according to Method E from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and 2-(trimethylsilyl)ethanol. Yellow solid, 192 mg. ES-MS m/z 520 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:19])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]([CH3:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(C)cn2Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C)CN2Cc1ccccc1
Reaction time: 8 h
Yield: 30.9 %

Procedure:
To a solution of 1-benzyl-5-methoxy-3-methylindole (200 mg, 0.796 mmol) in a 1:1 solution (2.4 mL) of acetic acid and tetrahydrofuran was added sodium cyanoborohydride (150 mg, 2.38 mmol) at room temperature. After being stirred overnight, sodium cyanoborohydride (50 mg, 0.80 mmol) was added with additional stirring for 6 h. After the reaction mixture was neutralized by saturated NaHCO3 aqueous solution, the reaction mixture was diluted with ethyl acetate. The separated organic layer was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=100/0 to 90/10) to obtain the title compound (62.4 mg, 31%).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:19])=[C:7]([CH3:18])[C:8]([OH:17])=[C:9]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C:10]=1[CH3:11])(=O)C.[OH-].[K+].C(OCC)C.Cl>C(O)C.O>[OH:17][C:8]1[C:7]([CH3:18])=[C:6]([CH3:19])[C:5]([OH:4])=[C:10]([CH3:11])[C:9]=1[CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)CCc1c(C)c(OC(C)=O)c(C)c(C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: C=C(C)CCc1c(C)c(O)c(C)c(C)c1O
Reaction time: 22 h

Procedure:
A solution containing 7.6 g (0.029 moles) of 4-(5-acetoxy-2-hydroxy-3,4,6-trimethylphenyl)-2-methyl-1-butene in 90 ml of 95% ethyl alcohol, is added with 90 ml of a solution containing 14.9 g (0.264 moles) of potassium hydroxide in 95% ethyl alcohol. The reaction mixture is kept for 22 hours at 90° C., then is diluted by adding ethyl ether and water, acidified to pH 5 with a 10% aqueous solution of hydrochloric acid and the product is extracted with ethyl ether. The crude product is obtained by evaporation of the solvent and used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]>[CH3:12][C:4]1[CH:3]=[C:2]([O:1][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: Clc1cnccn1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(Oc2cnccn2)cc1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 4.66 g, 28.4 mmol), 2-chloropyrazine (2.50 g, 21.8 mmol), copper (27.7 mg, 4.36 mmol), and potassium carbonate (9.05 g, 65.5 mmol) in 43.7 mL of DMF was stirred at 100° C. overnight. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), concentrated under reduced pressure, and purified by column chromatography on silica gel (50% EtOAc in hexanes as eluant) to give 1-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)ethanone (7-1, 4.65 g) as brown oils: 1H NMR (500 MHz, CDCl3) δ 8.43 (bs, 1 H), 8.29 (bs, 1 H), 8.14 (bs, 1 H), 6.83 (s, 2 H), 2.49 (s, 3 H), 2.27 (s, 6 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33](=[N:35]O)[NH2:34])[CH:32]=1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33]2[N:34]=[C:18]([C:17]3[CH:21]=[CH:22][C:14]([N:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]4[CH3:7])=[C:15]([N+:23]([O-:25])=[O:24])[CH:16]=3)[O:20][N:35]=2)[CH:32]=1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c([N+](=O)[O-])c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 8 (132 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 80/20) followed by crystallisation from ethyl acetate/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.[Cl:7][C:8]1[NH:12][C:11]2[CH:13]=[C:14]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH:15]=[C:16]([C:17]([OH:19])=O)[C:10]=2[N:9]=1>C1COCC1.CN(C=O)C>[Cl:7][C:8]1[NH:12][C:11]2[CH:13]=[C:14]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH:15]=[C:16]([C:17]([NH:9][C:10]3[CH:11]=[CH:13][CH:2]=[C:1]([Cl:6])[C:16]=3[CH3:15])=[O:19])[C:10]=2[N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(Nc1cc(C(=O)O)c2nc(Cl)[nH]c2c1)c1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.42 mL) was added dropwise to a stirring solution of 2-chloro-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylic acid (1.27 g) in THF (13 mL) under ice-cooling. To the mixture was added DMF (five drops), and it was stirred at room temperature for 2 hours. From the reaction mixture was removed the solvent and excessive oxalyl chloride under reduced pressure. To the residue was added toluene, and it was concentrated under reduced pressure, dried, and then dissolved in THF (10 mL). The solution was dropped slowly to a solution of 3-chloro-2-methylaniline (0.42 mL) and N,N-diisopropylethylamine (2.3 mL) in THF (10 mL) under ice-cooling for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (0.58 g) as white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Se:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(N(CC)CC)C>ClCCl.C(OCC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][Se:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=[O:13]
Reactant: O=C(O)c1ccccc1[Se]Cc1ccccn1
Reactant: Nc1ccccn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccn1)c1ccccc1[Se]Cc1ccccn1
Reaction time: 20 h

Procedure:
To a solution of 5.84 g (0.02 mol) 2-(2-picolylseleno)benzoic acid (from Example 1) in 40 ml dichloromethane that has been cooled to 0° C. are added in one portion 5 g (0.02 mol) bis[2-oxo-3-oxazolidinyl]phosphoryl chloride. After stirring for 2 hours at room temperature 1.88 g (0.02 mol) 2-aminopyridine, 50 ml dichloromethane and 6.4 ml triethylamine are added dropwise in succession at 10° C. and stirring is continued at room temperature for 20 h. The reaction mixture is extracted twice with 100 ml portions of water, dried over sodium sulfate and the solvent removed. The brown oil (7 g) is taken up in 100 ml 1 N HCl, filtered, the filtrate basified with 13 ml 10 N sodium hydroxide and extracted with 100 ml ethyl acetate. The organic phase is dried, concentrated and the solid residue obtained is stirred for 48 h with 100 ml diethyl ether. After filtration the crude product is cleaned up by column chromatography (silica gel/dichloromethane) and recrystallized from 20 ml 2-propanol.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.[CH2:20]=[C:21]([CH3:23])[CH3:22].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[CH2:20][C:21]([CH3:23])([CH3:22])[C:9]3[C:2](=[C:3]([CH3:10])[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=3)[NH:1]2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Cc1cc(C#N)ccc1N
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Temperature: 85 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
To a stirred solution of 4-amino-3-methyl-benzonitrile (10.3 g, 78.4 mmol) and 3-bromobenzaldehyde (9.2 mL, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-30% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (7.3 g, 26.1%) as a light yellow oil: LC/MS m/e obsd. (ESI+) [(M+H)+] 355.0 & 357.0.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]([F:21])([F:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[I-].[NH3:24].C1(S(O)(=O)=O)C=CC=CC=1>C(OC(C)C)(=O)C.CS(C)=O>[C:5]1([S:8]([OH:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1.[F:20][C:13]([F:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:12][NH2:24]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)c2ccccn2)cc1
Reactant: N
Agent: O=S(=O)(O)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: CS(C)=O
Product: NCC(F)(F)c1ccccn1
Temperature: 80 °C

Procedure:
10 g of 2,2-Difluoro-2-pyridin-2-ylethyl 4-methylbenzenesulfonate (J) obtained in step 3, 5 g of NaI, 20 mL of DMSO and 90 mL of aqueous ammonia were taken in a 500 mL autoclave vessel. The reaction mixture was heated to 80° C. and a pressure of 15 to 17 kg of ammonia maintained for 30-40 hours. The volume of the reaction mass was reduced by vacuum distillation. The RM was washed with 60 mL of IPE. The pH of the RM was adjusted to 10-14 by adding a 50% NaOH solution and extracted three times with 60 mL of MDC. The combined MDC layers were washed with brine, dried over sodium sulphate and distilled under vacuum (crude weight=8 g). The crude mass obtained was dissolved with 10 mL of MDC, and to this 4.5 g benzene sulphonic acid (BSA) dissolved in 30 mL isopropyl acetate (IPAc) was added dropwise over a period of 30 minutes with stirring at RT. The RM was stirred for 30 minutes at RT. The solid obtained was filtered and washed with IPAc and dried under vacuum, resulting in 5 g of the titled compound (Yield=49.5%).
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:14]>CO>[NH2:14]/[C:2](/[CH2:8][CH3:9])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CC/C(N)=C/C(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 18415.4 %

Procedure:
A mixture of methyl 3-oxovalerate (75.0 g, 576 mmol), ammonium acetate (222 g, 2.88 mmol) and methanol (750 mL) was stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure, water (500 mL) was added to the residue and the mixture was extracted with ethyl acetate (200 mL). The extract was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and dried to give the title compound (68.5 g, 92%) as a pale-yellow oil.