Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]CC.[Na+].[Na]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]#[N:10])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 45.3 g. (0.31 mol.) of p-chlorophenylacetonitrile and 107 g. (0.72 mol., 99 ml.) of diethyl oxalate in an alcoholic sodium ethoxide solution [prepared by dissolving 7.13 g. (0.31 g.-atom) of sodium in 120 ml. of absolute ethanol] was refluxed with stirring for 2 hours. The cooled reaction mixture was diluted with 700 ml. of water, acidified with acetic acid and cooled to ice bath temperature. The resulting solid was collected and recrystallized from aqueous methanol to give ethyl 3-(p-chlorophenyl)-3-cyanopyruvate, m.p. 134°-135°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[CH3:21][O:22][CH2:23]CCOS(C1C=CC(C)=CC=1)(=O)=O>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][CH2:15][CH2:16][CH2:21][O:22][CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCSC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.82 g) and potassium thioacetate (2.31 g) was heated to 60° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.80 g). To a solution of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (607 mg) in dry MeOH (5 mL) was added a solution of sodium methoxide in MeOH (25% wt, 0.59 mL). After stirring for 15 min, toluene-4-sulfonic acid 3-methoxy-propyl ester (described elsewhere, 571 mg) was added in MeOH. After 24 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to yield 4-(3-methoxy-propylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment with mCPBA (as described above) yielded 4-(3-methoxy-propane-1-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]=[O:25])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][Mg]Br>C1COCC1>[N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]([OH:25])[CH3:26])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/C=O)n2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/C(C)O)n2)cc1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A stirred solution of 3-(6-[3-pyrrolidin-1-yl-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-enal (1.41 g, 4.24 mmol) in anhydrous THF (50 ml) at -78° C. was treated dropwise with a solution of methyl magnesium bromide (1.56 ml, 3.0M in diethylether, 4.67 mmol). The reaction mixture was allowed to warm slowly to room temperature (~2 hours). The reaction was quenched with water (3 ml) and THF removed under reduced pressure. The residue was taken up in 1M HCl and then basified with solid sodium bicarbonate to pH 8. The product was extracted with ethyl acetate (×3). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by column chromatography eluting with 5% methanol in DCM. Product containing fractions were combined and solvent removed to provide 4-(6-[3-pyrrolidin-1-yl-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-but-3E-en-2-ol as a pale brown foam (544 mg, 37%). 1H-NMR; δ (CDCl3), 7.43 (1H, t, J=7.8 Hz), 7.24-7.18 (3H, m), 7.11-7.06 (3H, m), 6.94 (1H, dd, J=15.6 and 5.8 Hz), 6.71-6.64 (2H, m), 4.60-4.55 (1H, m), 3.23 (2H, d, J=7.0 Hz), 2.58 (4H, bs), 2.41 (3H, s), 1.82-1.77 (4H, m), 1.41 (3H, d, J=6.5 Hz).
Reaction SMILES: [Na+].[I-].[F:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:5]=1[CH2:6][NH:7][C:8]([NH2:10])=[O:9].[CH2:19]=[C:20]1O[C:22](=[O:23])[CH2:21]1.C[Si](Cl)(C)C>C(#N)C.O>[F:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:5]=1[CH2:6][N:7]1[C:20]([CH3:19])=[CH:21][C:22](=[O:23])[NH:10][C:8]1=[O:9]
Reactant: NC(=O)NCc1c(F)cccc1C(F)(F)F
Reactant: C=C1CC(=O)O1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
NaI (43.9 g, 293 mmol) was added to N-[2-fluoro-6-(trifluoromethyl)benzyl]urea 1b (46.2 g, 19.6 mmol) in 365 mL of acetonitrile. The resulting mixture was cooled in an ice-water bath. Diketene (22.5 mL, 293 mmol) was added slowly via dropping funnel followed by addition of TMSCl (37.2 mL, 293 mmol) in the same manner. The resulting yellow suspension was allowed to warm to room temperature slowly and was stirred for 20 hours. LC-MS showed the disappearance of starting material. To the yellow mixture 525 mL of water was added and stirred overnight. After another 20 hours stirring, the precipitate was filtered via Buchnner funnel and the yellow solid was washed with water and EtOAc to give 1c as a white solid (48.5 g, 16 mmol). 1H NMR (CDCl3) δ 2.152 (s, 3H), 5.365 (s, 2H), 5.593 (s, 1H), 7.226–7.560 (m, 3H), 9.015 (s, 1H); MS (CI) m/z 303.0 (MH+).
Reaction SMILES: C(OC([N:8]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)[C:13]1=[O:26])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=3)[C:13]2=[O:26])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc2ccn(CCCN(C(=O)OC(C)(C)C)c3ccc(OC)cc3)c(=O)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2ccn(CCCNc3ccc(OC)cc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.9 %

Procedure:
To a solution of methyl 2-{3-[(tert-butoxycarbonyl)(4-methoxyphenyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (71 mg, 0.15 mmol) in methylene chloride (2 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (2.0 mL, 8.0 mmol). The reaction mixture was stirred at rt for 1 d. The mixture was then concentrated to dryness to afford methyl 2-{3-[(4-methoxyphenyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (56 mg, quant.). LC-MS: (FA) ES+ 367.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: Cc1cc(-c2ccc(Cl)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (43 mg, 77%), MS (ISP) m/z=325.4 [(M+H)+], mp 258.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 11) (50 mg, 0.17 mmol) and commercially available 4-chloro-phenylboronic acid (34.7 mg, 0.22 mmol).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:16][O-:17].[Na+].[OH-].[Na+].O>CO>[CH3:16][O:17][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cnc(C(=O)O)cn1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
5-Chloropyrazine-2-carboxylic acid (5.0 g, 0.032 mol) was charged to a round-bottom flask equipped with a thermocouple, overhead stirrer and reflux condenser. Methanol (37.5 mL, 0.926 mol) was charged followed by conc. sulfuric acid (0.2 mL, 0.004 mol). The 3-neck flask was equipped with a heating mantle, and then the reaction mixture was heated to ca. 65.0° C. (T internal). The reaction mixture continued to stir at ca. 65.0° C. (T internal) for ca. 4 h. The reaction mixture cooled to ca. 25.8° C. (T internal). Methanol (12 mL, 0.31 mol) was charged and the slurry continued to stir at ca. 22.3° C. (T internal) for ca. 15 min then cooled to ca. 10.0° C. (T internal) under an atmosphere of nitrogen. 25% Sodium methoxide in methanol (1:3, Sodium methoxide:Methanol, 7.7 mL) was charged to flask while temperature remained below 30.0° C. (T internal). The reaction mixture was adjusted to 20.4° C. (T internal). After 30 min., sodium hydroxide (2.0 g, 0.04 mol) and water (37.5 mL, 2.08 mol) were combined to form a solution, and then the solution was charged to the reaction mixture. Water (50.0 mL, 2.78 mol) was charged and then the reaction mixture was heated to 40.0° C. (T internal) for ca. 60 mins. The heating mantle was removed, and then the reaction mixture cooled to ca. 25.4° C. (T internal). 38% aq. HCl Solution (38:62, hydrogen chloride:water, 4.0 mL) was added at a rate (ca. 5 min.) such that the temperature remained below 30.0° C. (T internal). The thick slurry was stirred for 1 h at ca. 21.4° C. (T internal), and then filtered over a sintered funnel. The solids were rinsed with water (10.0 mL, 0.555 mol) and dried under vacuum overnight to afford 5-methoxypyrazine-2-carboxylic acid (3.59 g). 1H NMR (500 MHz, DMSO) δ 13.24 (1H, br s), 8.79 (1H, d, J=1.2 Hz), 8.37 (1H, d, J=1.2 Hz), 3.98 (s, 3H); 13C NMR (125 MHz, DMSO) δ 165.36, 161.88, 143.88, 136.82, 135.55, 54.69.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=5[CH3:28])[NH2:24])[CH:19]=[C:18]([CH3:29])[N:16]4[N:17]=3)[CH:10]=[N:9]2)=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([S:43]([F:48])([F:47])([F:46])([F:45])[F:44])[CH:42]=1)[C:37](O)=[O:38].FC(F)(F)C(O)=O>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([S:43]([F:48])([F:44])([F:45])([F:46])[F:47])[CH:42]=1)[C:37]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([N:20]2[C:15]3[N:16]([N:17]=[C:13]([C:11]4[CH:12]=[N:8][NH:9][CH:10]=4)[CH:14]=3)[C:18]([CH3:29])=[CH:19]2)[CH:22]=1)=[O:38]
Reactant: COc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)cc(C)n4n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)Nc2ccc(C)c(-n3cc(C)n4nc(-c5cn[nH]c5)cc34)c2)cc(S(F)(F)(F)(F)F)c1

Procedure:
60 mg (0.15 mmol) of the compound of Example 9A and 40 mg (0.15 mmol) of the compound of Example 25A were reacted analogously to the procedure of Example 10, except that here the reaction was stirred with trifluoroacetic acid at 80° C. only for 3 h (instead of 6 h). This gave 36 mg (43% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[CH2:27][O:26][CH3:25])=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC[C@@H]1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, (S)-2-methoxymethylpyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.56 minutes; C22H22Cl2N4O3 (461.35); mass spectrum: (M+H)+=461.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: COc1nc(C)nc(Cl)n1
Product: COc1nc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 32 %

Procedure:
This compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4-methoxy-6-methyl-[1,3,5]triazine in analogy to example 1c. It was purified by chromatography on Si—NH2 (Isolute) using ethyl acetate as an eluent to give the title compound as a slightly yellowish solid in 32% yield.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19].CCOCC>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6])[CH3:19]
Reactant: OCCc1ccccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1ccccc1CCO
Temperature: 42.5 °C
Reaction time: 12 h

Procedure:
To a suspension of 1.00 g (7.24 mmol) of 2-hydroxyphenethyl alcohol and 1.35 g (8.68 mmol) of potassium carbonate in 15 ml of N,N-dimethylformamide was added 2.00 g (14.48 mmol) of iodoethane at 0° C. The reaction mixture was stirred at 40-45° C. for 12 h and was poured into 200 ml of ether. It was washed with water (20 ml ×3), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 9:1 hexane/ethyl acetate to afford the 2-ethoxyphenethyl alcohol as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[C:14]([C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:12][CH3:13])[C:2]=2[Cl:1])[CH:7]=1)(=[O:16])[CH3:15]
Reactant: COc1ccc2ccccc2c1Cl
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2cc(C(C)=O)ccc2c1Cl

Procedure:
A mixture of 1925 g. of 1-chloro-2-methoxynaphthalene, 80 g. of acetyl chloride, 400 g. of aluminum chloride and 2.5 liters of nitrobenzene are stirred for 60 hours at room temperature. The resulting mixture is then washed with dilute hydrochloric acid, dried over sodium sulfate and evaporated to yield 2-acetyl-5-chloro-6-methoxynaphthalene. The resulting acetyl product is added to a mixture of 39 g. of sulfur and 105 g. of morpholine and heated to about 150°C for 3 hours. The mixture is then added to 1 liter of concentrated hydrochloric acid and refluxed for 3 hours. The mixture is then cooled, diluted with 6 liters of ice-water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate and evaporated to yield 2-(5'-chloro-6'-methoxy-2'-naphthyl) acetic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10]O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.CS(Cl)(=O)=O.Cl.Cl.[C:19]([O:23][C:24]([N:26]([C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)[C:27]1[N:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CCN(CC)CC.C1COCC1>[C:19]([O:23][C:24]([N:26]([C@@H:40]1[CH2:44][CH2:43][N:42]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[CH2:41]1)[C:27]1[N:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1)=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: OCc1ccc2c(c1)CCO2
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc4c(c3)CCO4)C2)nc1
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a mixture of 2,3-dihydro-1-benzofuran-5-ylmethanol (95.1 mg), Et3N (0.120 mL), and THF (3 mL) was added methanesulfonyl chloride (0.053 mL) at 4° C. The reaction mixture was stirred for 3 hours, and added ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (250 mg) and Et3N (0.281 mL). After stirring for 2 hours at 60° C., the resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2,3-dihydro-1-benzofuran-5-ylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (134 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(P(CCCC)CCCC)CCC.[CH:23]1([C:26]2[CH:27]=[CH:28][C:29]([CH:42]([C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH:53]4[CH2:55][CH2:54]4)(=[O:52])=[O:51])=[CH:46][CH:45]=3)O)=[N:30][C:31]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH:23]1([C:26]2[C:31]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)=[N:30][C:29]([CH:42]([C:44]3[CH:45]=[CH:46][C:47]([S:50]([CH:53]4[CH2:54][CH2:55]4)(=[O:52])=[O:51])=[CH:48][CH:49]=3)[O:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1ccc(COc2nc(C(O)c3ccc(S(=O)(=O)C4CC4)cc3)ccc2C2CC2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2nc(C(Oc3ccc(F)cc3F)c3ccc(S(=O)(=O)C4CC4)cc3)ccc2C2CC2)cc1
Temperature: 86 °C
Yield: 77.1 %

Procedure:
2,4-Difluorophenol (219 mg), tributylphosphine (340 mg) and N,N,N′,N′-tetramethylazodicarboxyamide (289 mg) were sequentially added to a solution of {5-cyclopropyl-6-[(4-methoxybenzyl)oxy]pyridin-2-yl}[4-(cyclopropylsulfonyl)phenyl]methanol (390 mg) in tetrahydrofuran (12 mL). After replacement with nitrogen, the mixture was stirred under reflux at an external temperature of 86° C. for six hours, returned to room temperature and stirred overnight. The reaction solution was poured into water and a potassium carbonate solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=92:8→34:66) to give 3-cyclopropyl-6-{[4-(cyclopropylsulfonyl)phenyl](2,4-difluorophenoxy)methyl}-2-[(4-methoxybenzyl)oxy]pyridine as a yellow gum (373 mg, 77%).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#N)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:37]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:37])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(=O)(O)O
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C#N)cc3)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=O)cc3)cc2)CC1
Temperature: -35 °C
Reaction time: 2 h

Procedure:
A solution of 10.0 g of 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarbonitrile in 150 ml of methylene chloride was placed at -35° C. in a sulphonation flast while gassing with argon and treated within 8 minutes with 40 ml of an about 1.5N solution of diisobutylaluminium hydride in toluene. After completion of the addition, the mixture was stirred for 2 hours at -35° C. and then for a further 1.5 hours with gradual warming to 0° C., before it was treated cautiously with 100 ml of 1N sulphuric acid and extracted three times with 150 ml of diethyl ether each time. The organic phases were washed with 100 ml of 1N sulphuric acid, twice with 100 ml of water each time and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. There were obtained 9.5 g (95%) of 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxaldehyde as a colourless, crystalline mass (m.p. 115°-116° C.) which was used in the following step without further purification. Rf value [toluene/ethyl acetate (19:1)]: educt 0.65, product 0.52.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:12])[CH3:2].[Cl-].C[Al+]C.[CH3:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](Cl)=[O:29])=[CH:20][CH:19]=1>ClCCl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:28]([C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([CH3:17])=[CH:19][CH:20]=2)=[O:29])=[C:4]1[CH3:12])[CH3:2]
Reactant: CCn1c(C)cc2ccccc21
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Product: CCn1c(C)c(C(=O)c2ccc(C)c3ccccc23)c2ccccc21
Reaction time: 0.75 h

Procedure:
To a solution of 0.20 g (1.26 mmol) of 1-ethyl-2-methylindole in 4 mL of dry dichloromethane at 0° C. under argon, was added dropwise 0.17 g (1.89 mmol) of dimethylaluminum chloride. The solution was stirred at this temperature for 45 min and then 0.39 g (1.88 mmol) of 4-methyl-1-napthoyl chloride in 6 mL of dry dichloromethane was added, and the solution stirred at 0° C. for 4 hrs. The solution was carefully quenched by the addition of 1M HCl and extracted with dichloromethane (2×20 mL). The combined organic extract were washed with a saturated solution of NaHCO3, H2O, brine, dried (MgSO4), filtered and concentrated in vacuo. The oil was purified by chromatography (ethyl acetate/petroleum ether 1:9) to afford the desired compound as an orange solid 0.16 g (40%), recrystallization from petroleum ether/ether provided white crystals, mp 136-137° C.: 1H NMR (300 MHz, CDCl3) δ 1.42 (t, J=7.3 Hz, 3H), 2.51 (s, 3H), 2.80 (s, 3H), 4.25 (q, J=7.3 Hz, 2H), 6.92-7.05 (m, 1H), 7.17-7.29 (m, 2H), 7.32-7.39 (m, 2H), 7.46-7.53 (m, 2H), 7.54-7.61 (m, 1H), 8.11 (d, J=8.3 Hz, 1H), 8.21 (d, J=8.3 Hz, 1H); 13C NMR (300 MHz, CDCl3) δ 12.3, 14.75, 19.9, 38.0, 109.2, 115.1, 121.4, 121.9, 122.2, 124.3, 125.8, 126.1, 126.3, 126.5, 127.3, 130.5, 132.9, 135.6, 136.7, 138.9, 145.1, 193.6; GC/MS (EI) m/z (rel intensity) 327 (100), 312 (80), 186 (60), 115 (20). Anal. Calcd for C23H21NO: C, 84.37; H, 6.46; N, 4.28. Found C23H21NO: C, 84.23; H, 6.48; N, 4.29.