Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([F:31])[C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:28][CH2:27][CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][C:16]2[C:15]([F:31])=[CH:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[CH:18][N:17]=2)=[CH:30][CH:29]=1)(=[O:4])=[O:3]
Reactant: OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 63 μL (0.816 mmol) of methanesulfonyl chloride was added dropwise to a solution of 0.20 g (0.544 mmol) of 2-{4-[5-(4-chlorophenyl)-3-fluoropyridin-2-ylethynyl]phenoxy}ethanol and 0.11 mL (0.816 mmol) of triethylamine in 10 mL of DCM and the mixture was stirred for 16 hours at RT. A further 0.11 mL (0.816 mmol) of triethylamine and 63 μL (0.816 mmol) of methanesulfonyl chloride were added and the mixture was stirred for 8 hours. The reaction mixture was diluted with DCM, and the organic phase was washed with water and dilute aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.24 g (99% of theoretical); C22H17ClFNO4S (M=445.892); calc.: molpeak (M+H)+: 446/448 (Cl); found: molpeak (M+H)+: 446/448 (Cl); HPLC-MS: 6.19 minutes (method B).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1CN.Cl[C:11]1[NH:12]C2C=C(OC)C=CC=2[N:15]=1>C(Cl)Cl>[N:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[NH:12][C:11]=1[NH2:15]
Reactant: NCc1ccccc1N
Reactant: COc1ccc2nc(Cl)[nH]c2c1
Solvent: ClCCl
Product: Nc1nc2ccccc2[nH]1
Temperature: 120 °C

Procedure:
A mixture of 2-aminobenzylamine (500 mg, 4.1 mmol) and 2-chloro-5-methoxybenzoimidazole (210 mg, 1.2 mmol) was heated at 120° C. for 18 h. The resulting oily residue was dissolved in CH2Cl2 (30 mL) and washed with H2O (30 mL). The organic layer was separated, dried over Na2SO4, and concentrated to provide crude benzimidazole amine as a solid which was treated with CDI (1.0 g, 6.0 mmol) in anhydrous DMF (15 mL). After stirring at RT for 18 h, the reaction mixture was concentrated. The residue was purified by prep TLC to give an oil which was triturated from CH2Cl2 and hexane to yield a solid. Further purification by prep HPLC provided the title compound as white solid. MS m/z: 295 (M+H+); MALDI FTMS (DHB) m/z: 295.1184 (M+H; Calc'd for C16H15N4O2, 295.1189).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)#[N:6]>CN(C=O)C.C(OCC)(=O)C>[NH:1]1[C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:6][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.6 %

Procedure:
Sodium azide (228 mg, 3.50 mmol) was added to a stirred, cooled RT mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (243 mg, 1.167 mmol) in DMF (5 ml) and the mixture was stirred at 100° C. for 48 h. The mixture was cooled, diluted with ethyl acetate (100 mL), washed with brine (3×50 mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40S, eluting with 10% methanol in dichloromethane to afford the title compound (197 mg, 75%) as a colorless liquid. ESI-MS calculated for C11H19N5O2: Exact Mass: 253.13. Found 254.12.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8]([N:15]2[C:19]3=[N:20][CH:21]=[N:22][C:23](O)=[C:18]3[CH:17]=[N:16]2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]>>[Cl:6][C:7]1[C:8]([N:15]2[C:19]3=[N:20][CH:21]=[N:22][C:23]([Cl:3])=[C:18]3[CH:17]=[N:16]2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(O)ncnc21
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
Phosphorus oxychloride (7.93 mL, 85.03 mmol) was added to 3-chloro-2-(4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH5) (1.155 g, 4.25 mmol). The resulting mixture was heated to 100° C. and stirred for 4 hours. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was evaporated to near dryness. Poured onto ice/water with stirring. A solid precipitate was collected by filtration. This was dried overnight under vacuum to afford the product (0.928 g, 75%). 1H NMR (400 MHz, DMSO) δ 8.02-7.96 (1H, t), 8.26 (1H, d), 8.28 (1H, s), 9.05 (2H, d). m/z M+=289; GCMS tR=13.82 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1.[CH3:24][C@H:25]1[CH2:30][NH:29][C@H:28]([CH3:31])[CH2:27][NH:26]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:26]2[CH2:27][C@@H:28]([CH3:31])[NH:29][CH2:30][C@@H:25]2[CH3:24])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(Cl)c2ccc(Br)cc2)c1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Yield: 62 %

Procedure:
The crude benzhydryl chloride (approx. 135 mmol) was combined with 46.3 g (405 mmol) of trans-2,5-dimethylpiperazine (purified by recrystallization from toluene to mp=115°-119° C.) and 30 mL of toluene and heated at reflux overnight under nitrogen. The toluene was removed under vacuum, and the residue was redissolved in 2000 mL of diethyl ether and washed with 500 mL of 1.0M sodium hydroxide and 1000 mL of water. The ether solution was dried over sodium sulfate and the solvent removed to give a dark oil. The product was purified by chromatography on silica gel with 1-10% ethanol in dichloromethane to give 41.0 g (62%) of (±)-trans-1-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a 1:1 mixture of diastereomers. NMR (300 MHz, CDCl3); δ0.15 (s, 6H); 0.9 (m,12H); 1.2 (d,J=6 Hz,3H); 1.4-1.6 (m,2H); 2.2-3.0 (m,5H); 5.2 and 5.3 (s,1H); 6.6-7.5 (m,8H).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH2:7][CH3:8])([CH3:6])[CH3:5])=[O:3].[CH:9]#[CH:10].Cl>O1CCCC1>[CH3:1][C:2]([OH:3])([C:4]([CH3:6])([CH3:5])[CH2:7][CH3:8])[C:9]#[CH:10]
Reactant: C#C
Reactant: CCC(C)(C)C(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: C#CC(C)(O)C(C)(C)CC
Reaction time: 0.5 h
Yield: 85 %

Procedure:
50 g of tert-amyl methyl ketone were dissolved in 50 ml of tetrahydrofuran and the solution was added dropwise at 0° C. to 330 ml of a 1.5 molar acetylene Grignard solution in tetrahydrofuran. After 30 min, the mixture was hydrolyzed with 2N hydrochloric acid, the organic phase was separated, the solvent was removed and the residue was then fractionally distilled. 52 g (85%) of 3,4,4-trimethylhex-1-yn-3-ol were obtained (b.p.: 110° C./175 mbar).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH2:19]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([C:23]1[S:24][C:25]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:26][CH:27]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CCCCc1cccs1
Product: CCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-butyl-thiophene.
Reaction SMILES: [C:1]([Si:5]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C1COCC1.C(Cl)(Cl)(Cl)Cl>[C:1]([Si:5]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:12])[CH3:13])[N:6]1[CH:7]=[CH:8][C:9]([Br:17])=[CH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](C(C)C)(n1cccc1)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)[Si](C(C)C)(n1ccc(Br)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1-(tert-butyldiisopropylsilyl)-1H-pyrrole (1.0 g, 4.48 mmol) in THF was added N-bromosuccinimide at −78° C. The reaction mixture was slowly warmed to RT and stirred for 24 hours. The reaction mixture was concentrated to obtain dark black residue, which was suspended in CCl4 (100 mL) and stirred for 15 min and filtered. The filtrate was concentrated to obtain 1-(tert-butyldiisopropylsilyl)-3-bromo-1H-pyrrole as oily liquid (1.0 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[N-:11]=[N+:12]=[N-:13].[Na+]>>[N:11]([CH:4]([CH2:3][CH3:2])[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCCBr
Agent: [Na+]
Product: CCC(CCCC(=O)O)N=[N+]=[N-]

Procedure:
Reaction of 7-bromoheptanoic acid and NaN3, as described for the synthesis of 6, gave 5-azidoheptanoic acid 10. Saponification was not necessary. Used without further purification.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH3:12])(=[O:6])[CH3:5]>O1CCOCC1.O>[CH3:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[C:4](=[O:6])[CH:5]=[O:2]
Reactant: O=[Se]=O
Reactant: CC(=O)c1sccc1C
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccsc1C(=O)C=O

Procedure:
A 34.9 g portion of selenium dioxide was dissolved in a mixture of 85 ml of dioxane and 10 ml of water with stirring and heating to 55°-60° C. A 40 g portion of -acetyl-3-methylthiophene was added and the mixture was refluxed for 6 hours, then cooled, diluted with dioxane, filtered and evaporated to dryness. The residue was dissolved in ether and the crystals which formed collected, giving 12.03 g of 3-methyl-α-oxo-2-thiopheneacetaldehyde.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:20])([CH3:19])[CH2:13][C:14](=[O:18])[O:15]2)=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[OH:18][CH2:14][CH2:13][C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:17][C:16]=1[OH:15])([CH3:20])[CH3:19]
Reactant: COc1ccc2c(c1)OC(=O)CC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)CCO)c(O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a tetrahydorofran (THF) (20 ml) solution of 7-methoxy-4,4-dimethylchroman-2-one (4.1 g, 19.7 mmol) was added lithium aluminum hydride (750 mg, 19.7 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. To the mixture was added H2O (1 ml) carefully to form a white prepicitate. The organic layer was dried over magnesium sulfate. After filtration to separate solvent and magnesium sulfate and precipitate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=¼ to furnish 3.0 g (76% yield) of the title compound as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[I-:10].[K+].II>N.O>[Br:1][C:2]1[CH:7]=[C:6]([I:10])[C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1
Reactant: [I-]
Reactant: Oc1ccc(Br)cc1Cl
Agent: II
Agent: N
Agent: [K+]
Solvent: O
Product: Oc1c(Cl)cc(Br)cc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a solution of 4-bromo-2-chlorophenol (10 g, 48.2 mmol) in 25% aqueous ammonia solution (140 mL) was added a solution of potassium iodide (24 g, 144.6 mmol) and iodine (12.2 g, 48.2 mmol) in water (125 mL). The reaction mixture was stirred at ambient temperature for 4 h and quenched with 100 mL of water. The reaction was acidified by addition of concentrated HCl (150 mL) and extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 9:1 hexanes/ethyl acetate) providing 4-bromo-2-chloro-6-iodophenol (14 g, 89%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.74 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 5.93 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1F.[CH:14]1([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:19][CH2:18][CH:14]1[CH2:17][CH2:16][CH2:15]1
Reactant: OCC1CCC1
Reactant: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Product: CNc1ccc(Br)c(OCC2CCC2)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 11, Step 1, using 4-bromo-3-fluoro-N-methyl-2-nitroaniline and cyclobutylmethanol as the starting materials. LCMS calculated for C12H16BrN2O3 (M+H)+: m/z=315.0, 317.0. found: 315.0, 317.0.
Reaction SMILES: [CH3:1][CH:2]([OH:13])[CH2:3][C:4]([CH3:12])([O:6][O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5].N1C2C(=CC=CC=2)C=CC=1.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26].Cl.N1C2C(=CC=CC=2)C=CC=1>CCCCC>[C:25](=[O:26])([O:27][CH:28]([CH3:30])[CH3:29])[O:13][CH:2]([CH3:1])[CH2:3][C:4]([CH3:12])([O:6][O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(O)CC(C)(C)OOC(C)(C)C
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCCCC
Product: CC(C)OC(=O)OC(C)CC(C)(C)OOC(C)(C)C
Reaction time: 72 h

Procedure:
A four-necked 500 ml. round-bottomed flask was equipped with a mechanical stirrer, reflux condenser surmounted by calcium chloride drying tube, addition funnel and thermometer. A solution of 19 g. (0.1 mole) 1,3-dimethyl-3-(t-butylperoxy)butyl alcohol and 13.3 g (slightly over 0.1 mole) quinoline in 250 ml. pentane was placed in the flask which was placed in a water bath at 221/2° C. Then 12.3 g (0.1 mole) isopropyl chloroformate was added dropwise over 5 minutes; the temperature did not rise over 23° C. Reaction was not complete after 3 days. Another 3 g. of quinoline was added, and the reaction was completed after another 3 days as indicated by the fact that not further precipitate of quinoline hydrochloride formed when an aliquot of clean pentane solution was withdrawn from the reaction mixture and allowed to stand for 15 minutes. The quinoline hydrochloride was filtered off and washed with 25 ml pentane which was added to the pentane solution. This solution was then successively washed with 25 ml. of 7% hydrochloric acid, two 50 ml. portions of water, and finally dried over sodium sulfate. After removal of drying agent and pentane, a yield of 23.8 g. (86.4%) of material found to be 1,3-dimethyl-3-(t-butylperoxy)butyl isopropyl carbonate by infrared analysis, was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:6]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>C(Cl)Cl>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1ccc(-n2cc(N)cn2)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-n2cc(NC(=O)OCC(Cl)(Cl)Cl)cn2)cc1
Yield: 94.3 %

Procedure:
Intermediate 6b (150 mg, 0.87 mmol) dissolved in DCM (10 mL) was cooled using an ice bath, and then treated sequentially with triethylamine (0.18 mL, 1.30 mmol) and trichloroethyl chloroformate (0.15 mL, 1.08 mmol). The mixture was stirred with cooling for 45 min, then evaporated to dryness. Residue was purified by FCC, eluting with 0-30% ethyl acetate in cyclohexane, to give the title compound as a beige solid (286 mg, 95%). LCMS (Method 3): Rt 4.25 min, m/z 348/350/352 [MH+].
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)[CH3:5])[CH:2]=[CH2:3].C(Cl)Cl.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=[O:25]>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:24]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:5])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:25])=[CH:28][CH:29]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: C=CCN(C)CCCCCc1ccc2c(c1)CCN2
Solvent: ClCCl
Product: C=CCN(C)CCCCCc1ccc2c(c1)CCN2C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To 130 mg (0.5 mmol) Allyl-[5-(2,3-dihydro-1H-indol-5-yl)-pentyl]-methyl-amine in 2 ml CH2Cl2 0.34 ml (2 mmol) Huenig's base were added, followed by 0.28 ml (2 mmol) 4-chlorophenyl chloroformate. The solution was stirred at RT for 30 min, was concentrated and dissolved in 0.1 M NaOH and ether. The inorganic phase was extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 9:1 yielded 160 mg (77%) 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester as light yellow oil, MS: 413 (MH+, 1Cl).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([F:22])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH3:28][C:29](=[CH2:33])[C:30](Cl)=[O:31]>C(OCC)(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:30](=[O:31])[C:29]([CH3:33])=[CH2:28])=[C:17]([F:22])[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reaction time: 2 h

Procedure:
To 4′-Amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (5.000 g, 15.51 mmoles) at room temperature in ethyl acetate (50 ml) was added saturated sodium bicarbonate, aqueous, 50 ml and then 2-methyl-acryloyl chloride (1.25 equiv.). Stirred for 2 hours then added a further 1 ml of the acid chloride. After 2 hours an aliquot showed product by NMR. Product seems to co-run with starting material. Extracted into ethyl acetate, washed with brine, dried MgSO4, and then concentrated in vacuo. Collected some crystalline product from ethyl acetate hexane, 0.48 g. Columned mother liquor to afford product. Combined with previously crystallized fraction to afford N-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-yl)-2-methyl-acrylamide (4.520 g). APCI (AP+): 391 (M+H)+.
Reaction SMILES: C(OC([N:11]([CH2:33][C:34]1[CH:39]=[C:38]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:37]=[C:36]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:35]=1)[CH2:12][CH2:13][N:14]1[CH:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:32])[CH:20]=2)[CH2:15]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:44][S:41]([NH:40][C:38]1[CH:39]=[C:34]([CH:35]=[C:36]([NH:45][S:46]([CH3:49])(=[O:47])=[O:48])[CH:37]=1)[CH2:33][NH:11][CH2:12][CH2:13][N:14]1[CH:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:32])[CH:20]=2)[CH2:15]1)(=[O:42])=[O:43]
Reactant: CS(=O)(=O)Nc1cc(CN(CCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)C(=O)OCc2ccccc2)cc(NS(C)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1cc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)cc(NS(C)(=O)=O)c1
Reaction time: 1.5 h
Yield: 29.4 %

Procedure:
N-(benzyloxycarbonyl)-N-[3,5-bis(methanesulfonyl)aminobenzyl]-2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine (25.0 mg, 0.04 mmol) was dissolved in 1.5 mL of methanol, and 100 mg of Pd—C was added thereto at room temperature, followed by stirring for 1.5 hours under a hydrogen gas atmosphere. After completion of the reaction, the reaction liquid was filtered through Celite. The filtrate was concentrated under reduced pressure, and the solvent was removed by evaporation and purified by PLC to obtain 6.8 mg (yield 33%) of a desired product as a pale yellow oily substance.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[N:23].[H-].[Na+].Cl>O.O1CCOCC1>[C:22]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:11]1[CH:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15])#[N:23]
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2cc(C(C#N)C(=O)OCC)c(F)cc2c1=O
Reaction time: 3 h

Procedure:
8.8 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 5.1 g of ethyl cyanoacetate are initially introduced into 120 ml of dioxane. 1.74 g of NaH are added in portions. The mixture is then boiled for 3 hours, diluted with water and rendered acidic using HCl. It is extracted using methylene chloride. The organic phase is dried and concentrated. The residue is recrystallized from ethanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:20]O>Cl.O1CCOCC1>[CH3:20][O:18][C:17](=[O:19])[CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)[CH:11]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A mixture of [3-(1H-indol-4-yl)-phenyl]-acetic acid (4 g, 15.9 mmol), 4N HCl (20 drops) in methanol (30 mL) and dioxane was stirred at rt for 4 hours. The reaction was concentrated, diluted in ethyl acetate, washed with NaHCO3 (2×), brine (2×), dried and concentrated to give 3.72 g (88%) of [3-(1H-Indol-4-yl)phenyl]-acetic acid methyl ester. General Procedure for the Syntheses of the Precursor, 4-Aryl-1,3-dihydro-indol 2-one
Reaction SMILES: [Na].[C:2]1([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:31])[CH:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20](=[O:31])[CH:21]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:2]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=2)=[CH:15][CH:14]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:18]
Reactant: CCCCCCCCC(Br)C(=O)OCC
Reactant: Oc1ccc(C2=CCCCCCC2)cc1
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC(Oc1ccc(C2=CCCCCCC2)cc1)C(=O)OCC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 2.1 g of sodium in 100 ml of absolute ethanol are added stirring 15 g of p-(1-cyclooctenyl)-phenol. After stirring has continued for a further 30 minutes, 31.5 g of 2-bromo-decanoic acid ethyl ester are slowly added dropwise to this solution and the mixture is maintained at 50° C for 24 hours. After the solvent has been removed in vacuo, the residue is partitioned at 0° C between ether and 2N sodium hydroxide solution. The organic phase is washed until neutral, dried over sodium sulphate and evaporated in vacuo, to thus yield the oily α-[p-(1-cyclooctenyl)-phenoxy]-decanoic acid ethyl ester of the formula ##STR11##