Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](Cl)=[O:4].[CH3:13][CH:14]([CH3:28])[CH:15]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[N:16]1[CH:20]=[N:19][CH:18]=[N:17]1>C(Cl)Cl.N1C=CC=CC=1>[CH3:1]/[C:2](=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)/[C:3]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH:15]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:14]([CH3:28])[CH3:13])=[CH:22][CH:23]=1)=[O:4]
Reactant: CC(=Cc1ccccc1)C(=O)Cl
Reactant: CC(C)C(c1ccc(N)cc1)n1cncn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C/C(=C\c1ccccc1)C(=O)Nc1ccc(C(C(C)C)n2cncn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.2 %

Procedure:
A solution of 2-methyl-3-phenyl-2-propenoyl chloride (0.0554 mol) in CH2Cl2 (50 ml) was added dropwise to a solution of (±)-4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-benzenamine (0.037 mol) in pyridine (8 ml) and CH2Cl2 (100 ml) and the mixture was stirred at RT for 4 hours. The solvent was evaporated and the residue was taken up in water/EtOAc. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 99/1/0.1). The pure fractions were collected and evaporated. The residue was crystallized from (C2H5)2O/methylethylketone, yielding 2.7 g (21%) of (±)-(E)-2-methyl-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]-3-phenyl-2-propenamide (compound 154).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>O>[CH3:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: NC=O
Solvent: O
Product: Cc1cccc2c(=O)[nH]cnc12

Procedure:
6 g of 2-amino 3 methyl benzoic acid and 8 ml formamide were heated at 170° C. for 1.5 hours. Water was added and solid filtered to provide 4.6 g of 8-methyl 4-quinazolinone as a white solid, mp-260° C. NMR acetone d6 δ 8.14 (1H, br, S), 8.06 (1H, m), 7.66 (1H, m), 7.38 (1H, m), 2.58 (3H, S).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C1COCC1.[Ni]>[N:9]1([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(CN2CCCCC2)cc1

Procedure:
To a solution of 0.22 g (1.0 mmol, 1.0 eq.) of 1-(4-nitrobenzyl)piperidine (I-27) in 20 mL of THF was added ˜30 mg of Raney Nickel. The reaction mixture was stirred under at room temperature under 1 atm. of hydrogen for 12 h. The reaction mixture was through Celite® and the solvent removed in vacuo to provide 4-(piperidin-1-ylmethyl)benzenamine (I-28).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][C:9]1[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=1)(=[O:5])[CH3:4].CN(C)C=O.[CH3:25][O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1>[CH3:25][O:26][C:27](=[O:36])[CH:28]([N:12]1[C:11](=[O:15])[CH:10]=[C:9]([O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[C:3](=[O:5])[CH3:4])[CH:14]=[N:13]1)[CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(=O)c1ccccc1Oc1cn[nH]c(=O)c1
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(C)=O)cc1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Sodium hydride in mineral oil (3.65 g) was added to a solution of 5-(2-acetyl-phenoxy)-2H-pyridazin-3-one (16.3 g, 0.07 mol) in tetrahydrofuran (340 mL) at 0° C. The resulting mixture was stirred at 0° C. for 10 min and then was warmed to 20° C., where it stirred for 50 min. After this time, N,N-dimethylformamide (45 mL) and 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 25 g, 0.11 mol) were added to the reaction. The reaction was then warmed to 50° C. overnight. After this time, the reaction was concentrated in vacuo. Silica gel column chromatography afforded 2-[4-(2-acetyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (23.4 g, 86%); ESI-MS 385 [M+H+].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[F:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22](Cl)=[O:23])[CH:16]=[CH:17][C:18]=1[F:19].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22]([O:8][C@@H:6]2[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH:9]([CH3:11])[CH3:10])=[O:23])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=C(Cl)/C=C/c1ccc(F)c(F)c1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)/C=C/c1ccc(F)c(F)c1
Temperature: 65 °C

Procedure:
A solution of L-menthol (7.1 kg) in toluene (8.5 kg) was added over a 20 minute period to the solution of (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride (prepared as in Example 2) and pyridine (0.18 kg, 2.28 mol) stirring at 65° C. The reaction mixture was stirred at 65° C. for a further 4 hours and 40 minutes after the addition was complete, then cooled to 25° C. and stirred for a 14 hours. The solution was diluted with toluene (16 kg), washed with 5% is aqueous sodium chloride (6.4 kg), then 6% sodium hydrogen carbonate (6.47 kg), then water (6.1 kg). The solution was dried azeotropically by distillation of the solvent (20 L) under reduced pressure. Dimethyl sulfoxide (33.9 kg) was added and the remaining toluene was distilled off under reduced pressure, affording 47.3 kg of a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoate (approx. 13.3 kg) in dimethyl sulfoxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[N:31][CH:32]=1.O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:27]2[CH:32]=[N:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(O)cc1F)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.6 %

Procedure:
To a solution of benzyl (2-fluoro-4-hydroxyphenyl)carbamate (79 g, 303 mmol) in dimethyl sulfoxide (480 mL) were added cesium carbonate (123 g, 378 mmol) and 5-chloro-2-nitropyridine (40 g, 252 mmol), and the mixture was stirred at room temperature for 6 hr. Water (1000 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (=3/1) and collected by filtration to give the title compound (74 g, 77%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
To a solution of 3.2 mL (20.8 mmol) of 4-phenyl-1-butanol (Aldrich Chemical Co.) in 20 mL of CH2Cl2 at 0° C. was added 3.2 g of powdered 3 Å molecular sieves and then 5.37 g (24.9 mmol) of pyridinum chlorochromate (PCC). The resulting suspension was stirred at 0° C. for 1 h at which time an additional 2.16 g (10.0 mmol) of PCC was added and the reaction mixture was warmed to room temperature. After stirring at ambient temperature for 0.5 h, the reaction mixture was diluted with ether and filtered through celite to give 2.5 g of the crude product. Flash chromatography (elution with 5% ethyl acetate in hexane) yielded 700 mg of the aldehyde 119. 1H NMR was consistent with the structure.
Reaction SMILES: [C:1]1([N:7]=[C:8](Cl)[C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:14]=[N+:15]=[N-:16].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:8]([C:9]([F:12])([F:11])[F:10])=[N:16][N:15]=[N:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C(Cl)=Nc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nnnn1-c1ccccc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
Five grams (24.1 mmol) of N-phenyl-2,2,2-trifluoroacetimidoyl chloride obtained in Example 1, 2.83 g (43.4 mmol) of sodium azide, 1.66 g (12.1 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 16.5 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×3). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.81 g of 1-phenyl-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 93.2%). IR (neat, cm−1): 3071, 1531, 1499, 1312, 1207, 1167, 1013, 766, 691 1H-NMR (CDCl3): δ 7.60-7.54 (m, 3H), 7.38 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 3.89 (s, 3H) 13C-NMR (CDCl3): δ 145.90 (q, J=42.0 Hz), 132.41, 131.59, 131.58, 129.79, 129.76, 125.05, 117.73 (q, J=270.0 Hz) Elemental analysis: Value calculated for C8H5F3N4: C, 44.87%; H, 2.35%; N, 26.16% Value found: C, 44.27%; H, 2.24%; N, 25.95% Decomposition temperature (DSC): 290° C. (1.17 kJ/g), 367° C. (1.55 kJ/g)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13]>Cl>[O:8]=[C:5]1[NH:6][C:7]2[CH:10]=[CH:11][C:12]([CH3:13])=[N:1][C:2]=2[C:3](=[O:9])[NH:4]1
Reactant: C/C=C/C=O
Reactant: Nc1c[nH]c(=O)[nH]c1=O
Agent: Cl
Product: Cc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Reaction time: 0.17 h
Yield: 248.1 %

Procedure:
20 g of 5-aminouracil (40 mmol), 80 ml of 20% HCl and 4 ml of crotonaldehyde (50 mmol) were heated together under reflux for 1 hour. The solution was evaporated to dryness under rotarary evaporation. Water was added to the residue so as to make the mixture just stirtable and then it was triturated with ammonium hydroxide with strong stirring until the pH increased to 10-11. Stirring was continued for another 10 minutes. The precipitate was filtered and was washed with minimal methanol and then chloroform and dried to give 17.58 g (63%) of 1.
Reaction SMILES: O[C:2]1([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:6][C:5](=O)[CH:4]=[CH:3]1.Cl.[NH2:14]CC(OCC)=O.C(=O)(O)[O-].[Na+].C(O)C>O>[F:10][C:9]([F:12])([F:11])[C:2]1[CH:7]=[CH:6][C:5]([NH2:14])=[CH:4][CH:3]=1
Reactant: O=C1C=CC(O)(C(F)(F)F)C=C1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 19.2 %

Procedure:
A mixture of 200 mg (11 mmol) of 4-hydroxy-4-trifluoromethyl-2,5-cyclohexadien-1-one, 461 mg (3.3 mmol) of ethyl glycinate hydrochloride, 336 mg (4.0 mmol) of sodium bicarbonate, and 3 mL of 95% ethanol was heated to reflux for 3 hours, allowed to cool to room temperature, and poured into 20 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of dichloromethane. Combination, drying (MgSO4), and concentration of the organic layers afforded a residue which was subjected to PTLC (one 2 mm silica gel plate eluted with dichloromethane) to give 102 mg (56% yield) of 4-trifluoromethylaniline.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]([F:18])([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1)[CH:6]([F:8])[F:7].CCOCC>O>[F:4][C:5]([F:18])([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][C:1]#[N:2])=[CH:12][CH:11]=1)[CH:6]([F:8])[F:7]
Reactant: FC(F)C(F)(F)Oc1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: N#CCc1ccc(OC(F)(F)C(F)F)cc1
Reaction time: 0.67 h
Yield: 87.9 %

Procedure:
Over a period of 40 minutes, a hot solution of 75.1 g (1.15 mol) of potassium cyanide in 140 ml of water is added to a mechanically stirred 75° C. solution of 160.99 g (0.561 mol) of p-(1,1,2,2-tetrafluoroethoxy)benzyl bromide and 500 ml of anhydrous 2B alcohol. The resulting mixture is refluxed for 1.75 hours. After sitting overnight the reaction mixture is poured into 500 ml of cold water and 400 ml of ether. The combined ether solutions are washed twice with 500 ml of water, dried with sodium sulfate, filtered, and then evaporated on a rotary evaporator to give 114.95 g of an oil. A vacuum distillation of this oil gives, as one distillation fraction, 37.10 g (28%) of the nitrile, boiling point 85° C. to 100° C. at 0.29 mm Hg.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.CCCCCC.[C:22](#[N:26])[CH:23]([CH3:25])[CH3:24].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH3:24][C:23]([CH3:25])([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]#[N:26]
Reactant: CC(C)C#N
Reactant: ClCc1ccccc1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C#N)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
A solution of N-isopropylcyclohexyl amine (2.8 g, 19.72 mmol) in anhydrous tetrahydrofuran (25 mL) at −78° C. was treated with 1.6 M n-butyl lithium in hexane (12.23 mL, 19.72 mmol) drop-wise over 15 minutes. The reaction solution was stirred for 10 min at −78° C. The solution turned yellow from colorless. Isobutyronitrile (1.36 g, 19.72 mmol) was added to the reaction solution, and the reaction mixture was stirred for a further 10 min at −78° C. This solution was syringed into a solution of benzyl chloride (2.62 g, 20.71 mmol) in anhydrous tetrahydrofuran at −78° C. under a nitrogen atmosphere. The reddish/brown reaction was solution stirred for 1 h at −78° C. The dry ice/acetone bath was then removed, and the solution stirred at room temperature for 5 h. The reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL). Ethyl acetate (25 mL) was added to the quenched reaction solution. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield 3.18 g of crude material. The crude material was partitioned between 2 N hydrochloric acid solution and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to give 2.18 g (69%) 2,2-dimethyl-3-phenylpropanenitrile. 1H NMR (DMSO-d6, 400 MHz) δ 7.369-7.333 (m, 2H), 7.309-7.270 (m, 3H), 2.832 (s, 2H), 1.294 (s, 6H). This compound was used in subsequent reaction with out further analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([NH2:35])=[O:34])[C:28](=[O:36])[CH2:27]2>CN(C1C=CN=CC=1)C>[F:38][C:23]([F:22])([F:37])[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([NH2:35])=[O:34])[C:28](=[O:36])[CH:27]2[C:7](=[O:9])[C:4]1[S:5][CH:6]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)cs1
Reactant: NC(=O)N1C(=O)Cc2cc(C(F)(F)F)ccc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: NC(=O)N1C(=O)C(C(=O)c2cc(Cl)cs2)c2cc(C(F)(F)F)ccc21
Yield: 82 %

Procedure:
The experimental procedure used to produce the title compound was adopted from Example 55. A 388 mg (2.39 mmole) sample of 4-chloro-2-thiophenecarboxylic acid (prepared according to Iriarte, J., et al., J. Het. Chem., 13, 393 (1976)) was transformed into the acyl imidazole by reaction with 420 mg (2.59 mmole) of 1,1'-carbonyldiimidazole. The intermediate 4-chloro-2-thiophene-(1-imidazo)carboxamide coupled directly with 486 mg (1.99 mmole) of 5-trifluoromethyl-2-oxindole-1-carboxamide in the presence of 657 mg (5.37 mmole) of 4-(N,N-dimethylamino)pyridine to give 634 mg (1.63 mmole, 82%) of the title compound as a yellow solid m.p. 164°-6° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1.Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Cl>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2([C:15]#[N:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=[CH:12][CH:13]=1
Reactant: ClCCOCCCl
Reactant: N#CCc1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(Cl)c2)CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 156.3 %

Procedure:
Potassium tert-butoxide (8.90 g, 79.3 mmol, 2.20 eq) was added to a stirred solution of 2-(3-chlorophenyl)acetonitrile (4.26 mL, 36.1 mmol) in DMF (50 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 10 minutes at 0° C. before 1-chloro-2-(2-chloroethoxy)ethane (4.65 mL, 39.7 mmol) was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was then cooled to 0° C. and quenched with 10% HCl. The aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give the product as an orange oil (12.51 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[NH2:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[CH2:17]1>C(Cl)Cl>[C:1]([NH:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[CH2:17]1)(=[O:3])[CH3:2]
Reactant: CS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(S(C)=O)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
Acetic anhydride (0.173 ml, 1.83 mmol) and pyridine (0.296 ml, 3.67 mmol) were added to a solution of 5-(S)-aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.367 mmol) in DCM (3 ml). The reaction mixture was stirred for 4 h at r.t. and then evaporated to dryness under vacuum. The residue was purified by PTLC (10% methanol in DCM) to give product as a white solid (0.115 g, 99%). M.p. 143-5° C. MS (m/z): [M+H]+=315.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[C:3]=1[CH3:15].CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:14][N:5]1[C:4]2[C:3]([CH3:15])=[C:2]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: Cc1c(Br)sc2c1N(C)C(C)(C)NC2=O
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(-c2cn[nH]c2)sc2c1N(C)C(C)(C)NC2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
A mixture of 6-bromo-1,2,2,7-tetramethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (145 mg, 0.50 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylate (441 mg, 1.50 mmol), cesium carbonate (815 mg, 2.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1.25 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was stirred at 90° C. overnight. The mixture was poured into water (100 mL) and EtOAc (100 mL). The insoluble materials were filtered off, and the organic layer was collected from the filtrate. This organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residual oil was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 80:20 EtOAc/MeOH), then triturated with EtOAc/hexane. The solid was collected by filtration to afford the title compound (65.2 mg, 47%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C1C=CC=CN=1)C.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>ClCCl.C(OCC)(=O)C>[CH2:31]([NH:38][C:39]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][S:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)(=[O:11])=[O:10])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(Nc1ccc2[nH]ccc2c1)c1cc(Cl)cc(Cl)c1
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCc1ccccc1)n1ccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
130 mg 3,5-dichloro-N-(1H-indol-5-yl)-phenylsulphonamide are dissolved in 5 ml dichloromethane and 14 mg dimethylaminopyridine and 56 μl benzylisocyanate are added. The mixture is stirred overnight at ambient temperature, divided between 1 N HCl and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried with magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1:3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[C:22]2[C:23]3=[C:24]4[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[C:15]4[CH:14]=[CH:13][C:12]3=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[C:15]3[C:24]4=[C:23]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Temperature: 90 °C
Yield: 62.7 %

Procedure:
A mixture of 10 g (42.4 mmol) 1,4-dibromobenzene, 10.43 g (42.4 mmol) of Pyren-1-ylboronic acid, 0.5 g (0.424 mmol) of Tetrakis(triphenylphosphine)Palladium, 32 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 9.5 g (63%) as a white solid.
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=O)(C)(C)C.Cl[C:25]1[N:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:34][C:32]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([CH2:16][NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH:18]=2)[N:33]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(N)c1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1cccc(Nc2nc(Cl)ccc2C(=O)O)c1
Yield: 25.3 %

Procedure:
A mixture of 3-(di-(t-butoxycarbonyl)aminomethyl)aniline (81 mg), 2,6-dichloronicotinic acid (90%, 53 mg), di-i-propylethylamine (64 mg) and 1,4-dioxane (1 ml) was heated under reflux for 3 days and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, methylene chloride:methanol=20:1) to give 24 mg of the titled compound (yield, 25%).