Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:14]=[CH:13][CH:12]=[C:11]([F:15])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Li+].CC([N-]C(C)C)C.CCCCCCC.[Br:31]C(Br)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Br:31][C:12]1[CH:13]=[N:14][C:2]([F:1])=[C:3]([C:11]=1[F:15])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)c1c(F)ccnc1F
Reactant: ClC(Cl)(Cl)C(Cl)(Br)Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)c1c(F)ncc(Br)c1F
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
Into a solution of tert-butyl 2,4-difluoronicotinate (0.95 g, 4.4 mmol) in THF (15 mL) at −78° C. was added a solution of LDA in heptane (1.5 M×3.5 mL, 5.3 mmol) dropwise. The mixture was stirred for 10 min. Then a solution of dibromotetrachloroethane (1.86 g, 5.7 mmol) in THF (4.0 mL) was added dropwise. After 15 min, the temperature was allowed to rise to room temperature slowly. The reaction was quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to give a residue, which was purified by silica chromatography (5-50% dichloromethane in hexanes) to give tert-butyl 5-bromo-2,4-difluoronicotinate (0.55 g, 42%).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)=[O:2].[H-].[Na+].[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21](/[CH:25]=[CH:26]/[C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[CH2:30]Cl)=[N:22]2)=[CH:17][CH:16]=1>CN(C=O)C>[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21](/[CH:25]=[CH:26]/[C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[CH2:30][N:9]3[C:10]4[C:6](=[CH:5][CH:4]=[C:3]([CH:1]=[O:2])[CH:11]=4)[CH:7]=[CH:8]3)=[N:22]2)=[CH:17][CH:16]=1
Reactant: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc2ccn(Cc3cccc(/C=C/c4ccc5ccc(Cl)cc5n4)c3)c2c1

Procedure:
To a solution of 6-formyl indole (Example 29a) (0.63 g, 4.3 mmol) in dry DMF (20 ml) was added sodium hydride (60% dispersion in oil) (0.22 g, 5.5 mmol) portionwise over 5 minutes with stirring. The reaction mixture was stirred for a further 20 minutes, then solid 3-[2(E)-(7-chloroquinolin-2-yl)ethenyl]benzyl chloride (Example 14b) (1.7 g, 5.4 mmol) was added portionwise over 5 minutes, and the reaction mixture left to stir for 18 hours. The reaction was quenched with water, extracted into ethyl acetate, the combined organic extracts washed with water, then brine, dried, filtered and evaporated in vacuo. The crude solid was purified by flash chromatography on silica, eluting with 30% diethyl ether in hexane to give a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[Br:10]Br>CCOCC.[Fe]>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH3:9])=[CH:4][C:5]=1[F:8]
Reactant: BrBr
Reactant: Cc1cc(F)ccc1F
Agent: [Fe]
Solvent: CCOCC
Product: Cc1cc(F)c(Br)cc1F
Temperature: -5 °C
Reaction time: 3 h

Procedure:
A mixture of 2,5-difluorotoluene (25 g, 0.20 mol) and iron powder (11 g, 0.2 mol) was cooled to −5° C. Bromine was added dropwise such that the internal temperature of the reaction did not rise above 0° C. After stirring for 3 hours, the mixture was diluted with ether, filtered and washed with aqueous sodium thiosulfate solution. The aqueous layer was extracted with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Distillation at atmospheric pressure gave 34 g of 1-bromo-2,5-difluoro-4-methyl-benzene as a colorless oil (b.p. 180 oC). 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, 1H, J=6.0, 8.5 Hz), 6.93 (m,1H), 2.23 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:9][CH:10]=[C:11]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[N:3]=1.[Br:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>O>[Br:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[O:30][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:9][CH:10]=[C:11]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[N:3]=1
Reactant: CCC(CC)c1ccc(-c2ccco2)c2nc(Cl)n(C)c12
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)c1ccc(-c2ccco2)c2nc(Oc3ccc(Cl)cc3Br)n(C)c12
Temperature: 120 °C
Yield: 68.3 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1H-benzimidazole (42 mg, 0.139 mmol), 2-bromo-4-chlorophenol (87 mg, 0.417 mmol) and potassium carbonate (58 mg, 0.417 mmol) was heated at 120° C. for 18 h under an argon atmosphere. The mixture was diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 1-20% ethyl acetate/n-hexane gradient mixture to give 45 mg (0.0950 mmol, 68%) of the title compound) as a colorless crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][C:20]([F:27])=[C:21]([F:26])[CH:22]=2)[N:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:25]1[CH:16]=[N:17][C:18]2[C:23](=[CH:22][C:21]([F:26])=[C:20]([F:27])[CH:19]=2)[N:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cc2ncc(Cl)nc2cc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc2cc(F)c(F)cc2n1
Yield: 58.3 %

Procedure:
The title compound (0.53 g) was prepared from (S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g) and 2-chloro-6,7-difluoroquinoxaline (0.5 g) according to the method of D30.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15](F)=[N:16][CH:17]=1.Cl>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([F:19])[C:15]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:16][CH:17]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
A mixture of 27.5 g (0.25 mol) of hydroquinone, 11.2 g (0.2 mol) of potassium hydroxide in 600 ml of dimethylsulfoxide is stirred at room temperature under a nitrogen atmosphere until everything is dissolved. A solution of 30 g (0.2 mol) of 5-chloro-2,3-difluoropyridine in 200 ml of dimethylsulfoxide is added dropwise thereto. The reaction mixture is then heated to 70° and stirred at that temperature for 4 hours. Then it is poured into ice/water and the mixture is acidified with hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated to dryness. The residue is taken up in a hexane/ethyl acetate 2:1 solvent and passed over a silicagel column for purification. After concentrating the eluate, the residue crystallizes to yield 33 g of white crystals, melting at 97°-98° .
Reaction SMILES: O.O.[Na+].[CH3:4][N:5]([CH3:9])[C:6](=[S:8])[S-:7].[NH2:10][C:11]1[N:16]=[C:15]([CH2:17]Cl)[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1>C(O)C.O>[NH2:10][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([CH2:17][S:8][C:6](=[S:7])[N:5]([CH3:9])[CH3:4])[N:16]=1
Reactant: COc1cc(CCl)nc(N)n1
Reactant: CN(C)C(=S)[S-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(CSC(=S)N(C)C)nc(N)n1

Procedure:
18.5 g of dimethyldithiocarbamic acid sodium salt dihydrate and 17.4 g of 2-amino-4-chloromethyl-6-methoxypyrimidine are refluxed in 100 ml of ethanol for 30 minutes. After the mixture has been cooled, it is diluted with about 1 liter of water, and the product which has precipitated is separated and dried. The yield is 23.0 g (89% of theory) of 2-amino-4-methoxy-6-dimethylthiocarbamoylthiomethyl-pyrimidine, m.p. 118°-120° C.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:18][C:19]1[N:20]=[CH:21][N:22]=[C:23]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)[CH:12]=2)[CH:24]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cccc(Cn2ccc3ccccc32)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Nc2cccc(Cn3ccc4ccccc43)c2)ncn1

Procedure:
1.077 g 3-Indol-1-ylmethyl-phenylamine (obtained in Step 2, 4.84 mmol) and 0.722 g 4,6-dichloropyrimidine (4.84 mmol) was dissolved in 50 cm3 of isopropyl-alcohol, 1.27 cm3 N,N-diisopropyl-ethylamine (0.939 g, 7.27 mmol) were added and the mixture was refluxed for three days. Then the mixture was evaporated under reduced pressure, 100 cm3 of water was added and it was extracted with 3×70 cm3 ethyl-acetate. Combined organic layer was washed with brine, dried over MgSO4 and evaporated to a yellowish oil. The residue was crystallized from minimal amount of acetonitrile and washed with diethyl-ether to give the desired product as an off-white solid. Overall yield for Step 2 and Step 3: 1.015 g (63%). For analitical results and compound identification see Table 1. The compound was used as a starting material in the preparation of Example 91.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH2:11](Br)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:2][P:1]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: BrCCc1ccccc1
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCc1ccccc1)OCC
Temperature: -15 °C
Yield: 51.6 %

Procedure:
Diethyl phosphite (27.64 g, 200 m mole) was dissolved in DMF (200 ml), and to the solution at nitrogen atmosphere while stirring and -15° C., sodium hydride (60% in oil, 9.6 g, 220 m mole) was added. The mixture was stirred for 1 hour at not more than 0° C. To the solution phenethyl bromide (37.0 g, 200 m mole) was dropwise added and further the mixture was stirred overnight at room temperature. The DMF solution was distilled under reduced pressure leaving a residue, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated and the thus obtained oily product was distilled under reduced pressure to obtain diethylphenethylphosphonate (25.0 g, yield: 51.6%) of boiling point 136.5°~137.5° C./3 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](F)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C.N1CCNCC1.S(F)(F)(=O)=O>C(OCC)(=O)C>[CH2:24]([O:23][C:21]([N:15]1[CH2:16][CH2:17][N:18]([S:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=2)(=[O:13])=[O:12])[CH2:19][CH2:20]1)=[O:22])[CH3:25]
Reactant: O=C(O)c1cc(S(=O)(=O)F)ccc1Cl
Reactant: CCOC(=O)N1CCNCC1
Agent: C1CNCCN1
Agent: O=S(=O)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)CC1
Reaction time: 14 h
Yield: 80.8 %

Procedure:
2-Chloro-5-fluorosulfonylbenzoic acid (Acros Organics, 105 mg, 440 μmol, 1.0 eq) was placed in a vial and the vial was flushed with nitrogen and a positive pressure was maintained. Anhydrous dichloromethane (1.4 mL) was added, followed by ethyl 1-piperazine carboxylate (80 μL, 528 μmol, 1.2 eq) and ethyldiisopropylamine (redistilled, 80 μL, 440 μmol, 1.0 eq). The mixture was stirred for 1.5 h after which time additional piperazine was added (60 μL, 352 μmmol, 0.8 eq). After 14 h the mixture was analyzed by reverse-phase HPLC-MS in negative ionization mode. The sulfonyl fluoride starting material was present, as well as a less polar compound showing (M−1) ion in about 35:65 ratio. An additional 0.35 eq of piperazine and ethyldiisopropylamine each (154 μmol, 30 μl) were added and the mixture was stirred for 4 h. HPLC-MS at this time indicated little progress and an additional 0.25 eq of piperazine (100 μmol, 20 μL) was added. After stirring for 14 h HPLC-MS indicated the reaction was complete. The reaction mixture was diluted with 2 mL of ethyl acetate, washed with 1M HCl solution (2×1 mL) and dried over anhydrous sodium sulfate. The solution was filtered, the solvents removed on a rotary evaporator and vacuum pump to afford 134 mg of a white solid, 81%. NOTE: Addition of excess nucleophilic amine at the beginning of the reaction results in significant bis addition, giving sulfonamide and carboxamide product. Stepwise addition of nucleophilic amine as needed suppresses formation of this side product.
Reaction SMILES: [Na].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[F:14][C:15]([F:47])([F:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38](O)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34][CH:33]=1>C(OCC)(=O)C>[F:14][C:15]([F:46])([F:47])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34][CH:33]=1
Reactant: CCOC(=O)CC(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
The [4-(polyfluoroalkylamino)phenyl]alkenoic acids may be prepared by condensation of the appropriate aldehydes or by dehydration of the corresponding substituted-phenyl-hydroxyalkanoic acids. For example, ethyl 5-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}-2,4-pentadienoate is obtained by the Wittig reaction of 4-[15-(trifluoromethyl)pentadecylamino]benzaldehyde with the Wittig reagent, triethyl 4-phosphonocrotonate. Alternatively, these alkenoic acids are obtained by heating 4-[N-polyfluoroalkyl-N-(methyl or acetyl)amino]benzaldehydes with the sodium salt of the carbanion of ethyl acetate or with a mixture of ethyl acetate, acetic anhydride and potassium acetate. The second method is illustrated by dehydration of ethyl 3-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}-3-hydroxypropionate to yield ethyl 4-[15-(trifluoromethyl)pentadecylamino]cinnamate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>CO.O1CCCC1.[Ni]>[NH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)cc1F

Procedure:
Methyl 2-fluoro-4-nitrobenzoate (141 mg) was dissolved in methanol (1000 ml) and tetrahydrofuran (400 ml), and Raney nickel (20 g) was added to it, and stirred overnight in a hydrogen atmosphere. The catalyst was removed through filtration, and the solvent was evaporated away under reduced pressure to obtain methyl 4-amino-2-fluorobenzoate.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[CH3:18][O:19][C:20](=[O:29])[C@@H:21]([NH2:28])[CH2:22][O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][O:19][C:20](=[O:29])[C@@H:21]([NH:28][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:22][O:23][C:24]([CH3:25])([CH3:27])[CH3:26]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](COC(C)(C)C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 33.4 %

Procedure:
To a suspension of phenylboronic acid (1.46 g) and 4A molecular sieves (4.5 g) in dichloromethane (40 mL) were added triethylamine (1.66 mL), methyl-(2S)-2-amino-3-tert-butoxypropanoate hydrochloride (1.26 g) and copper (II) acetate (1.19 g), then the mixture was stirred at ambient temperature for 5 days. The reaction was quenched with 7N ammonia in methanol (15 mL) and the mixture was filtered through a bed of celite. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent; n-hexane/ethyl acetate (2:1)) to afford methyl-(2S)-2-phenylamino-3-tert-butoxypropanoate (500 mg) as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:4][CH:3]=1.[Br:25]Br.O>C(O)(=O)C>[Br:25][C:8]1[C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[C:6]=2[O:10][C:9]=1[CH3:11]
Reactant: Cc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc(Cl)c2c1Br
Reaction time: 6 h
Yield: 50 %

Procedure:
1.0 g (2.8 mmol) of 3-(4-chloro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 30 ml of acetic acid, and 0.9 g (5.6 mmol) of bromine was dropwise added thereto at room temperature. After completion of the dropwise addition, stirring was carried out at 40° C. for 6 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and 10% aqueous ammonia and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.6 g (yield: 50.0%) of a pale yellow glassy substance. Refractive index: 1.5632 (20° C.).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]([C:27](=[O:30])[CH2:28]Cl)[CH2:24][CH2:25]Cl)=[CH:22][C:16]=3[CH2:15][S:14](=[O:33])(=[O:32])[C:13]=2[CH:34]=1)=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:4]([CH:1]5[CH2:3][CH2:2]5)[CH2:28][C:27]4=[O:30])=[CH:22][C:16]=3[CH2:15][S:14](=[O:32])(=[O:33])[C:13]=2[CH:34]=1)=[O:8]
Reactant: NC1CC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C4CC4)CC3=O)cc(Cl)c1O2
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Cyclopropylamine (0.082 mL, 1.18 mmol) was added to a solution of Example 57k (0.2 g, 0.39 mmol) in DMF (5 mL) and stirred at 50° C. for 1.5 h. The reaction mixture was concentrated to obtain the title compound which was purified using flash chromatography (silica gel, 1.5% methanol/chloroform). Yield: 0.135 g (71%); 1H NMR (CDCl3): δ 0.49 (m, 2H, CH2), 0.56 (m, 2H, CH2), 1.77 (m, 1H, CH), 2.70 (s, 3H, CH3), 3.01 (t, 2H, CH2), 3.82 (s, 2H, CH2), 3.67 (t, 2H, CH2), 3.92 (s, 3H, OCH3), 4.70 (s, 2H, CH2), 7.36 (s, 1H, Ar), 7.44 (d, 1H, Ar), 8.10 (s, 1H, Ar), 8.46 (d, 1H, Ar); MS: m/e (ES+) 491 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16](B(O)O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.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>[C:15]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=1[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc2cc(CO)c(-c3ccccc3-c3ccccc3)nc12
Temperature: 120 °C
Yield: 27 %

Procedure:
A mixture of (2-chloro-8-methylquinolin-3-yl)methanol (342 mg, 1.65 mmol), 2-biphenylboronic acid (392 mg, 1.98 mmol) and K3PO4 (399 mg, 1.88 mmol) in DME (4 mL) and water (1 mL) was degassed. Pd(PPh3)4 (95 mg, 0.08 mmol) was added, the mixture was degassed and heated in the microwave at 120° C. for 1 h. The reaction mixture was allowed to cool and extracted with EtOAc (150 mL). The organic layer was washed with water (50 mL), separated, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 0-100% EtOAc in heptane) gave the title compound (145 mg, 27%) as a white crystalline solid. δH (MeOD-d4) 8.19 (s, 1H), 7.71 (d, J 8.1 Hz, 1H), 7.40-7.66 (m, 6H), 7.15-7.20 (m, 2H), 7.08-7.12 (m, 3H), 4.30-4.40 (br m, 1H), 4.11-4.22 (br m, 1H), 2.70 (s, 3H). LCMS (ES+) 326.3 (M+H)+, RT 3.98 minutes (Method 3).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37](Br)=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH2:60]CCC.IC>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37]([CH3:60])=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Br)CCC3)cc1
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2C)CCC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the intermediate 17 (0.95 g, 1.13 mmol) in anhydrous THF (12.0 mL) were added dropwise n-BuLi (2.5 M in hexane, 0.72 mL, 1.81 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 0.5 h at the same temperature. Then a solution of iodomethane (0.13 mL, 2.03 mmol) in THF (1.0 mL) was added dropwise, and the mixture was slowly warmed up to 0° C. for 3 h. The reaction mixture was quenched with 1 M HCl solution (30 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 20, which was used without further purification (0.88 g, 1.13 mmol, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1.CCOCC>[O:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)[Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of 6-bromo-2-napthol (1.12 g, 5 mmol) in anhydrous THF (15 mL) was added imidazole (0.476 g, 7 mmol) followed by TBSCl (1.05 g, 7 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 40 h and was diluted with ether, washed with brine and dried over anhydrous Mg2SO4. The solvent was removed to yield the crude product, which was recrystallized from methanol.