Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1([CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH2:5]1)[CH:3]=[O:4].[BH4-].[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1([CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH2:5]1)[CH2:3][OH:4]
Reactant: O=CC1(Br)C=CC=C(F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCC1(Br)C=CC=C(F)C1
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To 1-bromo-3-fluorobenzaldehyde (1.60 kg, 7.91 mol) in methanol (14 L) at 0° C. add sodium borohydride (284 g, 7.93 mol) in portions over 30 min to control the exotherm and gas evolution. After 15 min, quench with water (500 mL) and concentrate to obtain a yellow oil. Dissolve the oil in ethyl acetate (6 L) and wash with water (3 L). Extract the aqueous layer with ethyl acetate (1 L). Wash the combined organic phases with brine (2 L), dry over sodium sulfate, filter, and concentrate to obtain the title compound as an orange oil (1614 g, 100%). 1H NMR (CDCl3) δ 7.40 (d, 1H), 7.18 (m, 1H), 7.07 (t, 1H), 4.86 (s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[Cu][C:18]#[N:19].O>N1C=CC=CC=1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1nc(=O)c2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.4 g of 2-butyl-6-iodo-4(1H)-quinazolinone in 25 ml of pyridine is added 3.6 g of copper(I) cyanide followed by heating at reflux for 16 hours. The reaction mixture is poured into water and stirred at room temperature for 8 hours. The suspension is filtered and the cake washed well with water and air dried. The solid is dissolved in 3:1 chloroform-methanol and dried with MgSO4. The volatiles are evaporated in vacuo to give 3.2 g of the desired pro-duct as a solid. m.p. 243°-45° C.
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][O:6][C:7]([C:9]1[C:17]2[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([C@@H:24]([NH2:26])[CH3:25])=[N:14][C:13]=2[CH:12]=[CH:11][C:10]=1[F:27])=[O:8].Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2[CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:5][O:6][C:7]([C:9]1[C:17]2[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([C@@H:24]([NH:26][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][N:33]4[CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[CH3:25])=[N:14][C:13]=2[CH:12]=[CH:11][C:10]=1[F:27])=[O:8]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1c(F)ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c12
Temperature: 90 °C
Yield: 68.4 %

Procedure:
To a solution of 2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carboxylic acid methyl ester dihydrochloride dihydrochloride (1.4 g, 3.8 mmol) in IPA (20 mL) was added 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (1.18 mg, 4.94 mmol) and DIPEA (2.6 mL, 15.2 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give the title compound as a white solid (1.34 g, 67%). LCMS (Method C): RT=3.11 min, [M+H]+=516.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19])[C:13](=[O:30])[CH2:12]2>ClCCl>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=2)[CH2:12][C:13]1=[O:30])=[O:19]
Reactant: CN(C)CCCN
Reactant: O=C1Cc2cc(Cl)ccc2N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CN(C)CCCNC(=O)N1C(=O)Cc2cc(Cl)ccc21

Procedure:
12.08 mmol of 3-(dimethylamino)propylamine are added at ambient temperature to a solution of 12.08 mmol of 4-nitrophenyl 5-chloro-2,3-dihydro-2-oxo-1H-indole-1-carboxylate in 70 ml of dichloromethane. The reaction is immediate. After extraction of the resulting solution with a 0.05N solution of sodium hydroxide until the aqueous phase no longer exhibits a yellow colour, the organic phase is dried, filtered and evaporated under reduced pressure. The expected compound is isolated in the form of a brown solid.
Reaction SMILES: CS([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=O)=O.[CH3:19][NH:20][CH3:21]>C(O)C>[CH3:19][N:20]([CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CS(=O)(=O)CCCCC(=O)OCc1ccccc1
Reactant: CNC
Solvent: CCO
Product: CN(C)CCCCC(=O)OCc1ccccc1
Yield: 69 %

Procedure:
Benzyl 5-(methanesulfonyl)pentanoate (1.39 g, 4.85 mmol) was allowed to react in a 5.6M solution of dimethylamine in ethanol (100 mL) for 20 hours. The solution was then concentrated in vacuo to dryness. The resulting brown oil was purified by column chromatography (column 10″L×1″W; eluted with a gradient of 100% dichloromethane→2%/0.5%→4%/0.5% MeOH/NH4OH in dichloromethane) to afford the product as a yellow oil (0.79 g, 69%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([S:18](=[O:25])(=[O:24])/[N:19]=C/N(C)C)=[C:7]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]>C(O)C.Cl>[CH2:1]([O:4][C:5]1[C:6]([S:18](=[O:25])(=[O:24])[NH2:19])=[C:7]([NH:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:16])[CH3:14])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(NC(=O)C(C)(C)C)c1S(=O)(=O)/N=C/N(C)C
Agent: Cl
Solvent: CCO
Product: C=CCOc1cccc(NC(=O)C(C)(C)C)c1S(N)(=O)=O

Procedure:
A solution of N-(2-{[1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}-3-hydroxy-phenyl)-2,2-dimethyl-propionamide (600 mg, 1.84 mmol) in DMF (4 ml) is treated at 70° C. with allyl bromide (217 μl, 2.57 mmol) and K2CO3 (380 mg) for 45 min with stirring. After evaporation of the solvent, the residue is partitioned between water and EtOAc. The organic layer is dried (Na2SO4) and evaporated yielding N-(3-allyloxy-2-{[1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}-phenyl)-2,2-dimethyl-propionamide. A solution of N-(3-allyloxy-2-{[1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}-phenyl)-2,2-dimethyl-propionamide (387 mg, 1.05 mmol) in ethanol (12 ml) and 12 drops of conc HCl (aprox. 0.2 ml) is refluxed for 36 h. After evaporation of the solvent, the residue is partitioned between ammonia (pH 10 to 11) and EtOAc. The organic layer is dried (Na2SO4) and evaporated. Chromatography (silica gel, EtOAc/hexanes=2:1) afforded N-(3-allyloxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide containing some N-(3-allyloxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide. Treatment of this material with ethanol (20 ml) and conc. HCl (2 ml) for 30 h at reflux temperature and workup as above gives N-(3-allyloxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([F:13])([F:12])[F:11])=[N:4]1)[CH3:2].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>O.[OH-].[Na+]>[CH2:1]([N:3]1[C:7]([O:8][CH3:9])=[C:6]([N+:19]([O-:21])=[O:20])[C:5]([C:10]([F:11])([F:13])[F:12])=[N:4]1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCn1nc(C(F)(F)F)cc1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1nc(C(F)(F)F)c([N+](=O)[O-])c1OC
Temperature: 25 °C
Yield: 66050.8 %

Procedure:
1-Ethyl-5-methoxy-3-(trifluoromethyl)pyrazole (15.2 g, 0.0785 mmol) was added dropwise with stirring and cooling at about 0° C. to 150 mL of concentrated sulfuric acid and then 10.5 mL of 70 percent nitric acid (0.235 mmol) was added, also dropwise with stirring at about 0° C. The mixture was then allowed to warm to ambient temperature and stir overnight. An aliquot was removed, neutralized to a pH of about 11, extracted with dichloromethane, and analyzed by gas chromatography. Since there was still some starting material present another about 0.8 mmol of concentrated nitric acid was added with stirring and the mixture was allowed to react for 5 hours. Analysis of an aliquot as before did not reveal any remaining starting material so the mixture was poured slowly into 500 g of ice. The mixture was stirred for 15 min and was then extracted with dichloromethane (4×200 mL). The extracts were combined to obtain an acidic blue-green organic mixture. This was diluted with 100 mL of water and neutralized with 50 percent aqueous sodium hydroxide. The mixture, which turned yellow-orange, was separated into phases and the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 12.4 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[N:5][N:6]=1.Cl[CH2:9][CH:10]=O.C(=O)(O)[O-].[Na+]>O>[Br:7][C:4]1[S:3][C:2]2=[N:1][CH:9]=[CH:10][N:6]2[N:5]=1
Reactant: Nc1nnc(Br)s1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Brc1nn2ccnc2s1
Reaction time: 10 h

Procedure:
To a suspension of 2-amino-5-bromo-1,3,4-thiadiazole (1.65 g, 9.15 mmol) in water (27 mL) was added a water solution of chloroacetaldehyde (50% wt, 1.7 mL). The mixture was stirred at reflux. After 10 hours, a second addition of chloroacetaldehyde (1.5 eq, 1.7 mL) was done and stirring was continued until disappearance of starting material (20 hours). After cooling, the reaction mixture was neutralized with sodium bicarbonate (sat. aq. solution) and extracted with dichloromethane (3×30 mL). The combined organic layers were dried over sodium sulphate and the solvent evaporated under vacuum. The crude product was triturated with diethyl ether to yield 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole as a white solid. The mother liquor was purified by flash chromatography (Biotage™, ethyl acetate:hexane, 3:7 to 7:3) to yield another batch of compound (20% global yield) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:12][CH3:13])[CH2:9][C:10]#N)(C)(C)C.CCCCCC.CC(C[AlH]CC(C)C)C.Cl.CC[O:33]CC>>[CH2:12]([C@@H:8]([NH:7][C:6](=[O:14])[OH:5])[CH2:9][CH:10]=[O:33])[CH3:13]
Reactant: CCOCC
Reactant: CC[C@H](CC#N)NC(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCCCCC
Product: CC[C@H](CC=O)NC(=O)O
Temperature: -40 °C
Reaction time: 3.5 h

Procedure:
To a solution of ((R)-2-cyano-1-ethyl-ethyl)-carbamic acid tert-butyl ester (10 mmol; 1.98 g) in Et2O (50 mL) is slowly added a 0.97 M n-hexane solution (40 mmol; 41 mL) of DIBAL under nitrogen at −78° C. The reaction mixture is warmed to −40° C. and stirred for an additional 3.5 hours. Another 1.00 M n-hexane solution (30 mmol; 30 mL) of DIBAL is added to the suspension at the same temperature. After stirring for additional 1.5 hours, the solution is quenched by careful addition of 1 ml of MeOH then immediately poured into 25 ml of saturated aqueous ammonium chloride solution in a separatory funnel. Shake mixture and leave until it reaches room temperature. Aqueous 1M HCl is added to reach a pH of 3-4. The solution is extracted three times with EtOAc and the combined organic layer is washed with an aqueous 1M HCl/brine (1:1) solution and twice with a saturated aqueous NaHCO3/brine (1:1) solution, dried over Na2SO4, filtered and concentrated under reduced pressure and purified by column chromatography on silica gel (eluent; n-hexane/EtOAc) to give ((R)-1-ethyl-3-oxo-propyl)-carbamic acid tent-butyl ester (590 mg, 29%); ESI-MS m/z: 146 [M+−tBu+2], Retention time 2.17 min (condition A).
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CC([O-])(C)C.[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CC(O)(C)C>[CH3:13][C:12]([O:11][C:1](=[O:10])[CH:2]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A suspension of di-tert butyl malonate (10.80 g, 50 mmol) and t-BuOK (5.60 g, 50 mmol) was stirred (30 min, 75° C.) in t-BuOH (150 mL, dried over 4A sieves). To this was added a solution of 1-bromotetradecane (13.85 g, 50 mmol) and the reaction stirred at 75° C. overnight. Solvent was removed by rotary evaporation, giving a white semi-solid, which was partitioned between CH2Cl2 (100 mL) and saturated aqueous NaCl (2×300 mL), dried (MgSO4) and evaporated to a colorless oil (15.3 g). Purification by silica gel flash chromatography (100% hexane incremented to hexane:CH2Cl2 (70:30)) gave product (34) as a colorless oil (10.0 g, 48%). High resolution FAB MS:C25H49O4 (M+H); Theor. 413.3630855. Found 413.3627625.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.[CH:10]1([CH2:13][N:14]2[C:22]3[N:21]=[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][CH3:31])=[CH:26][CH:25]=4)[NH:19][C:18]=3[C:17](=[O:32])[N:16]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])[C:15]2=[O:41])[CH2:12][CH2:11]1>CN(C)C1C=CN=CC=1>[CH:10]1([CH2:13][N:14]2[C:22]3[N:21]=[C:20]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]([CH3:31])[C:7]([C:5]5[CH:4]=[N:3][CH:2]=[N:1][CH:6]=5)=[O:9])=[CH:28][CH:29]=4)[NH:19][C:18]=3[C:17](=[O:32])[N:16]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])[C:15]2=[O:41])[CH2:12][CH2:11]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: O=C(O)c1cncnc1
Agent: CN(C)c1ccncc1
Product: CN(C(=O)c1cncnc1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Yield: 72 %

Procedure:
This compound was prepared by a method similar to that described in example 79 except that pyrimidine-5-carboxylic acid was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, the reaction was performed using 0.75 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and 1.5 equivalent of 4-dimethylaminopyridine was added as the final reagent to the reaction mixture. Purification was performed by chromatography using silica eluted with 94:6 ethyl acetate/methanol followed by trituration with hot acetonitrile to give the product as a colorless solid (72%). MS, m/z(M+H)=540.2161.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:36])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH2:29][C@H:30]4[CH2:34][O:33]C(=O)[NH:31]4)[CH3:21])[C:14]3=[O:37])[CH:7]=2)[CH2:3][CH2:2]1.[OH-].[K+]>O.CO>[NH2:31][C@H:30]([CH2:34][OH:33])[CH2:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([NH:19][C:15]1[C:14](=[O:37])[N:13]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=2[CH3:12])[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:38])[CH:18]=[CH:17][N:16]=1)([CH3:21])[CH3:36]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@H]2COC(=O)N2)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@H](N)CO)c1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 18.4 %

Procedure:
A solution of N-cyclopropyl-4-methyl-3-[3-{[1-methyl-1-(2-{[(4S)-2-oxo-1,3-oxazolidin-4-yl]methoxy}phenyl)ethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide (Example 305a) (0.6 g) in water (10 mL) and MeOH (10 mL) was treated with potassium hydroxide (0.130 g) under nitrogen. The resulting mixture was stirred at 50° C. for 16 h. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (250 mL). The organic phase was dried (MgSO4), filtered and evaporated. Purification by preparative HPLC (Phenomenex Gemini column, eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia) gave the title compound as a solid (0.105 g).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:17]1[NH:22][C:21](=[N:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])[CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.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:1]1([C:17]2[NH:22][C:21](=[N:23][C:24]3[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=3[CH:33]([CH3:35])[CH3:34])[CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=c1cccc(Br)[nH]1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1N=c1cccc(-c2ccccc2)[nH]1
Temperature: 70 °C

Procedure:
Phenylboronic acid (316 mmol) and Na2CO3 (792 mmol) are dissolved into 200 mL of degassed 1:1 H2O/ethanol. This solution is added to a toluene solution (500 mL) of 6-bromo-2-(2,6-diisopropylphenyl)iminopyridine (109 g, 316 mmol). Inside of a dry box 1 g (0.86 mmol) of tetrakis(triphenylphosphine)palladium(0) is dissolved in 50 mL of degassed toluene. The solution is removed from the dry box and charged into the N2 purged reactor. The biphasic solution is vigorously stirred and heated to 70° C. for 4-12 h. After cooling to room temperature, the organic phase is separated, the aqueous layer is washed with toluene (3×75 mL), and the combined organic extracts are washed with H2O (3×200 mL) and dried over MgSO4. After removing the volatiles under reduced pressure, the resultant light yellow oil is purified via recrystallization from methanol to give a yellow solid. Yield is 109 g, 87.2 percent; mp 142-144° C.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:24])[CH:17]=3)[C:12](=O)[C:11]=2[CH:10]=1>CCOCC.CC(O)=O>[Br:8][C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:13]3[C:18]([C:19]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][C:16]([Br:24])=[CH:15][CH:14]=3)[CH:10]=1
Reactant: [Li]c1ccccc1
Reactant: O=C1c2ccc(Br)cc2C(=O)c2ccc(Br)cc21
Solvent: CCOCC
Solvent: CC(=O)O
Product: Brc1ccc2c(-c3ccccc3)c3cc(Br)ccc3c(-c3ccccc3)c2c1
Temperature: 130 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
6 g of phenyl lithium was dissolved in Et2O, and the resulting solution was gradually added dropwise to a solution containing 5 g of 2,6-dibromoanthraquinone dissolved in Et2O. This reaction was carried out on a dry ice bath. Then, the temperature of the reaction material was elevated to room temperature, thereby obtaining white solids. The obtained solids were dissolved in 100 mL of AcOH, followed by addition of KI and NaH2PO2 and the resulting mixture was stirred at 130° C. for 24 hours. After the reaction was complete, the resulting material was filtered with addition of water. The filtrate was then recrystallized from MC and MeOH, thereby obtaining 4.5 g of 2,6-dibromo-9,10-diphenylanthracene.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:25])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].[CH3:32][O:33][CH2:34][CH2:35]Cl>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:35][CH2:34][O:33][CH3:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Reactant: COCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCOC)cccc2c1Nc1ccc(F)cc1C
Yield: 10.3 %

Procedure:
A solution of 3-butyryl-4-(4-fluoro-2-methylphenyl-amino)-8-hydroxyquinoline (3.38 g,. 10 mmol) and potassium t-butoxide (1.68 g, 15 mmol) in tetrahydrofuran (75 ml) was warmed to near boiling, chloroethyl methyl ether (1.83 ml, 20 mmol) added, and the mixture heated at reflux for 3 days. The solvent was evaporated then the product taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, ethyl acetate/2% acetic acid/0-5% methanol) and recrystallisation from ethyl acetate/petroleum ether gave 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-(2-methoxyethoxy)quinoline (0.41 g), m.p. 124°-5°.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([S:14](=[O:21])(=[O:20])[NH:15][CH2:16][C:17]([OH:19])=[O:18])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:11][CH:10]=[C:9]([S:14](=[O:20])(=[O:21])[NH:15][CH2:16][C:17]([OH:19])=[O:18])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc2c(S(=O)(=O)NCC(=O)O)ccc(O)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc2c(S(=O)(=O)NCC(=O)O)ccc(OCc3ccccc3)c2o1
Yield: 56.1 %

Procedure:
A mixture of the 7-hydroxy compound (1.8 g) obtained in Example 28 (Compound No. 28), K2CO3 (1.6 g) and benzylbromide (2.9 g) in DMF was stirred at 80° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate, which was purified by a silica-gel column chromatography to give 1.3 g of 2-acetyl-4-(N-carboxymethylsulfamoyl)-7-benzyloxybenzofuran as yellow crystals. After the obtained product was added to 20 ml of 2N-NaOH aqueous solution and the mixture was stirred for 30 minutes, the resultant was acidified to form precipitate, which was recrystallized with ethanol to give 0.4 g of 2-acetyl-4-(N-carboxymethylsulfamoyl)-7-benzyloxybenzofuran. The physical constants are shown in Table 4.
Reaction SMILES: [F:1][C:2]([F:10])([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].[CH:11]1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:11][O:4][C:3](=[O:5])[C:2]([F:10])([F:1])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)CC(F)(F)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C(F)(F)CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
Commercially available 2,2-difluorosuccinic acid (8.0 g, 51.9 mmol) was dissolved in THF and cooled on ice before addition of 1,3-dicyclohexylcarbodiimide (11.8 g, 57.2 mmol). The mixture was stirred at room temperature for 3 hours, cooled and filtered. The filtrate was concentrated in vacuo. The residue was stirred with methanol (50 ml) for 3 hours at room temperature and then solvents were removed in vacuo to afford the crude ester as an oil (8.4 g). The oil was purified by column chromatography on silica gel column and elution with a 0-100% ethyl acetate/toluene gradient to afford 2,2-difluorosuccinic acid 1-methyl ester as a colorless oil (6.8 g).