Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:31][C:30]2[CH:29]=[CH:28][C:5]([C:6]([C@H:8]3[CH2:13][CH2:12][C@H:11]4[C@H:14]5[C@H:23]([CH2:24][CH2:25][C@:9]34[CH3:10])[C:22]3[CH:21]=[CH:20][C:19]([CH:26]=[O:27])=[CH:18][C:17]=3[CH2:16][CH2:15]5)=[O:7])=[CH:4][C:3]=2[O:2]1.CC(=CC)C.[O-:37]Cl=O.[Na+].[Na+].[Cl-]>O.C(O)(=O)C.C(O)(C)(C)C>[CH2:1]1[O:31][C:30]2[CH:29]=[CH:28][C:5]([C:6]([C@H:8]3[CH2:13][CH2:12][C@H:11]4[C@H:14]5[C@H:23]([CH2:24][CH2:25][C@:9]34[CH3:10])[C:22]3[CH:21]=[CH:20][C:19]([C:26]([OH:37])=[O:27])=[CH:18][C:17]=3[CH2:16][CH2:15]5)=[O:7])=[CH:4][C:3]=2[O:2]1
Reactant: [O-][Cl+][O-]
Reactant: C[C@]12CC[C@@H]3c4ccc(C=O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)c1ccc2c(c1)OCO2
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)c1ccc2c(c1)OCO2
Yield: 46.2 %

Procedure:
To a stirred mixture of 17β-(3,4-methylenedioxybenzoyl)-estra-1,3,5(10)-triene-3-carboxaldehyde (0.041 g, 0,1 mmoles), tert-butyl alcohol (1.05 mL), 2-methyl-2-butene (4 mL of 2M solution in THF, 8 mmoles) at 0° C. was added a solution of NaClO2 (9 mg, 0.1 mmoles) and NaH2PO4. H2O (0.137 g, 0.1 mmoles) in H2O (0.4 ml) and stirred for 2 hours at ambient temperature. Acetic acid (glacial, 0.8 ml) and saturated NaCl solution (1.3 mL) were added to the reaction mixture which was extracted with EtOAc. The organic layer was washed with H2O, brine, dried (MgSO4), concentrated and azetroped with toluene. The resulting solid was triturated with CH3CN- acetone and filtered to give 0.02 g (47%) of the title compound as a white solid, mp 235°-237° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][O:20][CH2:21][CH3:22])[N:14]([NH:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:23][CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[CH:5][C:4]=2[N:3]=1.Cl.[OH-].[Na+]>C(O)C.O>[NH2:27][CH2:26][CH2:25][CH2:24][O:23][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([NH:15][CH:16]([CH3:17])[CH3:18])[C:13]([CH2:19][O:20][CH2:21][CH3:22])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCNC(=O)OC(C)(C)C)ccc3c2n1NC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1NC(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of tert-butyl [3-(4-amino-2-ethoxymethyl-1-isopropylamino-1H-imidazo[4,5-c]quinolin-7-yloxy)propyl]carbamate (1.24 g, 2.62 mmol) in 5 mL of ethanol (EtOH) was treated with 5 mL of 4.3 M HCl in EtOH. The reaction was heated to 100° C. After 1 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure to yield a brown solid. The solid was dissolved in a minimum amount of H2O and treated with 10% NaOH solution until the pH of the liquid was 13. The basic aqueous mixture was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 7-(3-aminopropoxy)-2-ethoxymethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.84 g) as a tan solid.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](Cl)=[O:11])(=[O:4])=[O:3].[CH3:13][OH:14].Cl>C(Cl)(Cl)Cl>[CH3:13][O:14][C:10]([C:6]1[S:7][CH:8]=[CH:9][C:5]=1[S:2]([Cl:1])(=[O:4])=[O:3])=[O:11]
Reactant: CO
Reactant: O=C(Cl)c1sccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sccc1S(=O)(=O)Cl

Procedure:
48 G. (0.196 mol) of the obtained 3-chlorosulfonylthiophene-2-carboxylic acid chloride are dissolved in 500 ml. of absolute chloroform, 9.6 g. (0.3 mol) of absolute methanol are added and the solution is heated to reflux for 3 hours [until no more hydrogen chloride evolution]. The mixture is evaporated to dryness in vacuo and the residue allowed to crystallize out. There is obtained pure 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[C:7]2[C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:18]([O:20]C)=[O:19])=[CH:13][CH:14]=3)[O:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.[NH:25]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)[NH2:26]>>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([N:25]2[CH:6]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=3)[CH:7]3[CH2:8][O:9][C:10]4[CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=4[C:16]3=[N:26]2)=[CH:28][CH:29]=1)#[N:32]
Reactant: N#Cc1ccc(NN)cc1
Reactant: COC(=O)c1ccc2c(c1)OCC(=Cc1ccc(F)cc1)C2=O
Agent: Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2c2ccc(F)cc2)cc1
Yield: 25 %

Procedure:
The title compound was prepared from methyl 3-(4-fluorobenzylidene)-4-oxochroman-7-carboxylate; Preparation 30 (155 mg, 0.50 mmol) and 4-hydrazinylbenzonitrile hydrochloride (Aldrich) (127 mg, 0.75 mmol) according to Method B and Method C. The crude product was purified by reverse-phase HPLC (acetonitrile/water/0.05% trifluoroacetic acid) to give 2-(4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid (52 mg, 0.13, 25% yield). The title compound was largely present as (±)-(3SR,3aSR)-2-(4-cyanophenyl)-3-(4-fluorophenyl)-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (dd, J=12.89, 10.47 Hz, 1H), 4.19-4.32 (m, 1H), 4.39 (dd, J=10.47, 5.91 Hz, 1H), 5.97 (d, J=11.55 Hz, 1H), 6.93-7.27 (m, 6H), 7.40 (d, J=1.61 Hz, 1H), 7.57-7.63 (m, 3H), 7.99 (d, J=8.06 Hz, 1H), 13.18 (s, 1H). ES-MS m/z 414 (M+H).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[C:9]1([C:15]#[C:16][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Nc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
More particularly, 4-iodoaniline (17.38 g), phenyl acetylene (10.4 g), and triphenyl phosphine (193 mg) are added to a three-necked 500 mL flask, which is fitted with a reflux condenser, nitrogen blanket, and an overhead mechanical stirrer. Bis(triphenylphosphine)-palladium (II) dichloride (“Pd(PPH3)2Cl2]”) (94 mg) and CuI (38 mg) are then added with 100 mL of triethylamine (“Et3N”). The flask is maintained at room temperature overnight under a nitrogen atmosphere. Afterwards, the reaction mixture is cooled and filtered to remove the precipitate. The precipitate is washed with methylene chloride and the soluble portions are recombined with the filtrate. The solvent is then evaporated to yield 4-phenylethynyl aniline (“Compound E”) as a yellowish solid. Further purification, typically involves repeated re-crystallization from hexanes to give the final product as a pale yellow colored solid.
Reaction SMILES: Br[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.[Si](Cl)(C(C)(C)C)(C)[CH3:14].N1C=CN=C1.[Li]CCCC.CI>>[CH3:14][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
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Agent: c1c[nH]cn1
Solvent: CI
Product: Cc1ccc2cc(O)ccc2c1

Procedure:
React 6-bromo-2-naphthol with t-butyl dimethylsilyl chloride and imidazole, followed by adding n-BuLi and CH3I. Deprotect the hydroxyl group by reacting with n-Bu4F to produce the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[F:24]>C1COCC1>[CH2:10]([O:9][C:3]([CH:4]([C:5](=[O:6])[CH3:7])[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[F:24])=[O:8])[CH3:11]
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(C(=O)OC)cc1F)C(C)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 2.45 g) was added portionwise over 10 min to a solution of ethyl acetoacetate (7.5 mL) in THF (60 mL) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 10 min and a solution of methyl 4-(bromomethyl)-3-fluorobenzoate (12.1 g) in THF (40 mL) added over 10 min. The mixture was heated to 65° C. for 15 h and allowed to cool. The mixture was poured cautiously into ice/water (300 mL) and the aqueous extracted with EtOAc. The combined organic phase was dried, filtered and evaporated. The crude product was purified by chromatography eluting with 10 to 20% EtOAc in isohexane to give the subtitle compound as a colorless oil 110.10 g.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:13]1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CN(C=O)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH:14]2[N:13]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:25])=[O:26])[CH:12]([CH2:11][CH2:10][CH2:9][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH2:16][CH2:15]2)=[CH:22][CH:21]=1
Reactant: c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3cncn3)CCC2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a stirred solution of 1,2,4-triazol (105 mg, 1.52 mmol) in DMF (15 ml) was added at 0° C. sodium hydride (61 mg, 1.52 mmol; 60%-disp.). The mixture was stirred at RT for 1 h, cooled to 0° C. and (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine (0.50 g, 1.26 mmol) was added. The reaction mixture was stirred at RT for 3 h and at 50° C. for 16 h, poured into ice/water (70 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers were washed with water (70 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica gel (ethyl acetate) to yield the title compound (0.47 g, yield 87%) as a colorless oil, MS: m/e=429.5 (M+H+).
Reaction SMILES: BrC1C=CC(S(O[CH2:12][CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=O)=O)=CC=1.[I-:20].[Na+]>CC(C)=O>[I:20][CH2:12][CH2:13][O:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: [I-]
Reactant: O=S(=O)(OCCOC1CCCC1)c1ccc(Br)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCOC1CCCC1
Reaction time: 16 h
Yield: 36.8 %

Procedure:
To a solution of 2-(cyclopentyloxy)ethyl 4-bromobenzenesulfonate (Preparation 16, 60 mg, 0.17 mmol) in acetone (5 mL) at room temperature was added sodium iodide (200 mg, 1.3 mmol). The mixture was,heated at 35° C. for 16 hours and then cooled. The residual precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether (10 mL) and water (10 mL). The two layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (15 mg, 37%) as a brown oil.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15](=[O:38])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[CH:18][CH:17]=2)[CH2:7][C:6]1=[O:39])([OH:3])=O.C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:62][N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>ClCCl>[CH3:62][N:63]1[CH2:68][CH2:67][N:66]([C:1]([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:15](=[O:38])[C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:18][CH:17]=3)[CH2:7][C:6]2=[O:39])=[O:3])[CH2:65][CH2:64]1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CC(=O)N(CC(=O)O)c4ccccc43)cc2)cc1
Reactant: CN1CCNCC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CC(=O)N(CC(=O)N4CCN(C)CC4)c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(carboxymethyl)-4-{4-[2-(4methylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydro -quinoxalin-2-one (100 mg) in dichloromethane (10 ml) were added triethylamine (0.030 ml) and diphenylphosphinic chloride (54.7 mg) and the solution was stirred at ambient temperature for 30 minutes. Triethylamine (0.030 ml) and 1-methylpiperazine (0.032 ml) were added to the solution and the mixture was stirred at ambient temperature for 3 hours. The solution was washed with water and brine and dried over magnesium sulfate. The organic solution was evaporated in vacuo and the residue was subjected to a silica gel column (10 g, 2% methanol in chloroform). The object fractions were evaporated in vacuo and the residue was solidified with diethyl ether to give 1-[(4-methyl-1-piperazinyl)carbonylmethyl]-4-{4-[2-(4methylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydro -quinoxalin-2-one (77.0 mg) as a white powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][OH:17])=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2=[N:29][N:30]=[C:31]([C:32]3[CH:36]=[C:35]([CH3:37])[O:34][N:33]=3)[N:21]2[N:20]=1.C1C2C(=CC=CC=2)C=NN=1>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][O:17][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3=[N:29][N:30]=[C:31]([C:32]4[CH:36]=[C:35]([CH3:37])[O:34][N:33]=4)[N:21]3[N:20]=2)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CO)nc1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Agent: c1ccc2cnncc2c1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CO[Si](C)(C)C(C)(C)C)cn4)nn23)no1

Procedure:
The reaction was carried out as described in Example 1, Step 4 using 5-(tert-butyldimethylsilyloxymethyl)-2-(hydroxymethyl)pyridine (1.0 g, 3.95 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (1.12 g, 3.95 mmol) to give, after column chromatography on silica using 2-3% MeOH/CH2Cl2 as eluent, the title phthalazine (1.4 g, 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:8]([C:20]#[N:21])=[C:7]2[CH2:22][CH2:23][CH2:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.[C:36]1([CH3:45])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.[F-].[Cs+]>COCCOC.CO.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>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH3:45])[C:7]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[C:8]2[C:20]#[N:21])=[CH:13][CH:14]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1ccc(Cn2c(C#N)c(CCCOc3cccc4ccccc34)c3cccc(Br)c32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(Cn2c(C#N)c(CCCOc3cccc4ccccc34)c3cccc(-c4ccccc4C)c32)cc1

Procedure:
To a mixture of EXAMPLE 581C (300 mg) and o-tolylboronic acid (93 mg) in 1,2-dimethoxyethane (10 ml) and methanol (5 ml) was added tetrakis(triphenylphosphine)palladium(0) (33 mg) and CsF (260 mg). The mixture was stirred at reflux under nitrogen for 4 hours. The mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate (300 mL) and water (100 ml). The aqueous layer was further extracted with ethyl acetate and the combined extracts were washed with water, brine and dried over Na2SO4. After filtration, concentration of the solvent and column purification (5 to 10% ethyl acetate in hexane) gave EXAMPLE 581D.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[K+].[I-].[K+]>C1OCCOCCOCCOCCOCCOC1.O.CN(C=O)C>[CH2:17]([C:5]1([CH2:14][CH2:2][CH2:3][CH3:4])[C:4]2[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=2)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1(CCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 90 °C
Yield: 159.8 %

Procedure:
A mixture of 12.0 g (37 mmol) of 2,7-dibromofluorene 2-7, 12 mL (111 mmol) of 1-bromobutane, 6.3 g (1 mmol) of potassium hydroxide, 0.9 g (6 mmol) of potassium iodide, 0.29 g (1 mmol) of 18-crown-6 and 120 mL of DMF was stirred and heated to 90° C. for overnight under N2. After cooling to room temperature, the solution was poured to cold water and extracted with dichloromethane (3×50 mL). The combined organic layer was washed with water, dried over anhydrous NaSO4, filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography using petroleum ether as eluent affording the desired product as a white solid (12.9 g, 80%). Mp: 116.8-118.5° C. 1H NMR (400 MHz, CDCl3, δ) 7.53 (d, J=8.8 Hz, 2H), 7.46 (dd, J=7.2 Hz, J=2.2 Hz, 4H), 1.90-1.94 (m, 4H), 1.06-1.11 (m, 4H), 0.70 (t, J=7.4 Hz, 3H), 0.54-0.59 (m, 4H). 13C NMR (100 MHz, CDCl3, δ) 152.5, 139.1, 130.2, 126.2, 121.5, 121.2, 55.6, 40.1, 25.8, 22.9, 13.8. MS (FAB) m/z 436.1 (M+).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[Br:11]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH:9]1[CH2:8][CH2:7][CH2:6][C:5]2[N:4]=[CH:3][CH:2]=[N:1][C:10]1=2
Reactant: c1cnc2c(n1)CCCC2
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrC1CCCc2nccnc21
Temperature: 25 °C

Procedure:
To a solution of 5,6,7,8-tetrahydroquinoxaline (Intermediate 19) (3.08 g, 23.0 mmol, commercially available) in CCl4 (200 mL) was added N-bromosuccinamide (4.09 g, 23.0 mmol) and a catalytic amount (56 mg) of benzoyl peroxide. The reaction mixture was heated at reflux for 17 hours. The reaction mixture was cooled to room temperature and filtered through Celite and concentrated in vacuo gave 5-bromo-5,6,7,8-tetrahydroquinoxaline, (Intermediate 20) (3.8 g, crude).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[NH:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=[C:19]1[NH:13][C:14](=[O:15])[NH:16][C:17]1=[O:18]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: NCCO
Product: COc1ccc(OC)c(C=C2NC(=O)NC2=O)c1

Procedure:
A mixture of 2,5-dimethoxybenzaldehyde (2.504 g.) and hydantoin (1.507 g., 1 molar ratio) in water (15 ml) was heated to 70°. To this 2 layer liquid was added monoethanolamine (1.38 g., 1.5 molar ratio). The mixture was heated 4 hours at 90°-92° (bath temperature) with magnetic stirring. The title compound was isolated in the usual manner and obtained as a yellow solid (3.288 g.), m.p. 250°-252°. Crystallization from dioxane (86% recovery) gave m.p. 251°-252°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([CH3:31])[CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:74]=[CH:73][CH:72]=[C:71]([OH:75])[C:66]=1[C:67]([O:69][CH3:70])=[O:68].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([CH3:31])[CH:18]=1)[C:13]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:74]=[CH:73][CH:72]=[C:71]([OH:75])[C:66]=1[C:67]([O:69][CH3:70])=[O:68])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Reactant: Cc1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)ccc1C1CC(=O)NS1(=O)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
To a solution of (2S)-2-[(benzyloxy)carbonyl]amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-methylphenyl]propanoic acid (85 mg, 0.19 mmol) in N,N-dimethylformamide (2.0 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (88.4 mg, 0.200 mmol) at 0° C. under an atmosphere of nitrogen. After stirring for 15 min, methyl 2-(4-aminobutoxy)-6-hydroxybenzoate (54.7 mg, 0.228 mmol) and N,N-diisopropylethylamine (99.5 μL, 0.571 mmol) was added. The reaction mixture was warmed to room temperature for 1 h. The reaction was diluted with ethyl acetate and quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with EtOAc once. The combined organic solutions were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative LCMS to yield the desired product (73 mg, 57%). 1H NMR (400 MHz, CD3OD): δ 8.00 (m, 1H), 7.38–7.15 (m, 9H), 6.48 (m, 2H), 5.45 (m, 1H), 5.03 (m, 2H), 4.30 (m, 1H), 3.94 (m, 2H), 3.85 (s, 3H), 3.3 (m, 4H), 3.02 (m, 1H), 2.87 (m, 1H), 2.42 (s, 3H), 1.6 (m, 4H); MF=C33H37N3O10S; LCMS found for C33H38N3O10S (M+H)+: m/z=668.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[C:19]([NH:22][C:23]1[S:24][C:25]([S:29](Cl)(=[O:31])=[O:30])=[C:26]([CH3:28])[N:27]=1)(=[O:21])[CH3:20]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:29]([C:25]2[S:24][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[N:27][C:26]=2[CH3:28])(=[O:30])=[O:31])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 2-acetamido-4-methylthiazole-5-sulfonyl chloride (0.5 mmol) to obtain N-(5-(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)sulfamoyl)-4-methylthiazol-2-yl)acetamide. 1H NMR (CDCl3)) δ 2.1 (s, 3H), 2.2 (s, 3H), 5.9 (dt, 1H), 6.05 (s, 1H), 7.0-7.6 (m, 3H), 7.4 (dd, 1H), 8.0 (s, 1H).