Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][O:24][CH2:23][O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]>C1COCC1.CO.O.[Li+].[OH-]>[C:26]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]3[CH2:21][O:22][CH2:23][O:24][CH2:25]3)[C:11]([C@H:13]3[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]3)=[O:12])[CH:8]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2COCOC2)CC1

Procedure:
Crude 5-cyclohex-1-enyl-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (24 mg) was dissolved in a mixture of THF, MeOH and H2O (3:2:1) (1.8 mL) and 1N LiOH (0.15 mL) was added. Rest of the procedure has been described earlier (example 3, step VIII). Pure 5-cyclohex-1-enyl-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid was obtained by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH:13]([CH3:15])[CH3:14].[OH-].[K+]>CCO>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)[C:13]1[CH:15]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CC(C)Br
Reactant: O=C(O)Cc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cccc(OCc2ccccc2)c1
Yield: 70.6 %

Procedure:
A mixture containing 2-(3-hydroxyphenyl)acetic acid (0.800 g, 5.26 mmol), 2-bromopropane (0.971 g, 7.89 mmol), potassium hydroxide (0.740 g, 13.2 mmol), KI (18 mg, 0.11 mmol) in 20 mL EtOH was refluxed for 18 h. The solvent was removed and the residue was dissolved in 50 mL of water and extracted with ether. The aqueous layer was acidified with aqueous 1N HCl and extracted with EtOAc. The organic layers were dried (Na2SO4) and concentrated to afford a residue which was purified by silica gel chromatography (petroleum ether/EtOAc 4:1) to get 2-(3-(benzyloxy)phenyl)acetic acid as a white solid (0.45 g, 44%).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH3:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH2:25][CH2:26][NH:27][CH3:28])[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:3][CH2:2][C:1]([N:27]([CH2:26][CH2:25][O:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:14]([NH:13][C:11]1[CH:10]=[CH:9][C:8]([OH:29])=[C:7]([CH3:6])[CH:12]=1)=[N:15][CH:16]=[N:17]2)[CH3:28])=[O:5]
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncnc3cccc(OCCN(C)C(=O)CO)c23)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
A solution of glycolic acid (100 mg) in DMF (2 ml) was added dropwise to a solution of 2-methyl-4-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol (400 mg) in DMF (4 ml) and the mixture held under sonication for 5 minutes. A solution of HATU (519 mg) in DMF (2 ml) was then added and the solution was stirred at ambient temperature for 16 hours, and then concentrated in vacuo. The residue was treated with water to precipitate a brown solid that was collected by filtration, and washed with water to give 2-hydroxy-N-[2-({4-[4-hydroxy-3-methylanilino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide as a brown solid (406 mg, 86%); NMR spectrum (DMSO-d6) 2.15 (s, 3H), 2.94 (s, 3H), 3.87 (m, 2H), 4.04 (s, 2H), 4.48 (m, 2H), 6.81 (d, 1H), 7.20 (dd, 1H), 7.25 (d, 1H), 7.35 (m, 2H), 7.92 (t, 1H), 8.64 (s, 1H), 9.46 (s, 1H), 10.49 (s, 1H); Mass spectrum M+ 383.
Reaction SMILES: [N+](C1C=CC(N2CCNCC2)=CC=1)([O-])=O.[N+:16]([C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1)([O-])=O.CS(C1N=CC2=CC=C([C:43]3C=CC=[CH:45][C:44]=3[O:49]C)N2N=1)=O.[Cl:51][C:52]1[CH:53]=[CH:54][C:55]([O:70][CH3:71])=[C:56]([C:58]2[N:66]3[C:61]([CH:62]=[N:63][C:64](S(C)=O)=[N:65]3)=[CH:60][CH:59]=2)[CH:57]=1>>[Cl:51][C:52]1[CH:53]=[CH:54][C:55]([O:70][CH3:71])=[C:56]([C:58]2[N:66]3[C:61]([CH:62]=[N:63][C:64]([NH:16][C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28]([CH2:43][C@H:44]([OH:49])[CH3:45])[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)=[N:65]3)=[CH:60][CH:59]=2)[CH:57]=1
Reactant: COc1ccc(Cl)cc1-c1ccc2cnc(S(C)=O)nn12
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Agent: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: COc1ccc(Cl)cc1-c1ccc2cnc(Nc3cccc(N4CCN(C[C@@H](C)O)CC4)c3)nn12

Procedure:
The compound was prepared in an analogous fashion to Example 73 replacing 1-(4-Nitro-phenyl)-piperazine with 1-(3-Nitro-phenyl)-piperazine and 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 7-(5-Chloro-2-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine to afford 19.24 mg of (R)-1-(4-{3-[7-(5-Chloro-2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-propan-2-ol as a lyophilized powder. (M+H)=493.09. 1H NMR (400 MHz, DMSO, d6) δ 9.34 (s, 1H), 8.98 (s, 1H), 7.94 (m, 1H), 7.50 (dd, 1H, J=2.64, 6.24 Hz), 7.39 (d, 1H, J=8.12 Hz), 7.24 (d, 1H, J=8.96 Hz), 7.14 (m, 2H), 7.01 (d, 1H, J=4.68 Hz), 6.93 (d, 1H, J=4.68 Hz), 6.59 (dd, 1H, J=1.80, 6.48 Hz), 4.12 (m, 2H), 3.80 (s, 3H), 3.53 (m, 4H), 3.15 (m, 3H), 3.02 (m, 2H), 1.15 (d, 2H, J=6.16 Hz).
Reaction SMILES: [I-].[Li+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[C:11](C(OC)=O)([CH2:15][CH:16]=[CH2:17])[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:9][C:8]=2[CH:30]=1.C(OCC)(=O)C>N1C=CC=CC=1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH:11]([CH2:15][CH:16]=[CH2:17])[CH:10]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH2:9][C:8]=2[CH:30]=1
Reactant: C=CCC1(C(=O)OC)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: C=CCC1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Lithium iodide (0.90 g; 6.7 mmole) was added to 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-3-(2-propenyl)-2H-1-benzazepin-2-one (670 mg; 1.68 mmole) in pyridine (5 ml), three drops of water were added, and the mixture was refluxed with stirring overnight. The solution was dissolved into ethyl acetate and washed with 1N hydrochloric acid (three times). The organic layer was dried (magnesium sulfate) and concentrated. The crude, brownish solid was dissolved into ethyl acetate and suction-filtered through a pad of silica gel (to remove some of the brown color). The silica gel was rinsed several times with ethyl acetate, and the organic solution was concentrated and vacuum dried, leaving 0.52 g of the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH3:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:27][CH2:26][C:23]2[CH:24]=[N:25][C:20]([CH3:19])=[CH:21][CH:22]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1ccc(CO)cn1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)cn1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (6-methyl-pyridin-3-yl)-methanol hydrochloride and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Br:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[Cl:20])=[N:10][CH:11]=1>C(OCC)(=O)C>[Br:5][C:6]1[CH:11]=[N:10][C:9]([O:12][C:13]2[CH:19]=[CH:18][C:16]([N:17]=[C:1]=[O:2])=[CH:15][C:14]=2[Cl:20])=[N:8][CH:7]=1
Reactant: Nc1ccc(Oc2ncc(Br)cn2)c(Cl)c1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1ccc(Oc2ncc(Br)cn2)c(Cl)c1
Yield: 95.1 %

Procedure:
Into a flask, a solution of 0.02 mol of phosgene in 30 ml of ethyl acetate was introduced. To this solution, a solution of 3 g of 4-(5-bromo-2-pyrimidinyloxy)-3-chloroaniline in 10 ml of ethyl acetate was dropwise added at room temperature. The mixture was reacted at room temperature for 3 hours under stirring and further under reflux for one hour. After completion of the reaction, ethyl acetate was distilled off under reduced pressure, and the residue was vacuum-dried to obtain 3.10 g of 4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenylisocyanate having a melting point of from 63 to 68° C. (2) Into a flask, 1.22 g of 4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenylisocyanate obtained in the above step was introduced, and 20 ml of toluene was added thereto. Further, 0.62 g of 2-nitrobenzamide was added under stirring. The mixture was reacted under reflux for 4 hours. After completion of the reaction, 5 ml of methanol was added to the reaction product, and the mixture was cooled. The precipitated crystals were collected by filtration to obtain 0.79 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:19])=[N:4][C:5]2[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]3[CH2:15][CH2:14][CH2:13][CH2:12][C:9]=3[C:10]=2[N:11]=1>CN(C)C=O.[Pd]>[NH2:16][C:7]1[C:8]2[CH2:15][CH2:14][CH2:13][CH2:12][C:9]=2[C:10]2[N:11]=[C:2]([OH:1])[C:3]([OH:19])=[N:4][C:5]=2[CH:6]=1
Reactant: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2c1CCCC2
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cc2nc(O)c(O)nc2c2c1CCCC2

Procedure:
A solution of 7,8,9,10-tetrahydro-2,3-dihydroxy-6-nitrobenzo(f)quinoxaline (1.5 g, 5.7 mmol) in 50 ml of N,N-dimethylformamide was hydrogenated at atmospheric pressure and room temperature in the presence of 5% palladium-on-charcoal. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was triturated with water, the solid was collected and washed with water, and ethanol affording 1.2 g (90%) of the amino compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:13][C:14]1[C:27]2[CH2:26][CH2:25][C@H:24]3[C@H:19]([CH2:20][CH2:21][CH2:22][NH:23]3)[C:18]=2[CH:17]=[C:16]([F:28])[CH:15]=1>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:23]3[C@@H:24]4[C@@H:19]([C:18]5[CH:17]=[C:16]([F:28])[CH:15]=[C:14]([F:13])[C:27]=5[CH2:26][CH2:25]4)[CH2:20][CH2:21][CH2:22]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: Fc1cc(F)c2c(c1)[C@H]1CCCN[C@H]1CC2
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cc(F)cc(F)c3CC[C@@H]21
Yield: 72 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-7,9-difluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 72% of theory; TLC: rf=0.37 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=368 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH:12]2[CH:5]([CH2:6][O:7][Si:8]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:9][Si:10]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:11]2)[O:4][CH:3]1[N:25]1[CH:30]=[CH:29][C:28](=[O:31])[NH:27][C:26]1=[O:32].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(N(CC)CC)C.CO>N1C=CC=CC=1>[O:32]=[C:26]1[NH:27][C:28](=[O:31])[CH:29]=[CH:30][N:25]1[CH:3]1[O:4][CH:5]2[CH2:6][O:7][Si:8]([CH:22]([CH3:23])[CH3:24])([CH:19]([CH3:21])[CH3:20])[O:9][Si:10]([CH:16]([CH3:17])[CH3:18])([CH:13]([CH3:14])[CH3:15])[O:11][CH:12]2[CH:2]1[O:1][C:33](=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)[Si]1(C(C)C)OCC2OC(n3ccc(=O)[nH]c3=O)C(O)C2O[Si](C(C)C)(C(C)C)O1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)OC1C2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OCC2OC1n1ccc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 4 is O-Acetylated using well known literature procedures (Protective Groups in Organic Synthesis, 3rd edition, 1999, pp. 150-160 and references cited therein and in Greene, T. W. and Wuts, P. G. M., eds, Wiley-Interscience, New York.) Acetic anhydride (2 to 2.5 eq.) and triethylamine (4 eq.) is added to a solution of 4 (1 eq.) and N,N-dimethylaminopyridine (0.1 eq.) in anhydrous pyridine. After stirring at room temperature for 1 hour the mixture is treated with methanol to quench excess acetic anhydride and evaporated. The residue is redissolved in ethyl acetate, washed extensively with aqueous NaHCO3, dried over anhydrous Na2SO4, filtered, and evaporated. The compound is used without further purification.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH2:12]([NH2:17])[C:13]([CH3:16])([CH3:15])[CH3:14].[N:18]([O-])=O.[Na+].[OH-].[Na+]>CS(C)=O.O.C(O)(=O)C>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:12][N:17]1[C:2]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=2[N:4]=[N:18]1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: O=N[O-]
Reactant: CC(C)(C)CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)Cn1nnc2cc([N+](=O)[O-])ccc21
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
2-Fluoro-5-nitroaniline (6, 10.22 g, 65.5 mmol, 1.0 equiv.) was dissolved in anhydrous DMSO (100 ml) and treated with neopentylamine (1-2) (7.71 ml, 65.5 mmol, 1.0 equiv.). The reaction mixture was heated at 120° C. for 2 days, cooled to room temperature and treated with acetic acid (25 ml), followed by addition of 2.0 M aqueous solution of sodium nitrite (121 ml, 79 mmol, 1.2 equiv.). LCMS showed product after the reaction mixture was stirred at ambient temperature for 20 minutes. The mixture was then neutralized to pH=7 with NaOH (1N) and diluted with water which caused precipitation. The solid was collected on top of filter and washed twice with water. The crude solid was purified with normal phase silica gel chromatography (EtOAc/Hexane gradient from 0 to 100%) to yield 1-(2,2-dimethylpropyl)-5-nitro-1H-1,2,3-benzotriazole (8). 1H NMR δ (CDCl3): 9.02 (d, 1H, J=2.0 Hz), 8.40 (dd, 1H, J=9.1, 2.0 Hz), 7.62 (d, 1H, J=9.1 Hz), 4.47 (s, 2H), 1.07 (s, 9H) ppm. LRMS m/z (M+H) 235.1 found, 235.3 required.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:30]=4)[CH2:17][CH2:18]3)=[N:10][C:9]=2[CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCCl)cc1S(N)(=O)=O
Reactant: COCc1nc(C2CCNCC2)oc1-c1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COCc1nc(C2CCN(CCc3ccc(OC)c(S(N)(=O)=O)c3)CC2)oc1-c1ccc(F)cc1
Reaction time: 16 h
Yield: 38.6 %

Procedure:
A solution of 4-[5-(4-fluoro-phenyl)-4-methoxymethyl-oxazol-2-yl]-piperidine (0.3 g; 1.03 mmol) in dry dioxane (7 ml) is treated with 5-(2-chloroethyl)-2-methoxy-benzenesulfonamide (0.52 g; 2.06 mmol), sodium iodide (0.31 g; 2.06 mmol) and diisopropylethylamine (0.72 ml; 4.12 mmol) and heated to 100 C. for 16 hours. The reaction mixture is partitioned between ethyl acetate (50 ml) and dilute sodium bicarbonate (20 ml). The aqueous phase is washed with ethyl acetate (20 ml). The combined organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using a methanol/ethyl acetate gradient (5%-20%) is followed by a second chromatography using a methanol/dichloromethane gradient (5%-15%). Crystallization from dichloromethane/ethyl acetate afforded the product as a white solid (0.20 g; 40%). HNMR (CDCl3): 7.72 (d, 1H, J=2.1 Hz), 7.62 (m, 2H), 7.35 (dd, 1H, J=8.6; 2.1 Hz), 7.13 (t, 21H, J=8.6 Hz), 6.96 (d, 1H, J=8.6 Hz), 5.64 (broad s, 2H), 4.44 (s, 2H), 3.97 (s, 3H), 3.44 (s, 3H), 2.96 (m, 2H), 2.80 (m, 1H), 2.75 (m, 2H), 2.53 (m, 2H), 2.10 (m, 4H), 1.90 (m, 2H). Mass spectrum: m/e calculated (MH+)=504; observed (MH+)=504.
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].O>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:24]([C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:22]=2[F:21])=[O:25])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)c1cccc(F)c1F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1cccc(F)c1F
Temperature: -15 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of t-butyllithium (3.0 mL, 1.2 M in pentane) was added to a cooled (−78° C.) solution of benzyloxy-4-bromobenzene (500 mg, 1.9 mmol) in THF (20 mL). The temperature was raised to −15° C. over a period of 1 h and stirred at −15° C. for an additional 2 h. A slurry of MnCl2.2LiCl2 (1.9 mmol) in THF (13 mL) was added and the mixture was stirred for 30 min allowing the temperature to reach 0° C. 2,3-Difluorobenzoyl chloride was added and the reaction was stirred at r.t. for 1 h. Water (20 mL) was added, stirred for 10 min. The aqueous phase was extracted with dichloromethane (2×20 mL) and the organic phases were combined and washed with brine (20 mL), dried (Na2SO4), filtered and concentrated. Purified by flash chromatography (eluent: 100% heptane →10% ethyl acetate in heptane) to give the title compound 3 (320 mg, 52% yield). 1H-NMR (400 MHz, CDCl3): δ 7.88 (d, J=7.5 Hz, 2H), 7.48-7.15 (m, 8H), 7.08 (d, J=7.5 Hz, 2H), 5.18 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)CCC.C(=O)([O-])[O-].[Na+].[Na+].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(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)=[CH:7][C:6]=3[C:5]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:14]=1
Reactant: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
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
Solvent: CCO
Product: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(-c3cccs3)cc21
Reaction time: 1 h

Procedure:
A mixture of 2,7-dibromo-9,9-dihexylfluorene (7) (8.0 g, 16 mmol), 2-tributylstannylthiophene (2.98 g, 8.0 mmol), tetrakis(triphenylphosphine)palladium (0) (200 mg, 1.73×10′ mol) aqueous sodium carbonate (2M, 2 cm3), toluene (5 cm3) and ethanol (2 cm3) was heated under reflux for 24 h under argon. Toluene and ethanol were removed and hexane (10 cm3) and aqueous KI (2%, 10 cm3) added and the mixture stirred vigorously for 1 h. Diethyl ether (10 cm3) and dilute HCl(nq) (3M, 10 cm3) were added, the aqueous layer separated and washed with diethyl ether (2×10 cm3). The organic layers were combined, dried over anhydrous magnesium sulphate, filtered and concentrated to a dark brown oil which was purified by column chromatography [silica gel, hexane] to yield a pale jade coloured oil.
Reaction SMILES: [Cl-].[CH2:2]([N+:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:24][C:25]([N-:27][S:28]([C:31]1[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:26].[Na+].C(Cl)(Cl)Cl.CS(C)=O>O>[CH2:2]([N+:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:24][C:25]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:26]
Reactant: CC(=O)[N-]S(=O)(=O)c1ccc(N)cc1
Agent: CCCCCCCCCCCCCCCC[n+]1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Yield: 99.22 %

Procedure:
Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. Sodium sulfacetamide (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and an orange wax was obtained in 99.22% yield. 1H and 13C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=30-40° C. Thermal data determined by thermalgravimetric analysis (TGA): Tonset5%=211° C. and Tonset=219° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O.O.[NH2:20][NH2:21].NN>O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([C:8]#[N:9])[CH:4]=3)[NH:21][N:20]=2)=[CH:13][CH:14]=1
Reactant: NN
Reactant: N#Cc1ccc(F)c(C(=O)c2ccc(F)cc2)c1
Solvent: O
Product: N#Cc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reaction time: 8 h

Procedure:
To a flask containing 4-fluoro-3-{(4-fluorophenyl)carbonyl}benzenecarbonitrile (4.2 g, 0.017 mmol) was added hydrazine monohydrate (15 mL) and anhydrous hydrazine (10 mL). In an addition flask the procedure was repeated. Both flasks were allowed to stir overnight exposed to the atmosphere. LCMS confirmed the reactions were complete. To the flasks were added an excess amount of water. The reactions were allowed to stir for two hours. The product of the reactions was collected via a flitted funnel by filtration and combined to yield the title compound. The product was allowed to dry under vacuum and taken on crude into the next step of the synthesis. 1H NMR (DMSO-d6) 8.7 (s, 1H), 8.1 (m, 2H), 7.7–7.8 (m, 2H), 7.3–7.4 (t, 2H), ES-MS m/z 238 [M+1]+