Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=[O:14])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:3]=1.N[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([O:15][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:14])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:3]=1
Reactant: NCCN1CCCCC1
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3cccc(C(=O)O)c3)c(C#N)c(N)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: COc1ccc(COc2ccccc2-c2cc(-c3cccc(C(=O)OCCN4CCCCC4)c3)c(C#N)c(N)n2)cc1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a cold (0° C.) mixture of 3-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)benzoic acid (starting compound 5, 1.35 g, 3.00 mmol), N-(2-aminoethyl)piperidine (0.420 g, 3.30 mmol), and 1-hydroxybenzotriazole (0.490 g, 3.60 mmol) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g, 3.60 mmol) with stirring. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained solid was triturated with ethyl ether and dried under reduced pressure to give 2-(1-piperidinyl)ethyl 3-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)benzoate (0.98 g, yield 58%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[F:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([F:40])[CH:39]=1)[C:34](O)=[O:35]>>[F:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([F:40])[CH:39]=1)[C:34]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:35]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: Cl
Product: CN(C(=O)c1cc(F)cc(F)c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-difluorobenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-difluorobenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 506 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:22]([OH:24])=[O:23])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C@@H:11]2[CH2:12][NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OCc2ccc(Cl)cc2)C[C@H]1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1C[C@H](OCc2ccc(Cl)cc2)CN1
Reaction time: 8 h
Yield: 5.1 %

Procedure:
(2S,4S)-1-(tert-butoxycarbonyl)-4-[(4-chlorobenzyl)oxy]-2-pyrrolidinecarboxylic acid (Preparation 4, 96 mg, 0.38 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added and the mixture left overnight at room temperature. The reaction mixture was partitioned between dichloromethane (25 ml) and water (25 ml). The aqueous layer was separated, washed with more dichloromethane (25 ml) and evaporated to dryness. The product was purified using Dowex™ 50WX8-200 resin, eluting first with water then 9:1 water:ammonia yielding the title compound (5 mg, 5% yield) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]2[CH3:39])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][C:34]1[N:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:40])[NH:22][C:9]4[CH:10]=[C:11]([C:14]#[C:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:37]=[C:36]([CH3:38])[N:35]=1
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(C#Cc4ccccc4)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(-c2cccc(C3=Nc4ccc(C#Cc5ccccc5)cc4NC(=O)C3)c2)c(C)n1

Procedure:
Prepared from (2-{3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example K60) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (57 mg). MS (EI) 430 (M+); mp 134° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=1)[O:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)#[N:2].Cl>C(O)C>[CH3:24][O:23][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: COc1ccc(C#N)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C#N)cc1OC1CCNCC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-(5-cyano-2-methoxyphenoxy)piperidine-1-carboxylate (2, 39.31 g, 118.26 mmoles) was suspended in ethanol (155.53 g) and heated to 40° C. To this slurry was slowly added HCl (46.61 g, 573.04 mmoles). The mixture was heated to 60° C. and held for 3 hours. The reaction mixture was cooled to 20° C. and seed was charged initiating crystallisation. The resulting solid was isolated by filtration at 0° C., washed twice with ethanol (62.21 g) and then dried to give the title compound as the hydrochloride salt (29.84 g, 77% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (m, 2H) 2.09 (m, 2H) 3.02 (ddd, J=12.7, 8.9, 3.4 Hz, 2H) 3.20 (m, 2H) 3.84 (s, 3H) 4.63 (tt, J=7.7, 3.6 Hz, 1 H) 7.15 (d, J=8.5 Hz, 1H) 7.45 (dd, J=8.5, 1.9 Hz, 1H) 7.56 (d, J=1.9 Hz, 1H) 9.16 (br. s, 2H); Mass Spectrum: m/z (M+H)+ 233.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=O)[CH2:12][C:11]3([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[S:22])[CH2:12][C:11]3([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1(C)CC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(=S)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared by heating under reflux overnight a mixture of 6-(3-chlorophenyl)-4,4-dimethyl-3,4-dihydroquinoline-2(1H)-one and an equal weight of phosphorus pentasulfide in pyridine was stirred. Removal of the pyridine in vacuo followed by treating the residue with 6N hydrochloric acid and recrystallization of the residue in ethanol gave the product as a yellow solid: mp. 197-1980 C. 1H-NMR (DMSO-d6) 8 12.34 (s, 1H), 7.75 (m, 1H), 7.64 (m, 2H), 7.57 (dd, 1H J=9.3 and 2.1 Hz), 7.48 (t, 1H, J=7.7 Hz), 7.41 (m, 1H),7.20 (d, 1H, J=8.3 Hz), 3.34 (s, 2H), 1.26 (s, 6H); MS (APCI (−)) m/z 300 [M−H]− Anal. Calc. For C17H16CINS: C, 67.65, H, 5.34, N, 4.64. Found: C, 67.77, H, 5.57, N 4.54.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:22][C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[N:11]=1)[CH3:2].CN(C=O)C.[H-].[Na+].[CH3:30][O:31][CH2:32]Cl>O>[CH3:30][O:31][CH2:32][N:22]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]2[N:11]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[S:3][CH2:1][CH3:2]
Reactant: COCCl
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1COC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (98 mg) and DMF (6 ml), 60% of sodium hydride (in oil) (29 mg) and chloromethyl methyl ether (25 μl) were sequentially added under ice-cooling. The mixture was heated room temperature, and stirred for 4 hours. Then, water was poured thereinto, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 72 mg of 3-methoxymethyl-2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 37).
Reaction SMILES: [Br-:1].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][C:36]=1[CH3:44]>C1COCC1>[Br:1][CH2:42][C:41]([C:38]1[CH:39]=[CH:40][C:35]([Br:34])=[C:36]([CH3:44])[CH:37]=1)=[O:43]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(Br)c(C)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CBr)ccc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
Trimethyl phenylammonium tribromide (13 g, 0.036 mol) was added to a solution of 1-(4-bromo-3-methyl-phenyl)-ethanone (6.3 g, 0.030 mol) in THF (30 mL) and the reaction mixture was stirred at RT for 12 h, filtered, and concentrated to provide the title intermediate (8.6 g, 100% yield). 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.82 (m, 1H), 7.66 (m, 2H), 4.38 (s, 2H), 2.56 (s, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(Cl)Cl>[Br:31][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CO)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CBr)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a 100-mL round-bottomed flask was added (2-methoxy-4-pyridinyl)methanol (1.52 g, 10.92 mmol), triphenylphosphine (3.15 g, 12.02 mmol, Aldrich, St. Louis, Mo.), and carbon tetrabromide (1.165 mL, 12.02 mmol, Aldrich, St. Louis, Mo.) in DCM (20 mL). The reaction mixture was stirred at 0° C. for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give 4-(bromomethyl)-2-methoxypyridine (1.98 g) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]([C:14]([F:17])([F:16])[F:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.O[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[CH2:23][CH2:22]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:8]1([C:6]2[CH:7]=[C:3]([CH2:2][O:1][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[CH2:23][CH2:22]4)[S:4][C:5]=2[C:14]([F:17])([F:15])[F:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: OCc1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2cc(OCc3cc(-c4ccccc4)c(C(F)(F)F)s3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of 0.25 g (0.97 mmol) of 2-hydroxymethyl-4-phenyl-5-trifluoromethyl-thiophene (from Step D), 0.17 g (1.16 mmol) of 5-hydroxy-1-indanone and 0.31 g (0.16 mmol) of triphenylphosphine in 2.5 mL of THF at 0° C. was treated with 0.18 mL (0.16 mmol) of diethylazodicarboxylate. The resulting mixture was warmed to rt, and stirred for 2 h. The reaction was loaded onto silica gel and eluted with 33% ethyl acetate/hexanes to give 0.35 g (0.90 mmol, 78%) of the title compound as a white solid: 1H NMR (500 MHz) δ 7.76 (d, J=8.3 Hz, 1H), 7.42–7.47 (m, 5H), 7.14 (s, 1H), 7.01–7.03 (m, 2H), 5.34 (s, 2H), 3.15 (t, J=5.9 Hz, 2H), 2.72 (t, J=6.0 Hz, 2H); ESI-MS 388.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[CH:9]=[CH:10][C:11]=2Br)[C:6](Br)=[CH:5][CH:4]=1.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)CCC>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>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[CH:9]=[CH:10][C:11]=2[C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[C:6]([C:24]2[S:23][CH:22]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: COc1ccc(Br)c2c(OC)ccc(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccs2)c2c(OC)ccc(-c3cccs3)c12
Yield: 81 %

Procedure:
1,5-Dimethoxy-4,8-dibromonaphthalene (1.19 g., 0.0034 mol.) and 2-(tributylstannyl)thiophene (3.85 g., 0.0103 mol.) were dissolved in 100 mL dry toluene in argon atmosphere. Pd(PPh3)4 (100 mg.) was introduced into the reaction flask using a Schlenk tube under argon. The resultant mixture was subsequently refluxed for 18 hrs. The brownish black solution was cooled and poured into 300 mL of petroleum ether to afford crude yellow solid. Upon recrystallization from CH2Cl2:petroleum ether (1:5), the desired product was obtained as a light yellow solid. Yield: 81%. M.p. 216-218° C. Anal. Calcd. for C20H16O2S2: C, 68.15%; H, 4.58%; S, 18.19%. Found: C, 67.64%; H, 4.48%; S, 17.49%. Mass spectrum: 351.75 (M+). 1H-NMR (CDCl3; □ in ppm): 3.59 (s, 3H), 6.81 (d, 2H), 6.89 (d, 2H), 7.00 (dd, 2H), 7.26 (dd, 2H), 7.38 (d, 2H). 13 C-NMR (CDCl3; □ in ppm): 55.6, 106.5, 123.1, 123.5, 125, 125.5, 126.1, 131.1, 147.5, 156.8.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20]>O1CCOCC1>[Br:17][CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:20]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A solution of methyl 4-aminobenzoate (5.0 g, 33 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (6.66 g, 2.9 mL, 33 mmol) was added dropwise, keeping the internal temperature between 0° to 5° C. over a 1/2 h period. After the addition the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 6.83 g (76%) of the title compound as a pale brown solid; mp 153°-155° C.: 1H NMR (DMSO-d6) δ10.72 (s, 1H), 7.93 (d, J=8.8, 3H), 7.72 (d, J=8.8, 2H), 4.07 (s, 2H), 3.82 (s, 3H) 13C NMR (DMSO-d6) δ165.69, 165.36, 124.91, 130.26, 124.49, 118.64, 51.92, 30.25; MS (EI, m/z) 271 (M+ ).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH3:19][C:20]([CH3:23])([O-:22])[CH3:21].[K+]>C1COCC1.O>[Cl:8][C:6]1[CH:7]=[C:2]([O:22][C:20]([CH3:23])([CH3:21])[CH3:19])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: CC(C)(C)[O-]
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (2 g) in THF (20 mL) was added potassium tert-butoxide (0.8 g) and the reaction mixture was stirred at ambient temperature for 20 h. Further potassium tert-butoxide (0.8 g) was added and the reaction mixture was stirred at ambient temperature for 4 h. The mixture was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed with H2O and dried (MgSO4), filtered and evaporated. The resulting oil was purified by column chromatography on silica gel using MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the subtitle compound as a clear, colourless oil. Yield: 0.68 g
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.[OH-].[Na+].O>CO>[CH2:1]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][CH:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:24][NH2:25])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: N#CCc1ccc(F)cc1
Reactant: CCCCCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCOc1ccc(CC(CN)c2ccc(F)cc2)cc1
Reaction time: 12 h
Yield: 20 %

Procedure:
A solution of 51.5 g of 4-hexyloxybenzaldehyde and 33.8 g of 4-fluorophenylacetonitrile in methanol was stirred at room temperature and aqueous sodium hydroxide (50 percent) was added dropwise until a precipitate appeared. Water was then added and the solids were collected by filtration to render α-[[4-(hexyloxy)phenyl]methylene]-4-fluorophenylacetonitrile which was reduced as follows. 40.2 g of said nitrile, 10 g of Raney nickel, 150 ml of anhydrous ammonia and 300 ml of tetrahydrofuran were stirred at 110° for 12 hours at a pressure of 2000 psi. The catalyst and solvent were removed and the hydrochloride salt was made in the filtrate by the addition of anhydrous hydrochloric acid. Recrystallization from methanol rendered the title compound (20 percent yield).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=O.CO.[H][H]>[Ni].[Pd].C(O)(=O)C>[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])[CH3:1]
Reactant: [H][H]
Reactant: CC(=O)c1ccc(O)cc1O
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(O)cc1O
Temperature: 72.5 °C
Reaction time: 8 h

Procedure:
2,4-Dihydroxy acetophenone (76 g, 0.5 mole) was charged in a 1 liter autoclave reactor along with methanol (300 ml), acetic acid (5 ml), and Raney Nickel (15.2 g washed several times with water and water/methanol) and 750 mg of Pd/C. The pH of the system was 5.0. The autoclave was checked for leaks with nitrogen. The autoclave was pressurized to 500 psi with hydrogen and stirred at 70-75° C. up to 8 hrs. During this time 97% of the theoretical value for hydrogen was consumed. The reaction was vented and the contents were filtered through a milipore filter to give a yellow solution. Concentration of this solution in vacuo gave a solid. This solid was crystalized from 1,2-dichloroethane to give 4-ethyl resorcinol in 85% isolated yield. The unreacted 2,4-dihydroxy acetophenone was recovered (−13%) from the reaction mixture and was recycled. The structure of 4-ethyl resorcinol and 2,4-dihydroxy acetophenone were characterized by NMR (see FIG. 1), Gas Chromatography (see FIG. 2), IR (See FIG. 3) and Mass spectroscopy. The mass spectroscopy indicated that the mass was 138.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[CH:21][N:22]=[C:23](I)[N:16]3[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[CH:21][N:22]=[C:23]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)[N:16]3[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1CN(Cc2ccccc2)CC1c1nn2c(I)ncc2c(=O)[nH]1
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: [K+]
Solvent: Cc1ccccc1
Product: CC1CN(Cc2ccccc2)CC1c1nn2c(-c3ccc(F)cc3)ncc2c(=O)[nH]1
Temperature: 100 °C
Yield: 86.5 %

Procedure:
To a solution of compound 6 (500 mg, 1.14 mmol) and 4-fluorophenylboronic acid (300 mg, 2.14 mmol) in 30 mL of toluene was added K2CO3 (1.0 g, 7.24 mmol). The resulting mixture was degassed by purging with nitrogen for 15 min, before Pd(PPh3)4 (120 mg, 0.10 mmol) was added. The resulting suspension was bubbled with nitrogen for 10 minutes. The reaction mixture was heated to 100° C. for 18 hours and then cooled to room temperature. After removal of the solvent, the residue was purified by chromatography on silica gel column (eluted with PE/EtOAc=5:1 to 1:2) to afford compound 10 (398 mg, 86% yield) as a white solid. LC-MS: m/z 404.31 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 8.34˜8.31 (m, 2H), 7.95 (s, 1H), 7.38 (m, 4H), 7.31 (m, 1H), 7.16 (m, 2H), 3.85 (d, J=12.4 Hz, 1H), 3.63 (d, J=12.4 Hz, 1H), 3.44˜3.40 (m, 1H). 3.05 (d, J=10 Hz, 1H), 2.84 (m, 1H), 2.61 (m, 1H), 2.50˜2.47 (m, 1H), 1.99 (m, 1H), 1.22 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2.N1C=CC=CC=1>CO>[N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12][S:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)(=[O:10])=[O:9])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccnc1
Yield: 17.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, pyridine-3-sulfonyl chloride hydrochloride (0.30 g, 1.39 mmol), 8-aminoquinoline (0.20 g, 1.39 mmol) in pyridine (0.56 ml, 6.94 mmol) gave the title compound (70 mg, 18%) after trituration from MeOH.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1>>[Cl:1][S:2]([C:13]1[CH:12]=[C:11]([CH2:14][C:15](=[O:17])[CH3:16])[CH:10]=[CH:9][C:8]=1[O:7][CH3:6])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(CC(C)=O)cc1
Product: COc1ccc(CC(C)=O)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To 250 g of chlorosulfonic acid was added dropwise 50 g of 4-methoxyphenylacetone at 0°-5° C. After stirring the mixture for 4 hours at room temperature, the reaction mixture was poured into 2,500 ml of ice water and extracted thrice with 500 ml of ethyl acetate. The extract was washed with water and after drying the extract with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The crude crystals obtained were recrystallized from benzene-ether to provide 32 g of 3-chlorosulfonyl-4-methoxyphenylacetone.