Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[C:4]([CH3:30])[CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[C:4]([CH3:30])[CH:3]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 162, step 2, 3-(4-chloro-2-methylphenyl)-1-(6-methoxypyridin-3-yl)-3-(4-(methylsulfonyl)phenyl)propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as an off-white solid, MS (ESI+): m/z=430.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.C[OH:40]>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:40])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:32][CH:33]=3)(=[O:26])=[O:27])[N:14]([CH3:38])[N:13]=2)=[N:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cn1nc(OCCOc2ncc(Br)cn2)c(-c2ccc(CO)cc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a ¼ strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS7-H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. 2 mls of this inoculum medium was then transferred to each of sixteen 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 20 mg of N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 6 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid, 1.4 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2ccc3oc(-c4ccc(OC)c([N+](=O)[O-])c4)nc3c2)cc1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-methoxyphenylboronic acid (129 mg, 0.85 mmol) the subtitle compound was obtained (193 mg, 60%). 1H NMR (DMSO) δ 8.63(d, 1H), 8.45(dd, 1H), 7.99(d, 1H), 7.83(d, 1H), 7.67(d, 3H), 7.62(d, 1H), 7.05(d, 2H), 4.05(s, 3H), 3.81(s, 3H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14]CS([O-])(=O)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:20]([O:22][C:23](=[O:36])[CH:24]([O:33][CH2:34][CH3:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:20]([O:22][C:23](=[O:36])[CH:24]([O:33][CH2:34][CH3:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:14][CH2:13][CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=2)[CH:27]=1)[CH3:21]
Reactant: CCOC(=O)C(Cc1cccc(O)c1)OCC
Reactant: CS(=O)(=O)Oc1ccc(CCCCS(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1cccc(OCCCc2ccc(OS(C)(=O)=O)cc2)c1)OCC
Yield: 64.6 %

Procedure:
3-(4-Methanesulfonyloxyphenyl)propylmethanesulfonate (1.905 g; 6.18 mmole) dissolved in acetonitrile (13 ml) was added dropwise to a mixture of 2-ethoxy-3-(3-hydroxyphenyl)propanoic acid ethyl ester (1.47 g; 6.18 mmole) and potassium carbonate (2.56 g; 18.54 mmole) in acetonitrile (15 ml). The mixture was refluxed for 5 hours, then the solvent was evaporated in vacuo and water was added. The mixture was extracted twice with dichloromethane, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using diethyl ether/petroleum ether (gradient 33% to 100% diethyl ether) gave 1.80 g (yield 65%) of 2-ethoxy-3-{3-[3-(4-methanesulfonyloxyphenyl)propoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=2[N:10]([CH3:19])[C:9]1=[O:20].C1(C)C=CC(S([CH:30]([N+:38]#[C-:39])[C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[O:18][CH:39]=[N:38][C:30]=3[C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)=[CH:16][C:11]=2[N:10]([CH3:19])[C:9]1=[O:20]
Reactant: [C-]#[N+]C(c1cccc(C)c1)S(=O)(=O)c1ccc(C)cc1
Reactant: Cn1c(=O)n(-c2ccccc2Cl)c2ccc(C=O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ncoc2-c2ccc3c(c2)n(C)c(=O)n3-c2ccccc2Cl)c1
Temperature: 25 °C

Procedure:
A slurry of 1-(2-chloro-phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde (prepared as described previously, 100 mg, 0.35 mmol), [(toluene-4-sulfonyl)-m-tolyl-methyl]-isonitrile (prepared as described previously, 110 mg, 0.38 mmol) and potassium carbonate (53.1 mg, 0.38 mmol) in DMF was heated to 60° C. overnight. The reaction mixture was cooled to room temperature and quenched with water. The resulting aqueous solution was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a brown oil. Purification by HPLC (30–80% acetonitrile/water gradient) afforded 40 mg of the title compound. MS (M+1)=416.3
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].N1CCCC1.[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:18]([N:25]1[CH2:26][CH:27]=[C:28]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:29][CH2:30]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCNC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN(Cc4ccccc4)CC3)c2c1
Yield: 45 %

Procedure:
A solution of 5-nitroindole (38) (1.0 g, 6.167 mmol) in dry ethanol (20 mL) was treated with pyrrolidine (1.54 mL, 18.501 mmol), N-benzyl-4-piperidone (2.2 mL, 12.3 mmol) at room temperature and the resulting solution was refluxed for 4 days. The reaction was brought to room temperature and solvent was evaporated. The crude product was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 71 (0.925 g, 45%) as a solid. mp 168-170° C.; 1H NMR (DMSO-d6) δ 2.51-2.55 (m, 2H), 2.66 (t, 2H, J=5.4 Hz), 3.12-3.18 (m, 2H), 3.60 (s, 2H), 6.17 (s, 1H), 7.23-7.38 (m, 5H), 7.55 (d, 1H, J=9.0 Hz), 7.65 (s, 1H), 8.01 (dd, 1H, J=2.1, 8.7 Hz), 8.68 (d, 1H, J=2.1 Hz), 11.87 (s, 1H); ESI-MS m/z (%): 334 (M+, 100).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)no2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A mixture of methyl 4-[3-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-5-yl]benzoate (2.10 g), 1 M aqueous sodium hydroxide solution (12 ml), tetrahydrofuran (20 ml) and methanol (20 ml) was stirred at 60° C. for 1 hr. The mixture was acidified by adding 1 M hydrochloric acid. The crystals were collected by filtration to give 4-[3-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-5-yl]benzoic acid (1.82 g, yield 90%). Recrystallization from hexane-tetrahydrofuran gave colorless crystals. melting point: 293–294° C.
Reaction SMILES: [I:1][C:2]([C:5]([C:8]([NH2:10])=O)([F:7])[F:6])([F:4])[F:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[I:1][C:2]([F:4])([F:3])[C:5]([F:7])([F:6])[C:8]#[N:10]
Reactant: NC(=O)C(F)(F)C(F)(F)I
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#CC(F)(F)C(F)(F)I
Temperature: 140 °C

Procedure:
A mixture of 150 g of fine powder of ICF2CF2CONH2 and 235 g of P2O5 was heated at 130 to 150° C., during which time volatiles were distilled out. Final volatiles were collected in a -78° C. trap at 26.6 kPa. A total of 125.3 g of crude product was obtained, 95% pure by GC. Redistillation gave pure product, bp 60-61° C. 19F NMR: -63.3 (t, J=10.4 Hz, 2F), -100.5 (t, J=10.4 Hz, 2F). IR(neat): 2264 (w), 1235 (s), 1196 (s), 1172 (s), 1146 (s), 1089 (s), 1065 (s), 893 (s).
Reaction SMILES: NCCNC[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]([NH2:35])[N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]([NH2:35])[N:27]=2)[N:11]=1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Product: CN(CCNc1ccc([N+](=O)[O-])c(N)n1)c1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methylamine and 2-chloro-5-nitro-6-aminopyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methyl{2-[(5-nitro-6-amino(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][CH3:19])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N#N.[F:22]F>FC(F)(F)C(O)=O>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([NH:11][C:12]2[C:17]([F:22])=[C:16]([CH2:18][CH3:19])[N:15]=[CH:14][N:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)ncn1
Reactant: FF
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1F
Yield: 41 %

Procedure:
A solution of 2.62 g of 4-(cis-4-tert-butylcyclohexylamino)-6-ethyl pyrimidine in 40 ml of trifluoroacetic acid was charged into a reactor for direct fluorination. A stream of a mixture of F2/N2 (1:10 by volume) was passed through the mixture at 15° C. After 0.015 mol of fluorine was passed through, the reaction was flushed with nitrogen in order to remove unconsumed fluorine. The solvent was removed in vacuo and the residue was treated with 50 ml of 2N sodium hydroxide, extracted with diethyl ether, washed with water and dried over MgSO4. After ether evaporation, the product was isolated in 41% yield by column chromatography, eluting with a mixture hexane/ethyl acetate 2:1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:32]=[C:31](CBr)[CH:30]=[CH:29][C:28]=1[Cl:35]>>[Br:26][C:27]1[CH:32]=[C:31]([CH:30]=[CH:29][C:28]=1[Cl:35])[CH2:21][S:20][C:15]1[C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Clc1ccc(CBr)cc1Br
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)c(Br)c3)c2CC1

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylsulfanyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-bromo-4-bromomethyl-1-chloro-benzene, to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[F:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[CH:6]=[CH:5]2
Reactant: Fc1ccc(I)cc1
Reactant: Fc1cc2[nH]ccc2cc1Br
Product: Fc1ccc(-n2ccc3cc(Br)c(F)cc32)cc1

Procedure:
In analogy to example 23.3, 5-Bromo-6-fluoro-1H-indole and 1-fluoro-4-iodobenzene were converted to yield 5-Bromo-1-(4-fluoro-phenyl)-6-fluoro-1H-indole as a light yellow solid, MS: 307 (M, 1Br).
Reaction SMILES: [CH3:1][C@@:2]([OH:31])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:30])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].O>C(O)C>[O:31]1[C@:2]([CH3:1])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:30])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@](C)(O)CCCC(C)CCCC(C)CCCC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCC[C@]1(C)CO1
Reaction time: 16 h

Procedure:
1.52 g (3.3 mmol) of (2R,6RS,10RS)-2,6,10,14-tetramethyl-1-tosyloxy-2-pentadecanol were dissolved in 20 ml of ethanol. 2 ml of sodium hydroxide solution (50%) were then added and the mixture was stirred for 16 hours. Subsequently, 50 ml of water were added and the mixture was stirred up with HYFLO. The suspension was then filtered and washed with water. The residue was triturated with diethyl ether, dried over sodium sulphate, filtered and concentrated. There was obtained (2R,6RS,10RS)-1,2-epoxy-2,6,10,14-tetramethylpentadecane with [α]D20 =-0.21° (c=2% in CHCl3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[CH:14]=[C:15]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccc(Cl)c1
Yield: 60.3 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), 3-chlorobenzenesulfonyl chloride (270 mg, 1.3 mmol) and DMAP (cat.) gave the title compound (250 mg, 59%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[C:12]2=[N:11][C:10]=1[C:23]([OH:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:23]([C:10]2[N:11]=[C:12]3[N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:25])=[CH:29][CH:28]=1
Reactant: CCCCN1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1
Product: CCCCN1CCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Yield: 89 %

Procedure:
Coupling of 6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.87 mmol) and 4-fluorobenzylamine (0.120 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.349 g (88% yield) of the title amide as white crystals; mp 107-109° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.96 (3H, t, J=7.3 Hz, CH3), 1.33-1.43 (2H, m, CH2), 1.56-1.63 (2H, m, CH2), 3.41 (2H, t, J=7.4 Hz, CH2), 3.70 (2H, t, J=8.9 Hz, CH2), 4.13 (2H, t, J=8.9 Hz, CH2), 4.50 (2H, d, J=5.8 Hz, NCH2), 5.10 (2H, s, OCH2), 7.0 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.33-7.37 (3H, m, aromatics), 7.46-7.48 (2H, m, aromatics), 7.68 (1H, broad t, NH). MS (ESI+) m/e 451 [M+H+].
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)([O-:17])=[O:16]
Reactant: Sc1ccncc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Sc1ccncc1
Yield: 57.4 %

Procedure:
A mixture of 4-mercaptopyridine (2.00 g, 18.0 mmol), 1-fluoro-2-nitrobenzene (2.54 g, 18.0 mmol) and potassium carbonate (2.49 g, 18.0 mmol) in DMF (15 mL) was stirred under reflux for 2 h. After removal of DMF, the residue was dissolved in DCM and washed with NaOH (5%, 3×20 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash Master chromatography of the crude product using DCM to DCM/MeOH 98:2 gradient as eluent gave 4-(2-nitrophenylsulfanyl)-pyridine (2.4 g, 57%) as a yellow solid, mp 119-122° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20](OS(C(F)(F)F)(=O)=O)[CH:21]=[N:22][CH:23]=1.C(OCC)(=O)C>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:19]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cncc(Cl)c2)cc1
Temperature: 60 °C
Yield: 65 %

Procedure:
Add 4-fluorophenylacetylene (1.0 g, 8.35 mmol), triethylamine (4 mL, 30 mmol), copper (I) iodide (76 mg, 0.40 mmol), and bis(triphenylphosphine)palladium (II) dichloride (140 mg, 0.20 mmol) to a solution of trifluoromethanesulfonic acid 5-chloropyridin-3-yl ester, (prepared as described in PREPARATION 25) in ethyl acetate (1.95 g, 7.5 mmol), (7 mL) under nitrogen and heat at 60° C. for 12 h. Concentrate and purify the residue by silica gel chromatography, eluting with dichloromethane to give the title compound as a white solid (1.12 g, 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[N:21]([CH:22]4[CH2:24][CH2:23]4)[CH:20]=[N:19][N:18]=3)[CH:12]=2)=[O:9])[CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:22]1([N:21]2[CH:20]=[N:19][N:18]=[C:17]2[C:13]2[CH:12]=[C:11]([NH:10][C:8]([C:4]3[CH:3]=[C:2]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH:7]=[CH:6][N:5]=3)=[O:9])[CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2cccnc2)ccn1
Temperature: 100 °C
Yield: 48.4 %

Procedure:
A suspension of 4-bromo-N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)picolinamide (120 mg, 0.31 mmol), 3-pyridine boronic acid (77 mg, 0.62 mmol), dppf(Pd)Cl2 (23 mg, 0.03 mmol), potassium carbonate (86 mg, 0.62 mmol) in degassed toluene (2 mL), degassed water (1 mL) and degassed ethanol (1 mL) was heated at 100° C. for 1 hour. The solvent was removed under reduced pressure and the residue purified by reverse-phase HPLC, to give N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-3,4′-bipyridine-2′-carboxamide as a white powder (58 mg, 0.15 mmol, 48% yield). C22H18N6O. 383.1 (M+1). 1H NMR (DMSO) d 10.98 (s, 1H), 9.12 (d, J=1.6 Hz, 1H), 8.87 (d, J=4.8 Hz, 1H), 8.72 (dd, J=4.8, 1.2 Hz, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=1.2 Hz, 1H), 8.34 (m, 1H), 8.11 (m, 2H), 7.69 (d, J=8.0 Hz, 1H), 7.59 (m, 2H), 3.66 (m, 1H), 1.09 (m, 2H), 0.94 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[SH:12][C:13]1[S:14][C:15]([SH:18])=[N:16][N:17]=1>C(O)(C)C>[C:6]1([O:5][CH2:1][CH:2]([OH:4])[CH2:3][S:12][C:13]2[S:14][C:15]([S:18][CH2:3][CH:2]([OH:4])[CH2:1][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Sc1nnc(S)s1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: OC(COc1ccccc1)CSc1nnc(SCC(O)COc2ccccc2)s1

Procedure:
Phenyl glycidyl ether (179.4 grams, 1.20 moles) and isopropanol (200 ml) were charged into the reaction vessel. 2,5-Dimercapto-1,3,4-thiadiazole (85 grams, 0.568 moles) was added in increments and with stirring. The reaction mixture was refluxed for 5 minutes. The solvent was stripped off by using a rotary evaporator at about 20 mm Hg and 115° C. The product solidified on cooling and was characterized by the infrared absorption bands at 3400, 3060, 2920, 1600, 1500, 1380, 1240, 1040, 750, and 690 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][N:4]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>C(Cl)Cl>[Si:18]([O:11][CH2:10][C@@H:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1)[OH:12])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ncc([C@@H](O)CO)cn1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: COc1ncc([C@@H](O)CO[Si](C)(C)C(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-1-(2-methoxypyrimidin-5-yl)ethane-1,2-diol (3.46 g, 20.3 mmol) and imidazole (3.08 g, 44.7 mmol) was dissolved in methylene chloride (40 mL). The mixture was cooled to 0° C. and tert-butyldimethylsilyl chloride (3.48 g, 22.4 mmol) dissolved in methylene chloride (40 mL) was added. The reaction was stirred for 30 minutes at 0° C. and then reacted at room temperature overnight. The mixture was treated with water (200 mL) and extracted with methylene chloride (2×200 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Li]CCCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([B:17]([OH:22])[OH:18])[S:8][C:7]=2[CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc2ccsc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(B(O)O)sc2c1
Temperature: 9 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 6-methoxybenzo[b]thiophene (Graham, S. L., et al. J. Med. Chem. 1989, 32,2548-2554) (18.13 g, 0.111 mol) in 150 mL of anhydrous THF at −60° C. was added n-BuLi (76.2 mL., 0.122 mol. 1.6 M solution in hexanes), dropwise via syringe. After stirring for 30 min, triisopropyl borate (28.2 ml. 0.122 mol) was introduced via syringe. The resulting mixture was allowed to gradually warm to 9° C. and then partitioned between 1.0 N HCl and EtOAc (300 mL each). The layers were separated, and the organicphase was dried over Na2SO4. Concentration in vacuo produced a white solit that was triturated from Et2O/hexanes. Filtration provided 16.4 g (71%) of 6-methoxybenzo[b]thiophene-2-boronic acid as a white solid.