Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[CH3:27]>O1CCCC1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=[O:25])=[O:24])=[CH:19][C:18]=1[CH3:27]
Reactant: C1COCCN1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)N2CCOCC2)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisopropylethylamine (8.25 mL, 46.4 mmol) was added at 0° C. to a stirred solution of morpholine (1.62 g, 18.5 mmol) in tetrahydrofuran (40 mL) and the reaction mixture was stirred at room temperature for 15 minutes. A 0.1 M solution of 4-bromo-3-methyl-benzenesulfonyl chloride (5.0 g, 19 mmol) in tetrahydrofuran was added at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with ethyl acetate, and the inorganic salts were filtered through a celite bed. The filtrate was washed with 2 N aqueous HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 4-(4-bromo-3-methyl-benzenesulfonyl)-morpholine, which was used in subsequent reactions without further purification. MS cald. for C11H14BrNO3S [M+] 320.2, obsd. 321.9.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4]>FC(F)(F)C(O)=O.ClCCl>[F:34][C:2]([F:1])([F:35])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H]1CC[C@H](c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of 16.4 g of trans-4-{4-[benzyl(tert-butoxycarbonyl)amino]cyclohexyl}phenyl trifluoromethanesulfonate (32 mmol) in a mixture of trifluoroacetic acid (150 ml) and dichloromethane (900 ml) is stirred for 1 h 30. The solvents are evaporated under reduced pressure and then water, ethyl acetate and an aqueous ammonia solution are added. The organic phase is washed once with water and dried over sodium sulfate. trans-4-[4-(Benzylamino)cyclohexyl]-phenyl trifluoromethanesulfonate is obtained in the form of crystals (12.96 g, 98%) after evaporation of the solvents under reduced pressure. [M+H+]=414.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])/[CH:55]=[C:50]2\[S:51][C:52]([CH3:54])=[N:53][N:49]\2[CH2:45][CH2:46][CH2:47][CH3:48])[CH:8]=[CH:9][CH:10]=1
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-bromobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.86-0.96 (m, 3 H) 1.27-1.41 (m, 2 H) 1.69-1.78 (m, 2 H) 2.47-2.49 (m, 3 H) 4.29 (t, 2 H) 6.77 (s, 1 H) 7.36-7.48 (m, 1 H) 7.64-7.70 (m, 1 H) 7.98-8.04 (m, 1 H) 8.12-8.19 (m, 1 H); MS (ESI) m/z 353 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:4]=1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:35][C:36](Cl)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:35][C:36]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[N:6][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.22) (135 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (20 mg, 7%). MS (ISN) 569.2 [(M−H)−]; mp 168° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:15]=[C:14](S(C)(=O)=O)[N:13]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:15]=[C:14]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(S(C)(=O)=O)n1
Product: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(Nc2ccccc2)n1

Procedure:
Compounds of Formula I are alternatively prepared by the treatment of 4-(4-fluoronaphth-1-yl)-6-isopropyl-2-methanesulfonylpyrimidine with aniline in the absence of solvent at a higher temperatures of 120° C. to afford 4-(4-fluoronaphth-1-yl)-6-isopropyl-2-phenylaminopyrimidine, m.p. 85.7-86.3° C.
Reaction SMILES: [Mg].II.[CH:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21].Cl>O1CCCC1>[O:10]([C:11]1[CH:16]=[CH:15][C:14]([C:20](=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18])=[CH:13][CH:12]=1)[C:7]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask containing 33.6 g. of magnesium and a few crystals of iodine, is added 50 to 70 ml. of a solution of 300 g. of 4-bromodiphenyl ether in 500 ml. of absolute tetrahydrofuran. The remainder of the solution is added as needed to maintain a gentle reflux and the resulting mixture heated to reflux for 30 minutes. The resulting mixture is then added to a solution of trimethylacetyl chloride in 500 ml. of absolute tetrahydrofuran at a rate so as to maintain a temperature of from 40° to 50° C. The resulting mixture is then stirred at ambient temperature for 1 hour. 200 ml. of 2N. hydrochloric acid is then added. The organic layer is washed twice with 1 liter of 2N. sodium carbonate solution, dried and evaporated in vacuo to a liquid. The liquid thus obtained is distilled under reduced pressure to obtain p-phenoxypivalophenone, b.p. 136°-139° C. at 0.1 mm/Hg.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[CH2:5][C:3](=[O:4])[CH2:2]1.[H-].[Na+].[O:10]1[CH:16]2[CH:11]1[C:12]([CH3:24])([CH3:23])[O:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:15]=12>O1CCCC1.[Cu]Br>[OH:10][C@H:11]1[C@H:16]([O:4][C:3]2[CH2:2][CH2:1][C:6](=[O:7])[CH:5]=2)[C:15]2[CH:17]=[C:18]([C:21]#[N:22])[CH:19]=[CH:20][C:14]=2[O:13][C:12]1([CH3:24])[CH3:23]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=C1CCC(=O)C1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)CC2)[C@@H]1O
Reaction time: 67 h

Procedure:
10.1 g of 1,3-cyclopentadione are dissolved in 1000 ml of tetrahydrofuran under a protective gas, and 2.7 g of sodium hydride (80%) are slowly added. After half an hour, 18.5 g copper(I)bromide.dimethylsulphide complex were added to this mixture. To this reaction solution are added in drops 12.1 g of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (J. M. Evans et al., J. Med. Chem. 26, 1582 [1983]) in 100 ml of tetrahydrofuran. After 67 hours, the reaction is quenched with water, and the reaction solution is subsequently partitioned between dichloromethane and water. Drying of the organic phase over sodium sulphate, filtration and concentration on a rotary evaporator yields a yellowish mass, which is purified by flash-chromatography (dichlormethane, 1% methanol). Recrystallisation from dichloromethane/ethanol yields white crystals having a m.p. of 199°-201° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31]O)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:31][N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1ccc(CO)cc1OC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1OC
Reaction time: 0.08 h

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (275 mg, 1 mmol), (3,4-dimethoxyphenyl)methanol (201 mg, 1.2 mmol), N,N,N,N-tetramethylazodicarboxamide (344 mg, 2 mmol) were dissolved in 2 mL anhydrous THF. Tributylphosphine (404 mg, 2 mmol) was added and the reaction mixture was placed in a microwave reactor for 5 minutes at 90° C. The reaction was filtered, concentrated and purified by HPLC (10-95% Acetonitrile/Water, 25 minutes) to afford the title compound. Yield: 25 mg, 6%. 1NMR (DMSO, 400 MHz): δ2.119 (s, 3H), 2.385 (s, 3H), 3.724 (J=6.4 d, 6H), 3.946 (s, 2H), 4.435 (s, 2H), 5.178 (s, 2H), 6.885 (m, 3H), 7.776 (s, 1H), 8.166 (s, 1H). MS M+H calculated 426.1; found 426.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 uM.
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:13]=[C:12]([O:14]C(=O)C)[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH:6]C(=O)C>C(O)C>[ClH:1].[I:2][C:3]1[CH:13]=[C:12]([OH:14])[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH2:6]
Reactant: COc1cc(CNC(C)=O)c(I)cc1OC(C)=O
Agent: Cl
Solvent: CCO
Product: COc1cc(CN)c(I)cc1O

Procedure:
37% hydrochloric acid (0.2 ml) was added to a solution of 2-iodo-4-acetyloxy-5-methoxy-N-acetyl-benzylamine (0.1 g, 0.27 mmol) in abs. ethanol (5 ml) and the mixture was refluxed for 12 hours. After cooling, the solvent was evaporated off under reduced pressure and the residue was recrystallized from dry acetone to afford the title compound as pale yellow solid in quantitative yield.
Reaction SMILES: [H-].[Na+].[CH3:3]CCCCC.CI.[OH:11][C@@H:12]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:13]([CH3:16])[CH:14]=[CH2:15]>CN(C)C=O>[CH3:3][O:11][C@@H:12]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C@@H:13]([CH3:16])[CH:14]=[CH2:15]
Reactant: C=C[C@H](C)[C@@H](O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=C[C@H](C)[C@@H](OC)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
Sodium hydride (60% in mineral oil, 3.38 g, 84.4 mmol, 1.1 eq.) was combined with hexane (40 mL), and the mixture was subjected to rapid mechanical stirring for 5 minutes. The solids were allowed to settle and the hexane was removed. This procedure was repeated twice to remove mineral oil. N,N-Dimethylformamide (59 mL, 1.3 M) was added and the mixture was cooled to 0° C.; methyl iodide (5 mL; 81 mmol, 1.05 eq.) was then added drop-wise, followed by drop-wise addition of a solution of #9 (19.6 g, 76.8 mmol, 1 eq.) in N,N-dimethylformamide (59 mL) over 5 minutes, while keeping the temperature between 0° C. and 5° C. The reaction was stirred at 0° C. for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (150 mL), poured into aqueous sodium chloride solution (5% wt, 300 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with 10% aqueous sodium chloride solution (2×300 mL), washed with water (200 mL), and concentrated in vacuo. The resulting water-wet oil was reconcentrated from ethyl acetate (150 mL) and purified by silica gel chromatography (Gradient: 2% to 10% ethyl acetate in heptane) to afford #10 (15.0 g, 73%) as a colorless oil. 1H NMR (400 MHz, CDCl3), presumed to be a mixture of rotamers: δ 5.60-5.83 (m, 1H), 4.91-5.06 (m, 2H), 3.81-3.95 (br m, 1H), 3.43 (s, 3H), 3.36-3.61 (m, 2H), 3.19-3.31 (m, 1H), 2.09-2.21 (m, 1H), 1.86-2.02 (br m, 2H), 1.62-1.85 (br m, 2H), 1.47 and 1.49 (2 s, total 9H), 1.09 (d, J=6.6 Hz, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:27]([O:29]C)=[O:28])[CH2:4][C@@H:3]1[OH:31].[ClH:32]>O1CCOCC1.O>[ClH:32].[OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:27]([OH:29])=[O:28])[CH2:4][C@@H:3]1[OH:31]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CCN[C@@H]1C[C@]2(C)[C@@H](C(=O)O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)[C@@H](O)C[C@]3(C)[C@H]21

Procedure:
Methyl 2β,3α-dihydroxy-11α-(3-methylbutylamino)5α-androstane-17β-carboxylate (750 mg) in dioxan (20 ml) was treated with concentrated hydrochloric acid (3 ml) and water (10 ml) and heated on a steam bath for 5 days. The cooled mixture was diluted with water (200 ml) and acidified to pH 1 with dilute hydrochloric acid and extracted with ethyl acetate (3×). The extracts were washed with brine, dried and evaporated to give a foam (426 mg). This was purified by preparative t.l.c. in chloroform/methanol (4:1) to give the title compound (146 mg), [α]D +17° (in dimethyl sulphoxide).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C1CCCCC1
Reactant: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Yield: 99 %

Procedure:
To a solution of (3S)-1-Cbz-3-aminopyrrolidine (4.11 g, 16.0 mmol) and cyclohexanone (2.36 g, 24.0 mmol) in DCE (50 mL) was slowly added NaBH(OAc)3 (6.78 g, 32.0 mmol) at rt. The reaction mixture was quenched after 4 h using a saturated aqueous NaHCO3 solution and extracted with DCM followed by EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc/Hex=2/1) to give the title compound (4.79 g, 98.1%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:12]([CH2:15][C:16]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1)=[O:17])(=[O:14])=[O:13])=[CH:5][NH:6]2.[H-].[Na+].[Br:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>CN(C=O)C>[Br:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:6]1[C:7]2[C:3](=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=2)[C:4]([S:12]([CH2:15][C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[O:17])(=[O:14])=[O:13])=[CH:5]1
Reactant: Cc1cc(NC(=O)CS(=O)(=O)c2c[nH]c3cc(F)cc(F)c23)no1
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)CS(=O)(=O)c2cn(Cc3cccc(Br)c3)c3cc(F)cc(F)c23)no1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
In a 5 mL microwave vial, 2-((4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide (62.0 mg, 0.174 mmol) from Step C was dissolved in DMF (3 mL) and cooled to 0° C. Sodium hydride (60% by weight, 8.0 mg, 0.35 mmol) was then added in one portion and the reaction mixture was vigorously stirred at 0° C. for 15 minutes. 3-bromo-benzylbromide (44.0 mg, 0.174 mmol) was added in one portion and the reaction mixture was stirred while being allowed to warm to ambient temperature over 3 hours. The reaction mixture was quenched with water (2 mL) and the solution was extracted with ethyl acetate (3×4 mL). The organics were combined, dried over magnesium sulfate, and concentrated in vacuo to give an oily residue which was purified on a silica gel column (0-50% ethyl acetate:hexanes over 19 min) to yield the title compound (45 mg, 0.09 mmol, 50% yield). LCMS>98% 220 nm, RT=0.84 min, m/z=524 ([79Br]m+1), 526 ([81Br]m+1). 1H NMR (400 MHz, DMSOD6) 11.32 (s, 1H), 8.39 (s, 1H), 7.59 (s, 1H), 7.52 (m, 2H), 7.29 (t, J=7.6 Hz, 1H), 7.17-7.24 (m, 2H), 6.52 (s, 1H), 5.53 (s, 2H), 4.47 (s, 2H), 2.36 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[C:3]=1[C:15]#[N:16].C(N(CC)CC)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:15]([C:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:13]=[CH:14][C:2]=1[NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])#[N:16]
Reactant: N#Cc1c(N)ccc2sc3ccccc3c12
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc2sc3ccccc3c2c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-amino-1-cyanodibenzothiophene (J. Heterocyclyl. Chem., 1977, 14(7), 1209-1214; 0.043 g, 0.19 mmol), triethylamine (0.04 g, 0.4 mmol) and pivaloyl chloride (0.05 g, 0.4 mmol) in DCM (2 ml) was stirred at ambient temperature for 24 hours. The resultant mixture was extracted with water and the organic phase reduced to a residue which was triturated with ether/iso-hexane to give the title compound. NMR: 9.78 (s, 1H), 8.81 (m, 1H), 8.38 (d, 1H), 8.16 (m, 1H), 7.58 (m, 2H), 7.48 (d, 1H), 1.18 (s, 9H); m/z 307 (M−H)−.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=1[CH3:20].O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:20][C:12]1[C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: COc1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc([N+](=O)[O-])c1CBr
Temperature: 25 °C
Yield: 86.7 %

Procedure:
N-bromosuccinimide (590 mg, 3.30 mmol) was added to a solution of 1-methoxy-2-methyl-3-nitro-benzene (500 mg, 3.0 mmol) in carbon tetrachloride (5 mL) followed by a catalytic amount of dibenzoyl peroxide (25 mg). The reaction mixture was heated at reflux for 3 h then cooled to room temperature and poured into water. The organic phase was separated, washed with water (2×20 mL), dried over the anhydrous sodium sulfate and concentrated in vacuo to afford 2-bromomethyl-1-methoxy-3-nitro-benzene (640 mg, 86%) as a solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:17][C:18]([NH:24][C:25]([O:27][CH3:28])=[O:26])=[N:19][C:20]([O:22][CH3:23])=[O:21])=[O:2].[OH:29]O>C(OC(=O)C)(=O)C>[CH:1]([NH:3][C:4]1[CH:9]=[C:8]([S:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:29])[CH:7]=[CH:6][C:5]=1[NH:17][C:18]([NH:24][C:25]([O:27][CH3:28])=[O:26])=[N:19][C:20]([O:22][CH3:23])=[O:21])=[O:2]
Reactant: OO
Reactant: COC(=O)N=C(NC(=O)OC)Nc1ccc(Sc2ccccc2)cc1NC=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)N=C(NC(=O)OC)Nc1ccc(S(=O)c2ccccc2)cc1NC=O
Reaction time: 4 h

Procedure:
10.9 g of N-(2-formamido-4-phenylthiophenyl)-N',N"-bis(carbomethoxy)guanidine (Example 1) are dissolved in 200 ml of acetic anhydride. 25.8 ml of hydrogen peroxide (30% strength) are added and the mixture is stirred for 4 hours at 20° and is then concentrated in vacuo, and the residue is recrystallized from ethyl acetate to yield N-(2-formamido-4-phenylsulfinylphenyl)-N',N"-bis(carbomethoxy)guanidine (7.37 g), m.p. 168° C. (dec.).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>C(O)C>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: OCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc(OCCCCCCO)cc1
Yield: 55.7 %

Procedure:
A solution of potassium hydroxide (13.2 g) and 4-hydroxybenzaldehyde (20.6 g, 169 mmol) in ethanol (320 ml) was refluxed for 30 min. 6-Bromohexanol (24.5 g, 135 mmol) dissolved in ethanol (30 ml) were added and the reaction mixture was refluxed for 16 h. The solvent was then removed in vacuo. Dichloromethane (400 ml) was added no the residue. The organic layer was washed with aqueous sodium hydroxide (1 M, 300 ml), water (500 ml) and brine (250 ml), filtered, dried over anhydrous sodium sulfate and concentrated in vacuo. Recritstallisation of the residue from dichloromethane/petroleum ether yielded (13) as a pale yellow solid (16.7 g, 45%). The analytical data was in accordance with that reported by C. Noel, C. Friedrich, V. Leonard, P. LeBarney, G. Ravaux, and J. C. Dubois, Makromol. Chem., Macromol. Symp., 1989, 24, 283.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([I:11])=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH:15]([CH3:17])[CH3:16]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[N:9][N:10]([CH:15]([CH3:17])[CH3:16])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]nc(I)c12
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(I)c2c(Cl)nccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (103) (50 mg, 0.179 mmol) in DMF (1 mL) was cooled to 0° C., NaH (8.6 mg, 1.2 eq, 0.215 mmol) was added slowly and then 2-bromopropane was added dropwise. The solution was stirred overnight at room temperature. The mixture was concentrated in vacuo. The crude product was then purified by column chromatography using a gradient of CH2Cl2 in hexanes to afford 4-chloro-3-iodo-1-isopropyl-1H-pyrazolo[4,3-c]pyridine (301) (30 mg, 53% yield) as a white solid.