Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([OH:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH2:25])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8].[OH-].[Na+:32].O.[Na+].O[CH2:36][S:37]([O-:40])(=[O:39])=[O:38]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([O-:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH:25][CH2:36][S:37]([OH:40])(=[O:39])=[O:38])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8].[Na+:32].[Na+:32].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([O-:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH:25][CH2:36][S:37]([OH:40])(=[O:39])=[O:38])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=S(=O)([O-])CO
Reactant: NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nnc(CNCS(=O)(=O)O)s3)CS[C@H]12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a suspension of 7-{2-(2-thienyl)acetamido}-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.39 g.) in water (27 ml.) was added 1 N aqueous sodium hydroxide solution (3 ml.) to dissolve. After hydroxymethanesulfonic acid sodium salt hydrate (456 mg.) was added to the resultant solution, the solution was stirred at room temperature for 4.5 hours, was lyophilized to give di-sodium 7-(2-thienyl)acetamido-3-(5-sulfomethylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate m.p. 112° to 120° C. (dec.).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[CH2:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N+:55]1([O-:60])[CH2:56][CH2:57][CH2:58][CH:59]=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:60][N:55]4[CH2:56][CH2:57][CH2:58][C@@H:59]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [O-][N+]1=CCCC1
Reactant: C=Cc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4CCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 62.6 %

Procedure:
To a solution of 1.291 g of 2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 100 ml of toluene is added 1.5 g of 3,4-Dihydro-2H-pyrrole 1-oxide and the reaction mixture heated at reflux for 6 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel by elution with 8:1 ethyl acetate-hexanes to give 0.906 g of the desired product as a white foam. FAB mass spec 812 (M+Na).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[C:17]([CH3:24])=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][OH:20]>>[OH:20][CH2:19][C:18]1[C:17]([CH3:24])=[C:16]([NH:15][C:12](=[O:13])[CH2:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1c(N)cccc1CO
Product: Cc1c(CO)cccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Yield: 27.1 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (2.0 g) and 3-amino-2-methylbenzyl alcohol (1.29 g). Silica gel chromatography, eluting with 5% ethylacetate in dichloromethane gave the title compound as a white solid (0.80 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([OH:40])=[O:39])[CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([OH:40])=[O:39])[CH2:33]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: O=C(O)C1CCCNC1
Product: O=C(O)C1CCCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)C1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl) benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and piperidine-3-carboxylic acid (125 mg; 0.97 mmol) to give Example 158 as a yellow solid. 1H NMR: (DMSO-d6, 400 MHz) δ 12.25 (1H, br s), 8.75 (2H, dd, J=4.5, 1.6 Hz), 7.97-7.88 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.7 Hz), 7.57-7.47 (4H, m), 3.59 (2H, t, J=14.7 Hz), 2.85 (1H, d, J=11.0 Hz), 2.68 (1H, d, J=11.2 Hz), 2.50-2.42 (1H, m), 2.28-1.95 (2H, m), 1.84 (1H, d, J=12.1 Hz), 1.68 (1H, dd, J=12.2, 4.7 Hz), 1.58-1.31 (2H, m). LC/MS (Method C): 526 (M+H)+. HPLC (Method F) Rt 2.83 min (Purity: 98.7%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:20]=3[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>C1(C)C=CC=CC=1>[Cl:1][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:20]=3[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=2)[NH:9][CH:10]=1
Reactant: CCOC(=O)c1ccc(F)cc1Oc1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(F)cc1Oc1ccc2[nH]cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Chloro-succinimide (160 mg) was added portionwise to a solution of EXAMPLE 265A (300 mg) in toluene (10 mL) and the mixture was stirred at room temperature for about two hours. The mixture was chromatographed on a silica gel column with 30% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [NH:1]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2]1.[F:24][C:25]([OH2+])([F:27])[F:26]>>[F:24][C:25]([F:27])([F:26])[N:1]1[CH2:23][CH2:22][N:21]([C:25]([F:27])([F:26])[F:24])[CH2:20][CH2:19][N:18]([C:25]([F:27])([F:26])[F:24])[CH2:17][CH2:16][N:15]([C:25]([F:27])([F:26])[F:24])[CH2:14][CH2:13][N:12]([C:25]([F:27])([F:26])[F:24])[CH2:11][CH2:10][CH2:9][N:8]([C:25]([F:27])([F:26])[F:24])[CH2:7][CH2:6][N:5]([C:25]([F:27])([F:26])[F:24])[CH2:4][CH2:3][CH2:2]1
Reactant: [OH2+]C(F)(F)F
Reactant: C1CNCCNCCCNCCNCCNCCNCCNC1
Product: FC(F)(F)N1CCCN(C(F)(F)F)CCN(C(F)(F)F)CCN(C(F)(F)F)CCN(C(F)(F)F)CCN(C(F)(F)F)CCCN(C(F)(F)F)CC1
Yield: 50.2 %

Procedure:
8 g (0.024 mol) of 1,5,8,12,15,18,21-Heptaazacyclotricosane and 90.9 g (0.168 mol) of the trifluoromethyl oxonium salt were refluxed in an argon atmosphere for 3 hours to produce 9.7 g of 1,5,8,12,15,18,21-Heptakis(trifluoromethyl)-1,5,8,12,15,18,21-heptaazacyclotricosane represented by Formula 12 below.
Reaction SMILES: C([O:4][C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=O)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17]C(=O)C2C=CC=CC=2)[C@H:6]1[O:7]C(=O)C1C=CC=CC=1)(=O)C.[C:38]1([OH:48])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1.B(F)(F)F>ClCCl>[O:29]([C:30]1[C:31]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:47]=[CH:38][CH:39]=1)[C@@H:28]1[O:7][C@H:6]([CH2:5][OH:4])[C@@H:16]([OH:17])[C@H:26]1[OH:27].[C:38]1([OH:48])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: FB(F)F
Agent: Oc1cccc2ccccc12
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](Oc2cccc3ccccc23)[C@H](O)[C@@H]1O

Procedure:
A solution 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (500 mg, 0.99 mmol), α-naphthol (428 mg, 3.00 mmol) and boron trifluoride diethyletherate (141 mg, 0.99 mmol. 125 μl) in dry dichloromethane (5 ml) was stirred at room temperature under argon for 16 hours. The mixture was worked up as for Stage 1 of Example 1 and purified by flash chromatography on silica gel (eluting with dichloromethane:hexanes, 3:2) to afford the title compound contaminated with α-naphthol. The latter was removed by dissolving the residue in ethyl acetate and washing with 10% aqueous sodium hydroxide solution, which after conventional processing, gave 136 mg, 23% of product as a yellow gum.
Reaction SMILES: O=[C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:4]2[CH2:3]1.P(Cl)(Cl)([Cl:16])=O.[CH:19]([N:22](CC)C(C)C)([CH3:21])[CH3:20]>>[Cl:16][C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:22][CH:19]([CH3:21])[CH3:20])=[O:13])=[C:4]2[CH:3]=1
Reactant: O=C1Cc2c(C(=O)O)cnn2C=N1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cnn2cnc(Cl)cc12
Yield: 90 %

Procedure:
A mixture of 5-oxo-4,5-dihydropyrazolo[1,5-c]pyrimidine-3-carboxylic acid (2.0 g, 10 mM, 1.0 equiv), 30 mL of phosphorus oxychloride (300 mM, 30 equiv) and N,N-diisopropylethylamine (8 mL, 40 mM, 4 equiv) was heated with stirring to reflux for 2 hours. The reaction mixture was cooled and concentrated under vacuum. The brown oil was taken up in dichloromethane and isopropylamine added (3 mL, 30 mM, 3 equiv). The reaction mixture was stirred 5 minutes then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and vacuum filtered through a pad of silica gel. The filtrate was concentrated and cooled and the crystallized product collected by filtration to give 2.31 g (90%) of 5-chloro-N-isopropylpyrazolo[1,5-c]pyrimidine-3-carboxamide. LCMS (ESI) m+H=239.1 (mono chlorinated isotope pattern) 1H NMR (400 MHz, DMSO-d6) δ: 9.33 (d, 1H), 8.60 (s, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 4.09 (m, 1H), 1.20 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.CC(O)=O.S(=O)(=O)(O)O.C1C(=O)N([I:33])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([I:33])[C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cccc(F)c2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1I
Reaction time: 7 h
Yield: 85.1 %

Procedure:
A round-bottom flask was charged with 2-chloro-3′-fluoro-5-methoxy-1,1′-biphenyl (1.288 g, 5.44 mmol), DCM (8.00 ml), AcOH (8.00 ml), and sulfuric acid (0.160 ml, 2.99 mmol) to give a clear solution. n-Iodosuccinimide (1.224 g, 5.44 mmol) was added in one portion to give a maroon-colored solution. After 7 h, the mixture was diluted with DCM, washed with water, washed with saturated aq. sodium thiosulfate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel column, 0-5% EtOAc/Heptane) give 2-chloro-3′-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (1.68 g, 4.63 mmol, 85% yield) as a clear oil. m/z (ESI) 362.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:10](=[O:12])[CH:11]=1.C1C(=O)N([Br:35])C(=O)C1>C(Cl)Cl>[Br:35][C:11]1[C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[CH:8]=[N:7][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)cc1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cooled (0° C.) solution of 3-[4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (5.76 g, 15.5 mmol) in DCM (35 mL) was added NBS (2.48 g, 13.9 mmol). Allowed reaction to warm to ambient temperature. After 5 h, cooled (0° C.) reaction mixture, filtered solid, washed with cold DCM and cold hexane, and dried in vacuo. Obtained product as orange solid (5.57 g, 80%). Used without further purification. 1H NMR (CD3OD/400 MHz) δ8.29 (s, 1H), 8.05 (m, 1H), 7.91 (s, 1H), 7.60 (q, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 6.99 (m, 2H), 5.57 (s, 2H), 2.17 (s, 3H). ESHRMS m/z 451.0095 (M+H calculated for C19H14BrF2N2O4 requires 451.0100).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl-].CS(O[CH2:21][CH2:22][NH+:23]([CH3:25])[CH3:24])(=O)=O.C(O)(=O)C>COCCOC>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C[NH+](C)CCOS(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(OCCN(C)C)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
20 g (0.12 mol) of ethyl 4-hydroxybenzoate were dissolved in 300 mL of ethylene glycol dimethyl ether in a nitrogen atmosphere. 11.6 g (0.29 mol) of 60% sodium hydroxide were added in portions over the course of 25 minutes while stirring at room temperature followed by heating to 50° C. and stirring for 1 hour. Moreover, 29.4 g (0.14 mol) of [2-(methanesulfonyloxy)ethyl]dimethylammonium chloride were added in portions over the course of 1 hour at the same temperature followed by additionally stirring for 2 hours. After adding 4 mL of acetic acid while cooling with ice, the precipitate that formed was filtered out. The filtrate was concentrated and ethyl acetate was added to the residue followed by extraction with 3% sulfuric acid. After washing the aqueous phase with ethyl acetate, potassium hydrogen carbonate was added to bring to pH8 followed by extraction with ethyl acetate. The organic layer was dried with magnesium sulfate followed by distilling off the solvent to obtain 26.3 g of the target substance (yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:5][C:4](=[O:6])[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[O:11][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1c(F)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2.6 g (16.7 mmol) of 2-fluoro-6-hydroxybenzoic acid and 6.90 g (50 mmol) of potassium carbonate in 15 mL DMF is slowly added 8.5 g (50 mmol) of benzyl bromide. The mixture is stirred at room temperature for 5 h. Another 1 g of benzyl bromide is added and the mixture is stirred at RT for 18 h. The mixture is poured into water and is extracted with ethyl acetate. The organic phase is washed (3×) with water and 1× with saturated NaCl. The solution is dried over sodium sulfate and the solvent removed under vacuum. The residual oil is purified by flash chromatography to give the product. This is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[O:11][CH3:12].Br[C:14]1C(OC)=CC=C2[C:15]=1C=CN2>>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:5]([CH:14]=[CH:15][NH:8]2)=[CH:6][CH:7]=1
Reactant: COc1ccc2[nH]ccc2c1Br
Reactant: COc1c(Br)cccc1[N+](=O)[O-]
Product: COc1c(Br)ccc2cc[nH]c12
Yield: 14 %

Procedure:
6-Bromo-7-methoxy-1H-indole CXXXVII (14% yield) was prepared from 2-bromo-6-nitro-anisole using the procedure described above for preparation of 4-bromo-5-methoxyindole XLVI (Example 12).
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7]>C1COCC1>[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][S:6]([NH2:1])(=[O:8])=[O:7]
Reactant: N
Reactant: CN(C)CCS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)CCS(N)(=O)=O

Procedure:
Ammonia was cautiously added to a cooled solution of the subtitle product of step ii) in THF (50 ml) and stirring maintained until all of the ammonia had evaporated before filtering off the product as a white solid. Yield: 0.88 g.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]2[C:6]([C:7](O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:7]1[CH:8]=[CH:9][N:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[N:12]2
Reactant: CCc1ccc2c(O)ccnc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1ccc2c(Cl)ccnc2n1
Yield: 83 %

Procedure:
The product from Example 3e (200 mg, 1.14 mmol) was treated with POCl3 following the procedure from Example 1d giving the title compound as a brown solid (183 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:32])=[O:31]
Reactant: COC(=O)c1ccccc1CSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 57.9 %

Procedure:
Following General Procedure B, the title compound (277 mg, 58%) was prepared from methyl 2-(((2-amino-4-chlorophenyl)thio)methyl)benzoate (300 mg, 0.98 mmol) and benzofuran-2-sulfonyl chloride (211 mg, 0.98 mmol) in pyridine (3 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1C1=CCC(=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1ncccc1C1=CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was prepared as a white solid from reductive amination of 4-(2-methoxy-pyridin-3-yl)-cyclohex-3-enone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N+:9]2[O-])([O-:3])=[O:2].C1(C)C(S(Cl)(=O)=[O:22])=CC=CC=1.C(N([CH2:31][CH3:32])CC)C>CCO>[CH2:31]([O:22][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[N:9]=1)[CH3:32]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cccc2c1ccc[n+]2[O-]
Reactant: CCN(CC)CC
Solvent: CCO
Product: CCOc1ccc2c([N+](=O)[O-])cccc2n1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A suspension of 1 g (5 mmol) of 5-nitroquinoline-1-oxide, 1.23 g (6.4 mmol) of toluenesulfonic acid chloride and 1.4 ml (9.9 mmol) of triethylamine in 30 ml of EtOH is stirred for 60 hours at room temperature. The solid is suctioned off and washed with EtOH: 870 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].C(N(C(C)C)CC)(C)C.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(F)cc2[N+](=O)[O-])CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1-Chloro-2,5-difluoro-4-nitrobenzene (D1) (1.18 mmol, 228 mg) was dissolved in dry dimethylformamide (2 ml) and diisopropylethylamine (1 eq., 1.18 mmol, 0.209 ml), 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 1.18 mmol, 236 mg) were added at room temperature and the mixture was stirred at 50° C. overnight. The crude mixture was then cooled to room temperature and water (150 ml) was added; the aqueous solution was extracted with ethyl acetate (2×); organics were alternatively washed with brine and water (2×). The organics were combined dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, 340 mg, 80%, bright orange solid, M+−H=372.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5].C(N(CC)CC)C>C1COCC1>[CH:3]([S:4]([CH2:7][CH2:8][C:9]([F:27])([F:26])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])(=[O:6])=[O:5])=[CH2:2]
Reactant: O=S(=O)(CCCl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
2-(Perfluorohexyl)ethanyl 2-chloroethanyl sulfone (4.75 g, 10.0 mmole) was dissolved in 25 ml of THF at 30°, and triethylamine (1.52 g, 15.0 mmole) in 10 ml of THF was added in one minute. A white precipitate formed, and was filtered (1.37 g). The solvent was stripped carefully, as some foaming occurred.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH:12]=O)[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH:12]=[CH:17][N+:14]([O-:16])=[O:15])[CH3:2]
Reactant: CCc1c(C=O)[nH]c2ccccc12
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1c(C=C[N+](=O)[O-])[nH]c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 3-ethyl-2-indolecarbaldehyde (4.0 g) and nitromethane (4.93 g) in methanol (80 ml) was added dropwise 50% aqueous sodium hydroxide solution at 0~-5° C. for an hour. After being stirred at the same temperature for an hour and at room temperature an hour. The mixture was poured into a mixture of chilled water and 12N hydrochloric acid (4:1, 500 ml). The precipitates were collected, washed with water and dried to give 3-ethyl-2-(2-nitrovinyl)indole.