Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:29])=[CH:5][CH2:6][O:7][C:8]1[C:17]([C:18](=[O:20])[CH3:19])=[C:16]2[C:11]([C:12](=[O:28])[C:13]([CH3:27])=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:15]2)=[CH:10][CH:9]=1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>C(O)C.O>[CH3:27][C:13]1[C:12](=[O:28])[C:11]2[C:16](=[C:17]([C:18](=[O:20])[CH:19]=[CH:35][C:34]3[CH:37]=[CH:38][C:31]([Cl:30])=[CH:32][CH:33]=3)[C:8]([O:7][CH2:6][CH:5]=[C:4]([CH3:29])[CH3:3])=[CH:9][CH:10]=2)[O:15][C:14]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c(C)c(-c3ccccc3)oc12
Reactant: O=Cc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(3-methylbut-2-enyloxy)-8-acetyl-3-methylflavone (2.71 g, 0.0075 mol) and 4-chloro-benzaldehyde (1.05 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.9 g product m.p. 130-133° C., 1H-NMR (CDCl3) δ:1.69 (s, 3H), 1.72 (s, 3H), 2.19 (s, 3H), 4.65 (d. 2H), 5.31 (m, 1H), 6.97-8.42 (m, 13H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1)[C:6]([O:8][CH3:9])=[O:7]>C(O)C.C(OCC)(=O)C>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]2[N:16]=[CH:15][N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])[C:18]=2[CH:19]=1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc([N+](=O)[O-])cc32)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(Cn2cnc3ccc(N)cc32)c(OC)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A solution of (K) (0.77 g.) in anhydrous ethanol (23 ml.) was treated with stannous chloride dihydrate (2.6 g.). The mixture was stirred for 18 hours at 80° C. and then diluted with ethyl acetate. This mixture was washed successively with saturated sodium bicarbonate solution, water, and brine, then dried (MgSO4) and evaporated to give methyl 4-(6-aminobenzimidazol-1-ylmethyl)-3-methoxybenzoate (J) (0.63 g., 90%): partial NMR: 3.4 (br s, 2 H, NH2), 5.2 (s,2 H, NCH2).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[F:39])[CH:34]=O.O>C1COCC1>[F:39][C:38]1[CH:37]=[CH:36][C:33]([CH:34]=[CH:8][O:9][CH3:10])=[CH:32][C:31]=1[F:30]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 46.2 %

Procedure:
Potassium tert butoxide (11 g, 0.098 mol) was added to methoxymethyl triphenyl phosphonium chloride (31.12 g, 0.091 mol) in 150 ml of dry THF at −30° C. under argon atmosphere and stirred for 1 h. 3,4-difluorobenzaldehyde (10 g, 0.07 mol) in 60 ml of THF was added dropwise at the same temperature and stirring continued for 3 h at room temperature. The reaction mixture was treated with 100 ml water, 150 ml petroleum ether and filtered through celite. Organic layer was separated and aq. layer was extracted with petroleum ether (2×100 ml). Combined organic layer was washed with brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by purification over silica gel using petroleum ether as eluent afforded (5.5 g) of the sub-titles compound as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[Br:12].[Cl:13]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([Cl:13])=[CH:4][C:3]=1[Br:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(Br)c(N)n1
Solvent: CC(=O)O
Product: COC(=O)c1nc(N)c(Br)cc1Cl
Yield: 95.5 %

Procedure:
To a solution methyl 6-amino-5-bromopyridine-2-carboxylate (20.04 g) in acetic acid (900 ml) was added N-chlorosuccinimide (13.96 g) and the resultant solution was heated to 120° C. for 1 hour. The solution was then evaporated and treated with excess aqueous sodium bicarbonate and extracted with dichloromethane. The organic fraction was dried and evaporated to give the product (21.98 g).
Reaction SMILES: BrCC1C=C(C=CC=1)[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:19]=[C:20]([CH:46]=[CH:47][C:48]=1OC)[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][C:34](=[CH:37][C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=3[F:45])[CH2:33][CH2:32]2)=[O:30])[CH2:24][CH2:23]1.O>CN(C=O)C>[C:6]([C:18]1[CH:19]=[C:20]([CH:46]=[CH:47][CH:48]=1)[CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][C:34](=[CH:37][C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=3[F:45])[CH2:33][CH2:32]2)=[O:30])[CH2:26][CH2:27]1)#[N:7]
Reactant: N#Cc1cccc(CBr)c1
Reactant: COc1ccc(CN2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(CN2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
3-Bromomethylbenzonitrile (160 mg, 0.81 mmol) was dissolved in DMF (3.0 mL), and potassium carbonate (220 mg, 1.62 mmol) and the compound (300 mg, 0.81 mmol) obtained in Example 36 (1) were added thereto, followed by stirring overnight while heating at room temperature. Water was added to the reaction mixture, and after extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:200), thereby giving the title compound (151 mg, 42%) as a white solid.
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]([CH2:17][CH3:18])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH3:4].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>N1C=CC=CC=1>[CH2:17]([N:5]([CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:14][CH:15]=1)[CH3:18]
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)CCCOc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 6.00 g (20.3 mmol) of 4-[3-(diethylamino)propoxy)benzenamine dihydrochloride in 50 mL of pyridine under a nitrogen atmosphere and cooled to ca -10° C. add 2.0 mL (25.4 mmol) of methanesulfonyl chloride dropwise. Maintain the temperature below 0° C. during the addition. Stir the reaction mixture at ambient temperature for 5 h then add 10 mL of H2O. Evaporate the solvent in vacuo and dissolve the residue in 50 mL of H2O (pH=ca. 3). Extract the aqueous solution with 2×100 mL of diethyl ether. Adjust the pH of the aqueous solution to pH=13 with 20% aqueous sodium hydroxide solution and extract this solution with 3×50 mL of methylene chloride. Adjust the pH of the aqueous solution to pH=8.5 with concentrated hydrochloric acid and saturate the solution with sodium chloride. Extract the mixture with 3×100 mL of methylene chloride. Wash the organic extracts with 25 mL of saturated aqueous sodium chloride solution, combine the extracts and dry over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35](Cl)[N:34]=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=4)[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:34]=[CH:33][N:32]=1
Reactant: COc1ccc(Sc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)cc1F
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Sc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)cc1F
Yield: 69.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((3-fluoro-4-methoxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (203 mg, 0.43 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (102 mg, 0.66 mmol) and DIEA (230 μl, 1.32 mmol) in 10 ml of tert-BuOH were heated at 80° C. for 72 h. After evaporation of the solvent under reduced pressure, the residue (158 mg, 35% yield) was used in the next synthetic step without further purification. Purity 50%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH:39]([F:41])[F:40])[CH:29]=2)[CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[N:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:50])C=1>>[CH2:1]([NH:8][C:9]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:36])[F:37])=[C:30]([O:38][CH:39]([F:41])[F:40])[CH:29]=2)[CH2:21][C:22]2[CH:23]=[CH:24][N+:25]([O-:50])=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)=[N:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CN=C(NCc1ccccc1)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: N#CN=C(NCc1ccccc1)Nc1ccc([C@@H](Cc2cc[n+]([O-])cc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1

Procedure:
From the compound of Example 11 (340 mg, 0.62 mmol) and 50% m-chloroperbenzoic acid as a white solid (200 mg). 1Hnmr (300 MHz, CDCl3) δ 3.27 (2H, d, J 8.0 Hz), 4.14 (1H, t, J 7.86 Hz), 4.48 (2H, d, J 5.72 Hz), 5.29 (1H, br), 6.48 (2H, t, J 73.49 Hz), 6.85 (2H, d, J 7.02 Hz), 7.00 (1H, dd, J 2.19, 8.43 Hz), 7.06 (1H, br), 7.12-7.34 (1OH, c), 7.50 (1H, br) and 7.98 (2H, d, J 7.03 Hz). m/z (ESI, 60V) 580 (MH+, 85), 538 (100), 429 (41).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[S:15][C:14]([CH2:16][N:17]2[CH2:35][CH2:34][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH3:33])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][CH2:10][C:11]1[S:15][C:14]([CH2:16][N:17]2[CH2:18][CH2:19][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH3:33])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:34][CH2:35]2)=[CH:13][CH:12]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(Cc4ccc(CCO[Si](C)(C)C(C)(C)C)s4)CC3)C2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4ccc(CCO)s4)CC3)C2)cs1
Reaction time: 0.5 h

Procedure:
A solution of (9-((5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (example 14, step b) (0.3 g) in THF (5 mL) was treated dropwise with a solution of tetrabutylammonium fluoride (1M in THF, 0.672 mL). The mixture was allowed to stand at 20° C. for 30 minutes. The solvents were evaporated using a stream of nitrogen and the residue was purified by flash silica chromatography, elution gradient 1% triethylamine and 2.5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.187 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(OCCO)C>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:23]2[C:32]3[C:27](=[CH:28][N:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: Clc1nccc2cnccc12
Solvent: CCOCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(Nc2nccc3cnccc23)cc1)NC(=O)OC(C)(C)C
Yield: 46.7 %

Procedure:
(S)-3-(4-Amino-phenyl)-2-tert-butoxycarbonylamino propionic acid methyl ester (574 mg, 1.95 mmol), 1-Chloro-2,6-naphthyridine (350 mg, 2.13 mmol) (prepared according to the method of Van der Plas, H. C. et al J. Heterocyclic Chem. 1981, 18, 1349) and DIPEA (372 μl, 2.13 mmol) in 2-ethoxyethanol (0.5 ml) were stirred at 130° C. under N2 overnight. The reaction mixture was partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (30 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were dried (MgSO4) and the solvents eliminated in vacuo. The residue was purified by flash chromatography (5:1 to 1:1 hexanes/EtOAc) to give (S)-2-tert-butoxycarbonylamino-3-[4-([2,6]naphthyridin-1-ylamino)phenyl] propionic acid methyl ester (385 mg, 47%) as an orange foam.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:20])[C:15](=[CH:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.O>[N+](C)([O-])=O>[O:20]=[C:14]1[C:11]2[C:10](=[CH:9][C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])=[C:2]([Cl:1])[C:12]=2[Cl:13])[CH:18]([CH3:19])[CH:15]1[CH2:16][CH3:17]
Reactant: CC=C(CC)C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCC1C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1C
Temperature: 60 °C
Yield: 65 %

Procedure:
[2,3-Dichloro-4-(2-ethylidenebutyryl)phenoxy]acetic acid (22.5 g.) is added with stirring to concentrated sulfuric acid (88 ml.) and heated at 60° C. for six hours. The reaction mixture is then cooled and poured into a mixture of ice and water (1 liter). The crude product which separates is ground in a mortar with water (100 ml.), filtered, washed with water and dried. There is thus obtained 14.5 g. (65% yield) of (1-oxo-2-ethyl-3-methyl-6,7-dichloro-5-indanyloxy)acetic acid, which after recrystallization from nitromethane (75 ml.) melts at 167°-168° C.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[C:8]([O:16][CH2:17][CH2:18][O:19][C:20](ON1C(=O)CCC1=O)=[O:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:8]([O:16][CH2:17][CH2:18][O:19][C:20]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:21])=[O:15])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC1(C(=O)O)CC1
Reactant: O=C(OCCOC(=O)c1ccccc1)ON1C(=O)CCC1=O
Product: O=C(NC1(C(=O)O)CC1)OCCOC(=O)c1ccccc1
Yield: 38.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (121 mg, 1.1 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl benzoate (341 mg, 1.0 mmol) were reacted to provide 113 mg (35% yield) of the title compound (4) as a white powder after work-up and mass-guided preparative HPLC purification. M.p.: 173.8-175.8° C. 1H NMR (CD3CN, 400 MHz): δ=8.00 (d, 2H), 7.61 (t, 1H), 7.50 (t, 2H), 6.99 (q, 1H), 6.31 (s, 0.8H), 6.01 (br s, 0.2H), 1.60 (d, 3H), 1.42 (m, 2H), 1.09 (m, 2H). MS (ESI) m/z 294.10 (M+H)+; 311.12 (M+NH4)+; 316.11 (M+Na)+; 292.12 (M−H)−.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C@H:57]([NH2:59])[CH3:58])=[CH:53][CH:52]=1>>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:59][C@@H:57]([C:54]2[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=2)[CH3:58])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:37])=[O:38])[CH:27]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(F)cc1

Procedure:
(R)-4-Chloro-N-[1-(4-fluororhenyl)ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide. The title compound was prepared from the HATU-mediated coupling of 4-chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 3, Step B) and (R)-1-(4-fluorophenyl)ethylamine hydrochloride and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H18ClFN4O3S, 484.1; m/z found, 483 [M−H]−. HPLC (reverse phase): RT=9.95 min. 1H NMR (500 MHz, CDCl3): 11.40 (s, 1H), 8.84 (d, J=1.8 Hz, 1H), 8.77 (d, J=1.8 Hz, 1H), 8.57 (dd, J=7.4, 1.4 Hz, 1H), 8.31 (dd, J=7.4, 1.4 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.30-7.27 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.08-7.04 (m, 2H), 6.91 (dd, J=8.4, 2.0 Hz, 1H), 6.11 (br d, J=6.5 Hz, 1H), 5.24-5.20 (m, 1H), 1.53 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3](=[O:11])O1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1>C(Cl)Cl>[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[N:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:3](=[O:11])[CH2:4][C:5]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:1]2=[O:12])[CH2:19][CH2:20]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Solvent: ClCCl
Product: O=C1Cc2ccccc2C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mol of 2-benzopyran-1,3(4H)dione and 0.02 mol of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine are heated at 160°-170° C. for 1 hours under an atmosphere of N2, with stirring. The mixture is then allowed to cool and the substance is dissolved in methylene chloride. The substance is purified over a silica gel column (mobile phase: CH2Cl2 /iprOH (10:0.5)).
Reaction SMILES: [CH2:1]([N:4]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[S:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:18][CH2:17][C@@H:16](O)[C:15]2=[O:20])=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][CH:60]=1)[NH:57][CH2:56][CH2:55][CH2:54]2>C(Cl)Cl>[CH2:1]([N:4]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[S:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:18][CH2:17][C@H:16]([N:57]3[C:58]4[C:53](=[CH:52][C:51]([Cl:50])=[CH:60][CH:59]=4)[CH2:54][CH2:55][CH2:56]3)[C:15]2=[O:20])=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: Clc1ccc2c(c1)CCCN2
Reactant: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O)C2=O)nc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@H](N3CCCc4cc(Cl)ccc43)C2=O)nc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
Prepared using General Procedure 4, Method A. To a stirring solution of (R)-N-allyl-6-(3-hydroxyl-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)pyridine-3-sulfonamide (75 mg, 0.20 mmol) in DCM (0.6 mL), under N2, was added diisopropylethylamine (70 μL, 0.40 mmol). The solution was then cooled to −40° C. in a dry ice/acetone bath and triflic anhydride was added (37 μL, 0.22 mmol). The reaction was stirred at −40° C. for 30 minutes then a solution of 6-chloro-1,2,3,4-tetrahydroquinoline (50 mg, 0.30 mmol) dissolved in DCM (0.3 mL) was added. The solution was allowed to warm to −20° C. and was placed in the −20° C. freezer overnight. The solution was then allowed to warm to room temperature and was washed with saturated aqueous NaHCO3 (5 mL), and the aqueous layer extracted once with DCM (5 mL). The organic layers were combined and concentrated. The residue was purified by silica gel chromatography with 5%-70% EtOAc in hexanes to give (S)-N-allyl-6-(3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)pyridine-3-sulfonamide (94 mg) in 89% yield. LC/MS (10%-99% CH3CN/H2O (0.05% TFA)), m/z: M+1 obs=530.1, tR=2.05 min.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12](S(C2C=CC=CC=2)(=O)=O)[CH:11]=1)([CH3:3])[CH3:2].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccccc1-c1c[nH]c2ccccc12
Yield: 89.8 %

Procedure:
3-Bromo-1-(phenylsulfonyl)-1H-indole (7.45 g, 22.2 mmol), 2-isopropylbenzene boronic acid (4.00 g, 24.4 mmol), tetrakis(triphenylphosphine)palladium (0) (769 mg, 0.67 mmol) and sodium carbonate (7.05 g, 66.5 mmol) were combined in a round bottomed flask and placed under an argon atmosphere. Degassed solvent (3:1:1 toluene/ethanol/water) (100 mL) was added and the contents were heated to 80° C. for 14 h. Upon completion of the reaction, as determined by TLC, the phases were separated, the aqueous phase was extracted three times with 20 mL ethyl acetate and all the organic phases were combined, washed once with water (20 mL) and once with brine (20 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to yield a dark residue which was purified by silica gel chromatography eluting with a gradient of ethyl acetate/hexanes to yield 3-(2-isopropylphenyl)-1-(phenylsulfonyl)-1H-indole (6.79 g, 82%) as a glassine solid. LC/MS (ESI+) 376.2 (M+H)+. 3-(2-Isopropylphenyl)-1-(phenylsulfonyl)-1H-indole (119 mg, 0.317 mmol) was combined with anhydrous tetrahydrofuran (2 mL) and tetra-n-butylammonium fluoride (1 M in THF, 1.3 mL) and heated to reflux for 14 h. Upon completion as observed by analysis by LC/MS the reaction was diluted with methanol (1 mL) and the solvent was evaporated under reduced pressure to yield a residue which was purified by silica gel chromatography eluting with a gradient of ethyl acetate/hexanes to yield 3-(2-isopropylphenyl)-1H-indole (67 mg, 90%) as a colorless glassine solid. LC/MS (ESI+) 236.23 (M+H)+. To 3-(2-isopropylphenyl)-1H-indole (23 mg, 0.10 mmol) in anhydrous tetrahydrofuran (1 mL) was added sodium bis(trimethylsilyl) amide solution (0.1 mL, 0.1 mmol, 1 M in tetrahydrofuran) and stirred for 15 min at ambient temperature. Isocyanatobenzene (0.1 mmol, 1.0 eq.) in THF (1 mL) was added and the reaction was stirred at ambient temperature. Upon completion as observed by analysis by LC/MS the reaction was diluted with methanol (1 mL) and the solvent was evaporated under reduced pressure to yield a residue which was purified by reverse phase HPLC chromatography eluting with a gradient of methanol/water to yield Example 1 (7.8 mg, 22%) as a colorless solid. LC/MS (ESI+) 355.23 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:17][C:18]1[CH:19]=[C:20]([C:28]([C:30]2[O:31][C:32]([CH3:35])=[N:33][N:34]=2)=O)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.Cl>C1COCC1.O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[C:28](/[C:20]1[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=[C:18]([Br:17])[CH:19]=1)\[C:30]1[O:31][C:32]([CH3:35])=[N:33][N:34]=1)[CH3:16]
Reactant: Cc1nnc(C(=O)c2cc(Br)cc(C(F)(F)F)c2)o1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/c1cc(Br)cc(C(F)(F)F)c1)c1nnc(C)o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a suspension of NaH (60%, 1.13 g, 28.35 mmol) in dry THF (20 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (6.49 g, 28.35 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of (3-Bromo-5-trifluoromethyl-phenyl)-(5-methyl-[1,3,4]oxadiazol-2-yl)-methanone (9.047 g, 27 mmol) in 20 ml THF was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature followed by stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5N) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a petroleum ether/EtOAc mixture to afford 9 g of the desired product (Yield: 90%).