Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[CH3:23][C:24]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=2)[CH:31]=[CH:30]1)([CH3:28])[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:28][C:24]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:40])([F:41])[F:39])[CH:36]=2)[CH:31]=[CH:30]1)([CH3:23])[C:25]([N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)(=[O:16])=[O:15])=[CH:12][CH:13]=2)[C:2](=[O:1])[CH2:7]1)=[O:26]
Reactant: CC(C)(C(=O)O)n1ccc2ccc(C(F)(F)F)cc21
Reactant: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)(C(=O)N1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C(=O)C1)n1ccc2ccc(C(F)(F)F)cc21
Yield: 100 %

Procedure:
Synthesized according to general procedure 14, method B. The reaction was set up with 4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50 mg, 0.15 mmol), 2-methyl-2-(6-(trifluoromethyl)-1H-indol-1-yl)propanoic acid (27 mg, 0.10 mmol), HATU reagent (76 mg, 0.20 mmol), sodium bicarbonate (17 mg, 0.20 mmol), and DMF (0.20 mL) to obtain the desired amide as a white solid (50 mg, 0.10 mmol, 32% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=592.4; tR=3.04 min.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]([OH:18])=[O:17].OS(O)(=O)=O.[CH3:24][CH2:25]O>>[Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]([O:18][CH2:24][CH3:25])=[O:17]
Reactant: O=C(O)c1cccc2c(Cl)c3ccccc3cc12
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc2c(Cl)c3ccccc3cc12
Yield: 77 %

Procedure:
10-Chloroanthracene-1-carboxylic acid (37A, 17.3 g, 0.0674 mol), conc. H2SO4 (1.0 mL), and abs. EtOH (500 mL) was refluxed for 3 days using 4Å molecular sieves in a Soxhlet extractor to remove H2O. The solvent was removed and then partitioned between EtOAc and satd. NaHCO3. The solvent was then removed from the organic layer to give 14.86 g (77%) of ethyl 10-chloroanthracene-1-carboxylate, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([S:14]([N:17](CC3C=CC(OC)=CC=3OC)[C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[C:9]([F:34])[CH:8]=2)=[C:4]([C:37]2[N:42]3[CH:43]=[N:44][CH:45]=[C:41]3[C:40](=[O:46])[N:39](CC3C=CC(OC)=CC=3)[CH:38]=2)[CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([S:14]([NH:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:15])=[O:16])=[C:9]([F:34])[CH:8]=2)=[C:4]([C:37]2[N:42]3[CH:43]=[N:44][CH:45]=[C:41]3[C:40](=[O:46])[NH:39][CH:38]=2)[CH:3]=1
Reactant: COc1ccc(Cn2cc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)N(Cc4ccc(OC)cc4OC)c4ncns4)cc3F)n3cncc3c2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=c1[nH]cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ncns3)cc2F)n2cncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of 4-(4-chloro-2-(7-(4-methoxybenzyl)-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.20 g, 0.25 mmol) and anisole (0.54 mL, 5.0 mmol) in trifluoroacetic acid (2 mL) at 0° C. was added trifluoromethanesulfonic acid (0.22 mL, 2.5 mmol). The reaction mixture was allowed to warm to ambient temperature, stirred for 16 h and concentrated in vacuo. The residue was partitioned between dichloromethane (30 mL) and saturated aqueous sodium bicarbonate (30 mL). The aqueous phase was washed with dichloromethane (2×30 mL), acidified to pH 3-4 with 1 M hydrochloric acid and extracted with ethyl acetate (5×40 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in ethyl acetate/diethyl ether (5/95 v/v) to afford 4-(4-chloro-2-(8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-5-yl)phenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as an off-white solid in 77% yield (0.104 g): 1H NMR (300 MHz, DMSO-d6) δ11.22 (d, J=4.8 Hz, 1H), 8.55 (s, 1H), 8.49 (br s, 1H), 8.11 (br s, 1H), 7.80 (s, 1H), 7.76-7.63 (m, 2H), 7.41-7.29 (m, 2H), 6.95 (d, J=5.3 Hz, 1H); MS (ES+) m/z 536.7 (M+1), 538.7 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24]>C(O)(C)C.C(N(CC)CC)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24]
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Clc1ccc2ncnc(Cl)c2c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Yield: 92.6 %

Procedure:
3.00 g (0.015 mol) of 4,6-dichloroquinazoline and 3.80 g (0.0170 mol) of 4-chloro-3-nitrobenzylamine hydrochloride were dissolved in a mixture comprising 100 ml of isopropyl alcohol and 15 ml of triethylamine. The obtained solution was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate) and recrystallized from chloroform/n-hexane to give 4.85 g of the title compounds as a pale-yellow crystal.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH2:19]>CO>[CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1[NH:19][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1=C(N=O)C(=O)NC1=Cc1ccccc1
Reactant: CN
Solvent: CO
Product: CNC1=C(N=O)C(=O)NC1=Cc1ccccc1
Yield: 50 %

Procedure:
A solution of 0.11 g (0.5 mmol) 5-benzylidene-4-methoxy-3-nitroso-1,5-dihydropyrrol-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in methanol was boiled under reflux with 0.25 ml (0.25 mmol) methylamine solution for two minutes. The compound 5-benzylidene-4-methylamino-3-nitroso-1,5-dihydropyrrol-2-one was obtained in a yield of 50% after recrystallization from methanol. The compound decomposes at 220° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12](Cl)=[O:13]>CN(C)C1C=CN=CC=1.ClC(Cl)Cl>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:13]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Cc1ccccc1N
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a stirred solution of 42.8 parts of 2-methylbenzenamine in 375 parts of trichloromethane are added dropwise 41.8 parts of 2,6-dichlorobenzoyl chloride at reflux temperature. Then there are added 1.2 parts of N,N-dimethyl-4-pyridinamine and stirring is continued for 3 hours at reflux. The reaction mixture is allowed to cool to room temperature overnight and diluted with 375 parts of trichloromethane. The organic phase is washed successively with 100 parts of water, 100 parts of a hydrochloric acid solution 3 N and again 100 parts of water, dried, filtered and evaporated. The residue is crystallized from 200 parts of 2-propanol, yielding 40.6 parts (72.5%) 2,6-dichloro-N-(2-methylphenyl)benzamide; mp. 182.5° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C(=O)=O.C[O:21][C:22]([C:24]1[C:25]([CH2:40][CH2:41][O:42][CH3:43])=[N:26][C:27]([C:30]2[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)=[N:28][CH:29]=1)=O.C(OC(C1C(CCOC)=NC(C2C=NC(C(F)(F)F)=CC=2)=NC=1)=O)C>C1COCC1>[CH3:43][O:42][CH2:41][CH2:40][C:25]1[C:24]([CH2:22][OH:21])=[CH:29][N:28]=[C:27]([C:30]2[CH:31]=[N:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=2)[N:26]=1
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1C(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Agent: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)nc2)nc1CCOC
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 1.2 M solution of DIBALH in toluene (50 ml, 60 mmol) was dropped within 20 min to a dry ice cooled (−30° C.) solution of 4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-5-carboxylic acid methyl ester and 4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-5-carboxylic acid ethyl ester (6.83 g, 20 mmol) in THF (100 ml). The reaction mixture was warmed to 0° C., stirred for 1 h at this temperature, the cooling bath was removed and stirring was continued for 1 h at ambient temperature. The mixture was cooled to 0° C., neutralized with aqueous KHSO4 solution (10%) and extracted three times with ether. The combined extracts were washed with aqueous NaCl solution (10%), dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was crystallized (dichloromethane/ether, 0° C.) to give 6.72 g (21.4 mmol, quant.) [4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl) -pyrimidin-5-yl]-methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Br)(Br)[Br:12]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Cl)c(Br)c1
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(CBr)cc1Br
Temperature: -5 °C
Reaction time: 1 h

Procedure:
260 g (crude product of several batches, about 1.05 mol) of (3-bromo-4-chlorophenyl)methanol were dissolved in 2.86 liters of dichloromethane, the mixture was cooled to −5° C. and 127.1 g (44.6 ml, 459.6 mmol) of phosphorus tribromide were added slowly. After the addition had ended, the mixture was stirred at −5° C. for another 1 h and then diluted with dichloromethane and water. The organic phase was separated off, dried over magnesium sulphate and concentrated under reduced pressure. This gave, as a crude product, 280.5 g (about 84% of theory) of 2-bromo-4-(bromomethyl)-1-chlorobenzene.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[C:6](F)=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:4][C:5]1[C:6]([C:1]#[N:2])=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: N#Cc1ncc(C(F)(F)F)cc1Cl
Reaction time: 23 h
Yield: 82.1 %

Procedure:
Solid sodium cyanide (0.29 g) was added to a stirred mixture of 3-chloro-2-fluoro-5-trifluoromethylpyridine (0.8 g) and tetrabutylammonium bromide (0.06 g) at 20-25° C., and stirred for 23 hours to give 3-chloro-2-cyano-5-trifluoromethylpyridine (0.68 g, 82% yield by hplc).
Reaction SMILES: [C:1]1([CH2:15][OH:16])[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:23][C:24]([Cl:34])=[CH:25][C@@H:26]1[C@H:28]([C:29](Cl)=[O:30])[C:27]1([CH3:33])[CH3:32]>C1C=CC=CC=1>[Cl:23][C:24]([Cl:34])=[CH:25][C@@H:26]1[C@H:28]([C:29]([O:16][CH2:15][C:1]2[C:14]3[CH2:13][CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:30])[C:27]1([CH3:32])[CH3:33]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OCc1cccc2c1CCc1ccccc1-2
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc2c1CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 9,10-dihydrophenanthrene-1-methanol (0.5 gram, 0.0024 mole) and pyridine (1 gram, 0.013 mole) in benzene (25 ml) was added to a stirred solution of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (0.7 gram, 0.0031 mole) in benzene (25 ml). The mixture was stirred at room temperature for 2.5 days, then partitioned between water (80 ml) and diethyl ether (50 ml). The organic phase was separated and washed consecutively with water, 10% aqueous sodium carbonate and water. The organic phase was then dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to give a yellow oil. The oil was purified by chromatography on silica gel to give (9.10-dihydro-1-phenanthryl)methyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate as an oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([O:11]CC)=[O:10].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].Cl[C:67]1[CH:68]=[CH:69][CH:70]=[C:71]2[C:76]=1[N:75]=[CH:74][CH:73]=[CH:72]2>C(OCC)C.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[N:75]1[C:76]2[C:71](=[CH:70][CH:69]=[CH:68][C:67]=2[NH:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[C:9]([OH:11])=[O:10])[CH:72]=[CH:73][CH:74]=1
Reactant: Clc1cccc2cccnc12
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)C1CCCCC1Nc1cccc2cccnc12
Temperature: 90 °C
Reaction time: 17 h
Yield: 15.1 %

Procedure:
To an oven-dried Schlenk flask that was evacuated and backfilled with argon was added 726 mg (3.68 mmol) of ethyl cis-2-amino-1-cyclohexanecarboxylate HCl salt, 56 mg (0.06 mmol, 2 mol % Pd) of Pd2(dba)3, 77 mg (0.12 mmol, 4 mol %) of rac-BINAP, 881 mg (9.17 mmol) of sodium tert-butoxide, 500 mg (3.06 mmol) of 8-chloroquinoline, and 7.5 mL of toluene. The flask was sealed with a glass stopper and an argon balloon replacing the source. The reaction mixture was then heated to 90° C. and stirred at that temperature for 17 hours. The mixture was allowed to cool to room temperature, taken up in diethyl ether (35 mL), washed three times with saturated brine (30 mL), dried over magnesium sulfate, and concentrated to provide the crude reaction mixture. The crude mixture was re-dissolved in ethyl acetate, partitioned between ethyl acetate and 1N HCl, dried over magnesium sulfate and concentrated to provide 125 mg (15%) of 2-(quinolin-8-ylamino)cyclohexanecarboxylic acid with both cis and trans isomers in 1:1 ratio. Confirmed by 1H NMR.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:8][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1
Reactant: CC(=O)c1ccccc1
Reactant: CC(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1CCSC(C)(c2ccccc2)O1

Procedure:
74 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 6.6 grams (0.055 moles) of acetophenone is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The refluxing lasts for a period of 3 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with 10% aqueous sodium bicarbonate to a pH of 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 10.4 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 3 fractions:
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[C:8]1(O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(Cl)(Cl)(Cl)=O>O>[C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([O:5][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: Oc1ccccc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CC(=O)Oc1ccccc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Malonic acid (11 g, 106 mmol) was mixed with phenol (20 g, 212 mmol) at 0° C. under nitrogen and phosphorus oxychloride (11.5 mL, 123 mmol) was added dropwise to the solid mixture. The resulting mixture was stirred at 0° C. for 5 mins, and then heated at reflux for 5 h, causing the solid to melt and an orange solution to form. The reaction was cooled to room temperature, and then poured onto 100 mL water and extracted with diethyl ether (3×75 mL). The combined organics were washed with brine, dried over MgSO4, concentrated in vacuo to an orange oil of the title compound. (27 g, 99%).
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:22][C:23](=[O:46])[CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=3)[C:34]([OH:36])=[O:35])=[CH:29][CH:28]=2)[CH:14]=[CH:15][C:16]=1[S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=O)(C)(C)C>C(OCC)(=O)C>[NH2:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:22][C:23](=[O:46])[CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]([NH:37][C:38]3[CH:39]=[CH:40][C:41]([C:44]#[N:45])=[CH:42][CH:43]=3)[C:34]([OH:36])=[O:35])=[CH:29][CH:28]=2)[CH:14]=[CH:15][C:16]=1[S:17]([CH2:20][CH3:21])(=[O:18])=[O:19]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(C(Nc3ccc(C#N)cc3)C(=O)O)cc2)cc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(C(Nc3ccc(C#N)cc3)C(=O)O)cc2)cc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
Hydrogen chloride (4N solution in dioxane, 1 mL, 4 mmol) was added to a solution of 15D (78 mg, 0.12 mmol) in ethyl acetate (1 mL). The reaction mixture was stirred at rt overnight and then concentrated to give 15E (65 mg, 100%) as a yellow solid. MS (ESI) m/z 535.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:34]([NH:33][S:30]([C:28]1[CH:27]=[CH:26][C:18]2[N:19]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)=[N:16][C:17]=2[CH:29]=1)(=[O:32])=[O:31])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NS(=O)(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1)c1ccccc1
Yield: 21.2 %

Procedure:
Intermediate 69 (0.023 g, 0.05 mmol) and benzoyl chloride (0.005 ml, 0.06 mmol) were used to prepare the titled compound (0.006 g, 18%) by the same method as in example 15. 1H NMR (CDCl3) δ 8.59 (s, 1H), 8.26 (d, 1H, J=8.8 Hz), 7.84 (m, 3H), 7.59 (d, 211, J=8.8 Hz), 7.56-7.37 (m, 8H), 7.18 (d, 2H, J=8.4 Hz), 5.17 (s, 2H), 4.42 (m, 1H), 2.33 (br m, 4H), 1.99 (br m, 2H), 1.81 (br m, 1H), 1.36 (br m, 3H); ESI-MS m/e 566.1 (M+1); HPLC purity (ELSD) 100%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)=[O:23])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>>[CH3:14][C:15]1[C:20]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]=[C:11]([CH3:13])[O:10][N:9]=3)=[CH:4][CH:3]=2)=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)=[O:23])=[CH:17][CH:16]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Product: Cc1nc(-c2ccc(-c3cc(NC(=O)c4ccnc(N5CCCC5)c4)ccc3C)cc2)no1

Procedure:
Example 11 was prepared using 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-2-(1-pyrrolidinyl)-4-pyridinecarboxamide (Intermediate 20).
Reaction SMILES: B.O1CCCC1.[CH2:7]([N:14]1[CH2:32][CH2:31][C:17]2[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:16]=2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:33]>C(O)(=O)C>[ClH:33].[CH2:7]([N:14]1[CH2:32][CH2:31][C@H:17]2[N:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C@@H:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(CN2CCc3c(c4ccccc4n3-c3ccccc3)C2)cc1
Agent: B
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(CN2CC[C@@H]3[C@@H](C2)c2ccccc2N3c2ccccc2)cc1

Procedure:
To a solution of 0.140 moles of borane in 150 ml. of tetrahydrofuran stirred at 0° C. in a three-necked round bottom flask fitted with magnetic stirrer, thermometer, condenser and addition funnel, and maintained under a nitrogen atmosphere, was added a solution of 23.9 g. (0.071 mole) of 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b]indole in 460 ml. of dry tetrahydrofuran. The addition was carried out at such a rate as to maintain the reaction temperature below 9° C. When the addition was completed the resulting mixture was heated to reflux and maintained at this temperature for one hour. The solvent was then evaporated in vacuo to afford a white solid mass which was suspended in 40 ml. of dry tetrahydrofuran and heated, slowly at first, with 180 ml. of a 1:1 by volume mixture of acetic acid and 5 N hydrochloric acid. The resulting suspension was heated at reflux for one hour, then cooled. Evaporation of tetrahydrofuran and part of the acetic acid resulted in precipitation of a white solid which was separated by filtration and washed with water. The solid was resuspended in tetrahydrofuran, filtered, washed with ethyl ether and air dried to afford 16.7 g. (63%) of the desired trans-isomer. M.P. 256°-260° C.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Cl:20])=[C:14]([C:16]([F:19])([F:18])[F:17])[S:15][C:9]=2[CH2:8][CH2:7]1)=O)C.I[Si](C)(C)C>C(Cl)Cl>[Cl:20][C:13]1[C:10]2[CH2:11][CH2:12][NH:6][CH2:7][CH2:8][C:9]=2[S:15][C:14]=1[C:16]([F:18])([F:17])[F:19]
Reactant: CCOC(=O)N1CCc2sc(C(F)(F)F)c(Cl)c2CC1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: FC(F)(F)c1sc2c(c1Cl)CCNCC2
Yield: 18 %

Procedure:
A solution of the product from step c) (14.4 mg, 0.044 mmol) in CH2Cl2 (220 μl) was treated with iodotrimethylsilane (19 μl, 0.13 mmol) at 60° C. for 12 hours. The reaction was quenched by the addition of MeOH and the solvent was evaporated. The residue was purified by preparative LC/MS providing 2.3 mg (18%) of the title compound. MS: ESI (positive): 256 (M+H).