Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=3)[C:38]([O:40][CH3:41])=[O:39])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:45][CH2:46]OS(C)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:52]=[N+:53]=[N-:54].[Na+].CN(C=O)C>O>[N:52]([CH2:46][CH2:45][C:15]1[N:14]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:22]2[C:17]([C:16]=1[CH2:24][CH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=3)[C:38]([O:40][CH3:41])=[O:39])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)=[N+:53]=[N-:54]
Reactant: COC(=O)c1cccc(-c2ccc(S(=O)(=O)CCc3c(CCOS(C)(=O)=O)n(C(c4ccccc4)c4ccccc4)c4ccc(Cl)cc34)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc(S(=O)(=O)CCc3c(CCN=[N+]=[N-])n(C(c4ccccc4)c4ccccc4)c4ccc(Cl)cc34)cc2)c1
Temperature: 60 °C
Yield: 99 %

Procedure:
Methyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate (1 eq), sodium azide (5 eq), and DMF (0.05M) were placed together under N2 and heated to 60° C. After 1 hour the reaction was cooled and water was added. Extracted with EtOAc/Et2O mix and washed with water and brine and dried over sodium sulfate. Removed solvent to obtain methyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate (light-yellow solid) in 99% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([CH2:16][CH2:17][CH2:18][OH:19])[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1)=[O:10].[CH3:29][Mg]Br.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([CH2:16][CH2:17][CH2:18][OH:19])[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1)([OH:10])[CH3:29]
Reactant: C[Mg]Br
Reactant: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc(C(C)(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 67 %

Procedure:
To a stirred solution of (2,4-dichlorophenyl)[7-(diethylamino)-1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]methanone (300 mg, 0.714 mmol) in tetrahydrofuran (7 mL) was added a solution of methyl magnesium bromide in diethyl ether (3.0 M, 714 μL, 2.14 mmol) at 0° C. After being stirred for 6.5 h at room temperature, the reaction mixture was quenched with aqueous ammonium chloride at 0° C., diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The resulting solid was washed with diethyl ether to afford the desired product as a yellow solid (210 mg, 0.481 mmol, 67%).
Reaction SMILES: 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.[NH2:34][C:35]1[N:40]=[CH:39][C:38]([C:41]2[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[C:43]([CH3:50])[CH:42]=2)=[CH:37][C:36]=1[C:51]1[N:52]=[N:53][N:54]([CH:56]([CH3:58])[CH3:57])[CH:55]=1.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CN(C=O)C>[NH2:34][C:35]1[N:40]=[CH:39][C:38]([C:41]2[CH:49]=[CH:48][C:44]([C:45]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)=[O:46])=[C:43]([CH3:50])[CH:42]=2)=[CH:37][C:36]=1[C:51]1[N:52]=[N:53][N:54]([CH:56]([CH3:58])[CH3:57])[CH:55]=1
Reactant: C1COCCN1
Reactant: Cc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.4 %

Procedure:
HATU (336 mg, 0.88 mmol) and DIPEA (0.30 mL, 1.77 mmol) were added to a solution of 4-(6-amino-5-(1-isopropyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2-methylbenzoic acid (200 mg, 0.59 mmol) in DMF (10.0 mL) at room temperature, after 5 min, morpholine (0.06 mL, 0.71 mmol) was added, stirred at RT for 18 h. The reaction mixture was poured into ice cold water, extracted with EtOAc (2×50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude product was purified by washing with ether to afford 148 mg of (Yield: 61.4%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:1]2[CH:13]=[CH:17][CH:16]=[CH:15]2)[CH:7]=1
Reactant: COC1CCC(OC)O1
Reactant: CSc1nc(N)cc(Cl)n1
Solvent: CC(=O)O
Product: CSc1nc(Cl)cc(-n2cccc2)n1

Procedure:
As described above, both the dichloro and the difluoro-intermediates provide mixtures of regioisomers when reacted with nucleophiles (cf. 144 in Scheme 19). Although this is useful when both regioisomers are desired, the route shown in Scheme 20 below provides a regioselective synthesis. According to Scheme 20, 4-amino-6-chloro-2-methylthiopyrimidine 151 was reacted with 1 equivalent of 2,5-dimethoxytetrahydrofuran in refluxing acetic acid to provide 6-chloro-2-methylthio-4-(1-pyrrolyl)pyrimidine 152: 1H NMR (CDCl3) δ 2.75 (s,3H), 6.55 (d,2H), 7.05 (s,1H), 7.65 (d,2H). The 6-chloro-2-methylthio-4-(1-pyrrolyl)pyrimidine 152 is either (a) oxidized with 2.2 equivalents of m-chloroperoxybenzoic acid in dichloromethane at 0° C. to provide 6-chloro-2-methylsulfonyl-4-(1-pyrrolyl)pyrimidine 153 or (b) reacted with 1 equivalent of the N-(p-cyanobenzyl)amide of cyclohexylalanine and 1 equivalent of diisopropylethylamine in DMF at 80° C. to provide the 2-methylthiopyrimidine 154. The oxidation and nucleophilic displacement steps are then reversed [i.e. 153 is reacted according to (b) or 154 is reacted according to (a)] to provide the 2-methylsulfonylpyrimidine 155, which is dissolved in n-butanol saturated with ethylamine and heated in a sealed tube to produce 156.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:30]([C@H:13]1[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N+:31]=[N-:32]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of trans-tert-butyl 4-(benzyloxycarbonylamino)-3-(methylsulfonyloxy)piperidine-1-carboxylate (6.0 g, 14 mmol) in dimethyl sulfoxide (40 mL) was added sodium azide (9.11 g, 140 mmol), and the reaction mixture was stirred at 90° C. overnight under N2. The solution mixture was cooled to ˜30° C., diluted with ethyl acetate (˜300 mL), and washed with water (700 mL×3) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to the title compound (3.8 g, 72%) as a yellow oil. MS (ES+) C18H25N5O4 requires: 375, found: 276 [M+H−100]+, 373 [M+Na]+.
Reaction SMILES: [N:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)=[C:2]=S.C1CCC(N=C=NC2CCCCC2)CC1.[F:40][C:41]1[CH:42]=[C:43]([NH2:49])[C:44]([NH2:48])=[CH:45][C:46]=1[F:47].C1COCC1>C(Cl)Cl>[F:40][C:41]1[C:46]([F:47])=[CH:45][C:44]2[NH:48][C:2]([NH:1][C:4]3[CH:24]=[CH:23][C:7]([O:8][C:9]4[C:14]([C:15]5[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=5)=[CH:13][CH:12]=[CH:11][N:10]=4)=[CH:6][CH:5]=3)=[N:49][C:43]=2[CH:42]=1
Reactant: CSc1nccc(-c2cccnc2Oc2ccc(N=C=S)cc2)n1
Reactant: Nc1cc(F)c(F)cc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSc1nccc(-c2cccnc2Oc2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A resealable pressure vial, under nitrogen, was charged with 4-(2-(4-isothiocyanatophenoxy)pyridin-3-yl)-2-(methylthio)pyrimidine (1.12 g, 3.18 mmol), PS-DCC (1.27 mmol/g polymer supported cyclohexyl carbodiimide) (7.50 g, 9.53 mmol), 4,5-difluorobenzene-1,2-diamine (0.69 g, 4.77 mmol), and THF (45 ml, 0.07 M). The vessel was sealed and the reaction mixture stirred at 70° C. for 4 h. The reaction mixture was cooled to RT, diluted with DCM, and filtered over celite. The filtrate was concentrated to afford yellow residue, which was triturated with DCM, filtered, and dried under high vacuum to afford 5,6-difluoro-N-(4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a tan solid. MS m/z=463.1 [M+H]+. Calc'd for C23H16F2N6OS: 462.48.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([I:28])=[CH:23][N:22]=1>C(#N)C>[Cl:20][C:21]1[N:26]=[C:25]([NH:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:24]([I:28])=[CH:23][N:22]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1ncc(I)c(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(I)c(NCCCN2CCOCC2)n1
Temperature: -35 °C
Reaction time: 1 h

Procedure:
In accordance with procedure 2, 3-morpholin-4-yl-propylamine (0.73 ml, 5 mmol) and N-ethyldiisopropylamine (1.71 ml, 10 mmol) are dissolved in 100 ml acetonitrile under argon and cooled to −35° C. The solution of 2,4-dichloro-5-iodo-pyrimidine (1.37, 5.0 mmol) in 50 ml acetonitrile is then added dropwise at −35° C. internal temperature. Stirred 1 hr further at −30 to −20° C., then slowly warmed up to RT and stirred for 3 days at RT.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9](=[O:25])[C:8]=2[C:26]#[N:27])[CH2:3]1.[Cl:28][CH2:29][C:30](Cl)=[O:31].CCN(C(C)C)C(C)C>ClCCl>[Cl:28][CH2:29][C:30]([N:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:9](=[O:25])[C:8]=2[C:26]#[N:27])[CH2:3]1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1c(NC2CNC2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1c(NC2CN(C(=O)CCl)C2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(Azetidin-3-ylamino)-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt (1 eq, 0.150 g, 0.43 mmole) in dichloromethane at −10° C. was added chloroacetyl chloride (1.1 eq, 0.054 g, 0.474 mmole) followed by the addition of N,N′-diisopropylethylamine (1.5 eq, 0.083 g, 0.646 mmole, 0.110 mL). The resulting solution stirred at −10° C. for 1 hour then warmed to RT and stirred for an additional 2 hours. The reaction was quenched into ice cooled water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-[1-(2-Chloro-acetyl)-azetidin-3-ylamino]-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.027 g, 15% calc M+H 425, obs M+H 425).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([S:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22].B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([S:9]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH:6]=[CH:5][C:4]=1[NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:23])([F:24])[F:22]
Reactant: COc1cc(S(=O)(=O)c2ccncc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccncc2)cc1O)C(F)(F)F
Yield: 12 %

Procedure:
To a stirred suspension of N-[2-methoxy-4-(4-pyridylsulfonyl)phenyl]-3,3,3,-trifluoro-2-hydroxy-2-methyl propanamide (1.30 g) and sieve dried methylene chloride (50 mL) was added boron tribromide (1.6 mL of a 1.0M solution in methylene chloride), and the mixture (a gummy ball of material and solvent) was stirred at reflux for 2 hours and then stirred overnight at room temperature. The reaction mixture was poured into water, made basic with saturated sodium bicarbonate solution and extracted with methylene chloride (2×250 mL; discarded) followed by ethyl acetate (100 mL). The ethyl acetate solution was dried, filtered, evaporated to a brown oil and purified by chromatography twice (eluent ethyl acetate and eluent methylene chloride-ethyl acetate (1:4)) to yield the title compound (0.15 g); mp 218°-220° C. Analysis for C15H13F3N2O5S: Calculated: C, 46.16; H, 3.36; N, 7.18: Found: C, 45.87; H, 3.47; N, 6.91. ##STR2##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:28])[NH:18][C:19]3[C:24]\2=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:29](OCC)=[O:30]>CN(C=O)C>[CH:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:28])[NH:18][C:19]3[C:24]\2=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)/[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1)=[O:30]
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Reactant: CCOC=O
Solvent: CN(C)C=O
Product: O=CNc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29b from (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene}-5-nitro-2-indolinone and ethyl formate in DMF.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]3[B:11]([OH:14])[O:12][CH2:13][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[OH:14][B:11]1[C:10]2[CH:15]=[CH:16][C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][C:26](=[O:28])[CH3:27])=[CH:3][CH:4]=3)=[CH:8][C:9]=2[CH2:13][O:12]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-amino-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (68 mg, 0.28 mmol, 1.0 eq.) in DCM (3.0 mL) was added Et3N (47 μL, 0.33 mmol, 1.2 eq.), followed by acetyl chloride (22 μL, 0.31 mmol, 1.1 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-acetamide as a white solid. LCMS (m/z) 284 (M+H); 1H NMR (DMSO-d6) δ: 10.17 (s, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.58-7.63 (m, 2H), 6.94-6.99 (m, 2H), 6.88 (dd, J=8.0, 2.1 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 4.85 (s, 2H), 3.12 (s, 1H), 2.00 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH:18]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25]>CN(C)C=O>[C:19]1([CH3:25])[CH:20]=[CH:21][CH:22]=[C:23]([O:24][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:18]=1
Reactant: Cc1cccc(O)c1
Reactant: O=C1CCc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc3c(c2)CCC3=O)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
5 g of 5-fluoro-1-indanone are dissolved in 50 ml of dry dimethylformamide, and 18.2 g of anhydrous, powdered potassium carbonate and 3.57 g of m-cresol are added. The reaction mixture is stirred at 110° C. for 6 h. The solvent is removed by distillation in vacuo, and the residue is mixed with 100 ml of water and stirred for 2 h. The aqueous residue is extracted with ethyl acetate, and the organic extract is washed 3× with water, dried over sodium sulfate, filtered and concentrated in vacuo. 5-m-Tolyloxy-1-indanone is obtained as a brown oil which is reacted further without further purification.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:45]=[C:44]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][C:53]5[CH2:58][CH2:57][C:56]([CH3:60])([CH3:59])[CH2:55][C:54]=5[C:61]5[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=5)[CH2:48][CH2:47]4)[CH:43]=[CH:42][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[C:21]([N+:39]([O-:41])=[O:40])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.FC(F)(F)C(O)=O>ClCCl>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:45]=[C:44]([N:46]4[CH2:47][CH2:48][N:49]([CH2:52][C:53]5[CH2:58][CH2:57][C:56]([CH3:60])([CH3:59])[CH2:55][C:54]=5[C:61]5[CH:62]=[CH:63][C:64]([Cl:67])=[CH:65][CH:66]=5)[CH2:50][CH2:51]4)[CH:43]=[CH:42][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:21]([N+:39]([O-:41])=[O:40])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCNCC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of EXAMPLE 139A (960 mg) in dichloromethane (10 mL) was added dropwise trifluoroacetic acid (5 mL). The mixture was stirred at the temperature for 3 hours. Then, the mixture was concentrated under vacuum and the residue was dissolved in dichloromethane (200 mL) and washed with aqueous NaHCO3 and brine. After drying over Na2SO4, the mixture was filtered, and evaporation of the solvent from the filtrate gave the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:35][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccccn5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccccn5)cc4)CC3)n2CCS1
Yield: 95.2 %

Procedure:
A solution of the compound (346 mg, 0.68 mmol) obtained in Example 16-6) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (2 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (254 mg, 95%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH2:18][CH2:19][NH:20][C:21]([C:23]1[C:32]([OH:33])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:22].[CH2:34]([O:36][C:37](=[O:40])[CH2:38]Br)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OC(=O)C)C>[CH3:34][O:36][C:37](=[O:40])[CH2:38][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH2:18][CH2:19][NH:20][C:21]([C:23]1[C:32]([OH:33])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)=[O:22]
Reactant: CCOC(=O)CBr
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(CCNC(=O)c3cc4ccccc4cc3O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1CCNC(=O)c1cc2ccccc2cc1O
Reaction time: 12 h
Yield: 24 %

Procedure:
To a solution of the 3-Hydroxy-naphthalene-2-carboxylic acid [2-(4-hydroxy-4′-methanesulfonyl-biphenyl-3-yl)-ethyl]-amide (18 mg, 0.039 mmol) was in DMF were added ethylbromoacetate (0.039 mmol) and Cs2CO3 (0.039 mmol, 13 mg). The reaction mixture was for 12 hr and the reaction mixture was diluted with ethylacetate and washed with water. The organic layer was separated, dried and the crude obtained after removal of the solvent was purified on a silicagel column to afford the desired product 5 mg, and 5 mg of bis ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]([NH:9][NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)=O)[CH3:2].N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1[O:20][C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)=[N:10][N:9]=1)[CH3:2]
Reactant: CCOC(=O)CCC(=O)NNC(=O)c1ccc(F)c(F)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCc1nnc(-c2ccc(F)c(F)c2)o1
Temperature: 25 °C

Procedure:
To a solution of 4-[N′-(3,4-difluorobenzoyl)hydrazino]-4-oxo-butyric acid ethyl ester (590 mg, 1.96 mmol) and pyridine (474 μL, 5.88 mmol) in methylene chloride (25 mL) at −78° C. was added dropwise triflic anhydride (397 μL, 2.35 mmol) and the reaction was allowed to warm up to rt overnight. The reaction mixture was diluted with methylene chloride (100 mL), washed with 0.1 M HCl and brine, dried over sodium sulfate and concentrated to provide 3-[5-(3,4-difluorophenyl)-[1,3,4]oxadiazol-2-yl]propionic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ 7.89-7.77 (m, 2H), 7.31 (m, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.24 (t, J=7.2 Hz, 2H), 2.92 (t, J=7.4 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[I:19][CH2:20]I>C1COCC1>[I:19][CH2:20][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: ICI
Reactant: COC(=O)C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(CI)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a stirred solution of methyl tetrahydropyran-4-carboxylate (3.00 g) in anhydrous THF (50 ml) under nitrogen at 0° C. was added a solution of lithium di-isopropylamide (2.0 M, 10.9 ml). After 30 minutes, diiodomethane (8.36 g) was added and the mixture was allowed to warm up to RT and then stirred for 1 h. The mixture was poured onto water (50 ml) and extracted with ether (3×40 ml). The combined ether layers were washed with water (2×20 ml), aqueous hydrochloric acid (2 M, 20 ml), water (20 ml) and brine (20 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified on silica gel, eluting with 3:1 hexane/ether, to give the title compound (3.11 g) as a colourless oil.