Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:17](Cl)=[O:18])([O-:13])=[O:12]>C1(C)C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:17]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:18])([O-:13])=[O:12]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: -10 °C
Yield: 84.8 %

Procedure:
A solution of 10.9 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 12.6 g (0.055 mole) 3,5-dinitrobenzoyl chloride in 200 ml toluene was refluxed for 20 hours. The crude product precipitated from the reaction mixture upon cooling to -10° C. After isolation by filtration, the residue was washed with hot petroleum ether and finally recrystallized from methylene chloride to give 17.5 g (85% yield) of pure product; m.p. 197° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:17][CH:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21].[BH4-].[Na+]>ClCCl.CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:17][CH:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(N)CCC
Reactant: O=Cc1ccccc1Br
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCC(CCC)NCc1ccccc1Br
Reaction time: 2 h
Yield: 95 %

Procedure:
Added to a solution of 7.4 g of 2-bromobenzaldehyde in 80 cm3 of dichloromethane are 6.25 g of sodium sulfate and 5.07 g of 4-aminoheptane at a temperature close to 20° C. After stirring for 2 h, the reaction mixture is filtered through a cartridge and washed with 2 lots of 10 cm3 of dichloromethane. The filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). The oil obtained is dissolved in 80 cm3 of methanol. 0.757 g of sodium borohydride is added in 3 lots. The reaction mixture is stirred for 1 h at 20° C., then 0.757 g of sodium borohydride is again added. This operation is carried out twice. After stirring at 20° C. for 20 h, the reaction mixture is concentrated using a rotary evaporator under reduced pressure (5 kPa). The concentration residue is taken up in 100 cm3 of dichloromethane and 50 cm3 of water. The organic phase is washed with 2 lots of 50 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 10.8 g of colorless oil obtained are purified by filtration through a pellet of 150 g of silica with 1 dm3 of an 80% heptane/20% ethyl acetate mixture. After concentrating the fractions under reduced pressure, 9.75 g of N-(2-bromobenzyl)heptan-4-amine are obtained in the form of a colorless clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.3 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (75 mg, 61%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[F:18][C:19]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1O>CCOC(C)=O>[F:18][C:19]1[C:20]([O:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[C:21]([F:28])[C:22]([F:27])=[C:23]([F:26])[C:24]=1[F:25]
Reactant: O=C(O)c1ccccc1NCc1ccncc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOC(C)=O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.9 %

Procedure:
To a stirred suspension of 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid (preparation 1, 300 mg) in EtOAC (10 ml) was added 2,3,4,5,6-pentafluorophenol (413 mg) followed by drop-wise addition of a solution of N,N-dicyclohexyl-carbodiimide (461 mg) in EtOAc (5 ml). The reaction mixture was stirred at room temperature for 15 hours. The formed precipitate was removed by filtration and the filtrate was evaporated under reduced pressure. The remaining material was subjected to column chromatography on silica gel (petroleum ether/EtOAc as eluent) and gave the title compound (352 mg). 13C-NMR (DMSO-d6) δ 163.2, 151.4, 149.7, 148.1, 140.9, 138.9, 137.6, 136.9, 131.9, 124.7, 121.9, 115.6, 112.5, 105.5, 44.7.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[Br:16][C:17]([CH3:22])([CH3:21])[C:18](Br)=[O:19].[OH2:23]>ClCCl>[OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[Br:16][C:17]([CH3:22])([CH3:21])[C:18]([O-:19])=[O:23]
Reactant: CC(C)(Br)C(=O)Br
Reactant: O
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)[O-]
Reaction time: 0.75 h

Procedure:
N-Hydroxysuccinimide (11.51 g, 0.1 mol) was dissolved in anhydrous dichloromethane (100 ml) with triethylamine (28.1 mL, 0.2 mol) under nitrogen in a 250 ml round-bottomed flask equipped with a magnetic stirrer. The flask was cooled to 0° C. with an ice bath before the dropwise addition of 2-bromo-2-methylpropionyl bromide (13.9 mL, 0.11 mol). Next the mixture was stirred for 45 minutes and allowed to reach room temperature. After this the reaction mixture was poured into an excess of cold water and extracted with diethyl ether (3×50 mL). The organic layer was subsequently washed with a saturated aqueous solution of sodium carbonate (3×50 mL), acidified water (pH=4.5, 3×50 mLl), and again the saturated aqueous solution of sodium carbonate (3×50 mL). The organic layer was dried over anhydrous magnesium sulphate and filtered. Finally the solvent was removed under reduced pressure by using the rotary evaporator in order to isolate the title compound in quantitative yield as a white solid. 1H NMR (CDCl3) δ (ppm) 2.08 (s, 6H, C(CH3)2Br), 2.87 (s, 4H, Hcycl). 13C NMR (CDCl3) δ (ppm) 26.03 (2C, Ccycl) 31.09 (2C, C(CH3)2Br), 51.60 (1C, C(CH3)2Br), 167.89 (1C, C═O), 169.02 (2C, Ccycl═O). IR (solid, ATR cell) ν (cm−1) 1803, 1772 (Ccycl═O), 1728 (C═O), 1394, 1359, 1197, 1121, 1071, 996, 924, 856, 811, 731, 648. Mass spectroscopy (+EI, m/z) 266, 265, 156, 151, 149, 123, 121, 116, 115, 91, 87, 70, 69. Elem. Anal. Theoretical for C8H10NO4Br: C, 36.39; H, 3.82; N, 5.30; Br, 30.26. Found: C, 36.35; H, 3.82; N, 5.03; Br, 30.17. Melting point 72-74° C.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C(Cl)Cl>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][N:18]([S:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[Cl:23])(=[O:32])=[O:31])[CH2:17][CH2:16]2)=[O:14])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC1(C(=O)Nc2ccc(C(C)(C)C)cc2)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1(C(=O)Nc2ccc(C(C)(C)C)cc2)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 25.5 mg (0.078 mmol) 4-Methoxy-piperidine-4-carboxylic acid (4-tert-butyl-phenyl)-amide, hydrochloride, 21.4 mg (0.1 mmol) 2-chlorobenzenesulfonyl chloride and 39.4 mg (0.39 mmol) NEt3 in 1.5 mL DCM was stirred for 16 h at room temperature. The mixture was concentrated and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 20.2 mg (56%) of the title compound as light yellow oil. MS (m/e): 465.2 [(M+H)+].
Reaction SMILES: B.C1COCC1.[O:7]=[C:8]1[CH:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][NH:9]1.CO>C1COCC1>[OH:15][CH2:14][C:12]1[CH:11]=[CH:10][NH:9][C:8](=[O:7])[CH:13]=1
Reactant: O=C(O)c1cc[nH]c(=O)c1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: O=c1cc(CO)cc[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Borane-THF (29 mL, 1.0 M) was added to a solution of 2-oxo-1,2-dihydropyridine-4-carboxylic acid (1 g, 7.19 mmol) in THF (15 mL) at 0° C. The mixture was stirred at 25° C. for 2 hours. Methanol was added and the mixture was concentrated under reduced pressure to afford 4-(hydroxymethyl)pyridin-2(1H)-one. MS ESI calc'd. for C6H8NO2 [M+H]+ 126. found 126. 1H NMR (400 MHz, CD3OD) δ 7.40 (d, J=6.8 Hz, 1H), 6.58 (s, 1H), 6.38 (d, J=6.4 Hz, 1H), 4.52 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[Cl:25][C:26]1[N:27]=[N:28][C:29]([Cl:33])=[CH:30][C:31]=1Cl.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[Cl:25][C:26]1[N:27]=[N:28][C:29]([Cl:33])=[CH:30][C:31]=1[N:23]1[CH:24]=[C:20]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:12])=[O:13])[CH:7]=2)[CH:21]=[N:22]1
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3cc(Cl)nnc3Cl)c2)c2ccc(F)cc21
Temperature: 85 °C
Reaction time: 24 h
Yield: 38.7 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 200 mg; 0.59 mmol) in MeCN (10 mL) was added 3,4,6-trichloropyridazine (97 mg; 0.529 mmol) and K2CO3 (146 mg; 1.06 mmol) under nitrogen. The mixture was stirred at 85° C. for 24 hours, diluted with EtOAc (100 mL), washed with water (50 mL×3), brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by reversed phase flash chromatography to afford 100 mg (39%) of the title compound a the yellow solid.
Reaction SMILES: S([O-])([O:4][CH2:5][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:7])(=O)=O.[Na+].[CH2:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:6]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:7])[C:5]([O:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCO
Reactant: CCCCCCOC(C)(COS(=O)(=O)[O-])OCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOC(=O)C(C)(OCCCCCC)OCCCCCC
Yield: 84 %

Procedure:
To a solution of methyl pyruvate 1 (10.0 g, 98.0 mmol) in toluene (100 mL) is added 1-hexanol 2 (40.1 g, 392 mmol) and p-TsOH (186 mg, 0.98 mmol). The mixture is heated to reflux for 10 hours with azeotropic removal of water from the reaction mixture. The reaction is quenched with saturated NaHCO3 (100 mL), and the reaction mixture is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give hexyl 2,2-bis(hexyloxy)propanoate 3 (29.5 g, 84%) as a colorless oil: Rf (15% EtOAc/hexane)=0.53; IR (thin film, cm−1) 2956, 2930, 2860, 1746 (C═O), 1467, 1280, 1137, 1062. 1H NMR (600 MHz, CDCl3) δ 4.14 (t, J=7.2 Hz, 2H), 3.48 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 3.35 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 1.65-1.63 (m, 2H), 1.59-1.54 (m, 4H), 1.49 (s, 3H), 1.35-1.24 (m, 18H), 0.86 (t, J=7.2 Hz, 9H); 13C NMR (150 MHz, CDCl3) δ 170.2, 99.5, 65.4, 62.6, 31.7, 31.3, 29.7, 28.5, 25.8, 25.5, 22.6, 22.5, 21.9, 14.0, 13.9.
Reaction SMILES: [C:1]([N:3]([CH2:14][C:15]#[CH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)#[N:2].C(N(CC)CC)C.[SH2:24]>CO>[NH:2]=[C:1]1[N:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)[CH2:14][C:15](=[CH2:16])[S:24]1
Reactant: S
Reactant: C#CCN(C#N)c1cccc(C(F)(F)F)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C1CN(c2cccc(C(F)(F)F)c2)C(=N)S1

Procedure:
To a solution of N-cyano-3-trifluoromethylaniline (5.0 g) in acetone (100 ml), potassium carbonate (7.4 g) and propargyl bromide (3.5 g) were added, and the resultant mixture was stirred at room temperature for 10 hours, followed by filtration of the reaction mixture. The solvent was removed from the filtrate by distillation under reduced pressure, and the residue was subjected to column chromatography to give N-cyano-N-propargyl-3-trifluoromethylaniline (3.8 g). The thus obtained N-cyano-N-propargyl-3-trifluoromethylaniline (1 g) and a catalytic amount of triethylamine were dissolved in methanol (30 ml), and the resultant mixture was cooled to 0° C. Hydrogen sulfide was gradually introduced into the mixture for 20 minutes while keeping the temperature at 0° C., followed by introduction of nitrogen gas to remove hydrogen sulfide. The solvent was removed by distillation, and the residue was subjected to column chromatography to give 0.2 g of 2-imino-3-(3-trifluoromethylphenyl)-5-methylenethiazolidine (Compound (ix)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)[C:5]#[N:6].[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21].COC(=O)C1C=CC(NC2CC3N(C)C(CC3)C2)=C(O)C=1.F[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[C:50]=1[N+]([O-])=O.FC1C=CC=CC=1[N+]([O-])=O>>[CH3:56][O:55][C:51]1[CH:52]=[CH:53][CH:54]=[C:49]2[C:50]=1[O:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[N:10]2[CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Reactant: CN1C2CCC1CC(Nc1ccc(C#N)cc1O)C2
Agent: COC(=O)c1ccc(NC2CC3CCC(C2)N3C)c(O)c1
Agent: O=[N+]([O-])c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1Oc1cc(C#N)ccc1N2C1CC2CCC(C1)N2C

Procedure:
Using an adaptation of Procedure 2, substituting the TFA salt of 3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzonitrile, 2p for the TFA salt of 3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic acid methyl ester, 1a, and 1-fluoro-3-methoxy-2-nitrobenzene, 1e for 2-fluoronitrobenzene, the title compound 6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile, 3p was obtained as TFA salt and as a mixture of endo and exo isomers after purification via reverse phase HPLC (eluent gradient: 20% to 45% CH3CN in water containing 0.1% TFA). MS m/z=362 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][N:16](CC3C=CC(OC)=CC=3OC)[C:15](=[O:30])[C:14]3[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][NH:16][C:15](=[O:30])[C:14]3[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CN2Cc3c(-c4nc(C5CC5)no4)ncn3-c3ccc(OC)cc3C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(=O)NCc1c(-c3nc(C4CC4)no3)ncn1-2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxy-benzyl)-8-methoxy-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one (5 g, 10.3 mmol) were dissolved in CH2Cl2 (30 mL), cooled to 0° C., then TFA (30 mL) was added, followed by trifluoromethanesulfonic acid (2 mL, 22.9 mmol). The mixture was stirred for 4 h at rt, evaporated, the residue dissolved in CH2Cl2 (100 mL), and extracted with 10% NaHCO3. The product precipitated upon evaporation of CH2Cl2. Yield: 3 g (86%); mp 245° C. m/z 337 (M).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[NH3+:15][C@H:16]([C:25]1[NH2+:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][N:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23].CCN(CC)CC.[Cl-].Cl[S:45]([N:48]([CH3:54])[CH2:49][CH2:50][NH+:51]([CH3:53])[CH3:52])(=[O:47])=[O:46]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[CH3:52][NH+:51]([CH3:53])[CH2:50][CH2:49][N:48]([CH3:54])[S:45]([NH:15][C@H:16]([C:25]1[NH2+:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][N:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])(=[O:47])=[O:46]
Reactant: CN(CC[NH+](C)C)S(=O)(=O)Cl
Reactant: CC(=O)CCCCC[C@H]([NH3+])C1=NC=C(c2ccccc2)[NH2+]1
Agent: O=C([O-])C(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CCCCC[C@H](NS(=O)(=O)N(C)CC[NH+](C)C)C1=NC=C(c2ccccc2)[NH2+]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution Example 1, A3 and Et3N (4 eq.) in DCM was added crude C1 (1.2 eq). The mixture was stirred at RT for 16 hr. The mixture was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound C2 as a colourless oil. 1H NMR (300 MHz, DMSO-d6) δ: 8.18 (1H, br. s), 7.87 (1H, br. s), 7.83-7.71 (2H, m), 7.58-7.28 (3H, m), 4.64-4.45 (1H, m), 3.41-3.16 (4H, m), 2.79 (6H, s), 2.63 (3H, s), 2.39 (2H, t, J=6.8 Hz), 2.05 (3H, s), 1.98-1.78 (2H, m), 1.53-1.19 (6H, m). MS (ES) C22H35N5O3S requires: 449, found: 450 (M+H)+.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC([O-])(C)C.[K+].[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][C:39]=1[CH3:46]>C1C=CC=CC=1>[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:40][C:39]=1[CH3:46]
Reactant: Cc1cc(C=O)ccc1F
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1cc(C=CCCCCCC(=O)O)ccc1F
Temperature: 25 °C
Yield: 107 %

Procedure:
To a suspension of 7-Carboxyheptanyltriphenylphosphonium bromide (9.240 g, 19.602 mmol) in 100 mL of benzene, was added t-BuOK (58.8 mL, 58.8 mmol, 1M in THF). The resulting mixture was refluxed for 1 h and then 4-fluoro-3-methylbenzaldehyde (1.43 mL, 11.761 mmol) was added via a syringe. The mixture was continued to reflux under N2 for 63 h. After cooling to room temperature, the reaction mixture was washed with water (80 mL). The aqueous layer was acidified with concentrated HCl to pH=2 and extracted with ethyl acetate (30 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as colorless oil (3.150 g, >99% yield). LC-MS: tR=9.6 min, m/z 251 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C@H:6]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])C.[OH-].[Na+]>CO.O>[C:21]([O:20][C:18]([NH:17][C@H:6]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[CH2:5][C:4]([OH:25])=[O:3])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F

Procedure:
(R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1 mmol) were dissolved in the solvent mixture of 100 mL of methanol and 50 mL of water under stirring. The reaction mixture was reacted at 40-45° C. for 1-1.5 hours, then part of the solution was evaporated under reduced pressure. The residue was added with some water, then pH was adjusted to 2-3 with 1 N hydrochloric acid in an ice-water bath. The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then recrystallized from ethyl acetate/n-hexane to obtain the title compound (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid if (9.2 g) as a white solid, which was directly used in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]#[N:32])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([C:31]#[N:32])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(C#N)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-Butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 1H-indole-5-carbonitrile
Reaction SMILES: C[N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][CH:10]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CN(c1ccccc1)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Nc2ccccc2)cc1
Yield: 14.2 %

Procedure:
A solution of 4-(methyl(phenyl)amino)benzoic acid (0.045 g, 0.198 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.046 g; 0.198 mmol), HATU (0.083 g; 0.217 mmol) and N,N-diisoproylethylamine (0.085 mL; 0.495 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.011 g (14%) of the title compound as a white solid.