Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]([O-])(C)[CH3:4].[K+].O.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH:11]1[C:10]2[C:1](=[CH:2][CH:3]=[CH:4][CH:9]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCC(C)(C)[O-]
Reactant: CCCCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the suspension of ethyl triphenyl phosphonium bromide (5.69 g, 15.3 mmol) in anhydrous THF (30 ml), a solution is added by drops of potassium tert-amylate (8.7 ml, 14.7 mmol, 1.7 M solution in toluene) using a syringe at room temperature. After 1 hour, the reaction mixture is cooled to a temperature of 0° C., the solution of crude aldehyde previously obtained is added (3.32 g, 11.79 mmol) in THF (10 ml), and mixing is continued for hours at room temperature. Then, water (1 ml) is added, and dilution takes place with n-hexane (30 ml). The sediment created is filtered, and the residue is chromatographed on silica gel (cyclohexane), obtaining naphthalene derivative with formula 25 in the form of a yellow oil (3.12 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2Br)[C:35]([F:38])([F:37])[F:36])[N:3]=1.O1CCOCC1.CC1(C)C(C)(C)OB([C:61]2[CH:62]=[C:63]([S:67]([NH2:70])(=[O:69])=[O:68])[CH:64]=[CH:65][CH:66]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([S:67](=[O:69])(=[O:68])[NH2:70])[CH:62]=2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4cccc(S(N)(=O)=O)c4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.688 mmol) in 10:1 dioxane:water (11 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (195 mg, 0.7 mmol), KHCO3 (207 mg, 2.06 mmol), and PdCl2(dppf)-CH2Cl2 (56 mg, 0.069 mmol). The reaction was heated to 100° C. for 15 h, cooled to RT, and concentrated in vacuo. The residue was diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:13]1([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH2:7][C:21]2[S:20][C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:23][CH:22]=2)[CH:10]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: Cc1cc(C)c(C(=O)O)cc1Br
Product: Cc1cc(C)c(Cc2ccc(-c3ccccc3)s2)cc1Br

Procedure:
2,4-dimethylbenzoic acid (20.0 g) was suspended in chloroform (100 ml), and thereto were added oxalyl chloride (6.8 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (200 ml). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2,4-dimethylbenzoate as pale yellow oil, which was used in the subsequent step without further purification. (2) To a mixture of the above methyl 2,4-dimethylbenzoate (19.75 g) and activated aluminum neutral oxide (120 g) was added dropwise bromine (9.25 ml) while stirring at room temperature. The mixture was stirred at room temperature for 8 hours, and diluted with diethyl ether (1000 ml). Insoluble materials were filtered off, and washed with diethyl ether (500 ml). The combined filtrate was washed successively with 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and brine. The filtrate was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from methanol (40 ml) to give methyl 5-bromo-2,4-dimethylbenzoate (6.34 g) as colorless crystals. APCI-Mass m/Z 243/245 (M+H). (3) The above methyl 5-bromo-2,4-dimethylbenzoate was treated in a manner similar to Reference Example 4-(1) to give 5-bromo-2,4-dimethylbenzoic acid as colorless crystals. ESI-Mass m/Z 227/229 (M−H) (4) The above 5-bromo-2,4-dimethylbenzoic acid and 2-phenylthiophene were treated in a manner similar to Reference Example 5 to give 5-bromo-2,4-dimethyl-1-(5-phenyl-2-thienylmethyl)benzene as colorless crystals. APCI-Mass m/Z 357/359 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:18][CH2:19][C:20]1[CH:31]=[CH:30][C:23]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:22][CH:21]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16])[C:8]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:30][CH:31]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C(C)(C)C
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(OC(C)C)c(C(C)(C)C)c2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 4.1 g (16 mmol) of 3-tert-butyl-4-isopropyloxybenzoyl chloride with 3.1 g (16 mmol) of allyl 4-hydroxymethylbenzoate, 5.1 g (77%) of allyl ester, melting point 63°-4° C., are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12].C(N(CC)CC)C.[C:28](C1NC=CN=1)(C1NC=CN=1)=[S:29]>O1CCCC1>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([OH:12])=[C:5]([N:4]2[C:3]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:18])[F:19])=[CH:16][C:2]=3[NH:1][C:28]2=[S:29])[CH:10]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Nc1cc(Cl)ccc1O
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Oc1ccc(Cl)cc1-n1c(=S)[nH]c2cc(C(F)(F)F)ccc21
Reaction time: 0.5 h

Procedure:
2-amino-N-(5-chloro-2-hydroxyphenyl)-4-trifluoromethyl-aniline (0.51 g, 1 5 mmol), triethylamine (0.28 ml, 2 mmol) and thiocarbonyl diimidazol (0.36 g, 2 mmol) was dissolved in dry tetrahydrofuran (15 ml) and the mixture was stirred for 30 minutes. The reaction mixture was evaporated in vacuo. The residue was redissolved in ethanol and water and light petroleum were added. The precipitate was isolated and was purified by column chromatography on silica gel with ether/light petroleum (2:1) as eluent. Yield of title compound was 200 mg, M.p. 248°-250° C.
Reaction SMILES: [I:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-])=O.O.O.[Sn](Cl)Cl.C(O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[I:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[NH2:10]
Reactant: O=[N+]([O-])c1cc(F)cc(Br)c1I
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(F)cc(Br)c1I
Yield: 75.5 %

Procedure:
Treat 1-iodo-2-nitro-4-fluoro-6-bromobenzene (5.0g, 14.46mmol) with tin (II) chloride dihydrate (12g, 58mmol) in refluxing ethanol (150mL). Stir at reflux for 24 hours, pour into a mixture of ethyl acetate (200mL) and saturated sodium hydrogen carbonate (500mL). Filter and wash the filtrate with saturated sodium hydrogen carbonate (200mL) and water (200mL). Dry (MgSO4), evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compound as an off-white solid (3.45g, 76%).
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31]>>[F:23][C:24]1[CH:29]=[C:28]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH:15]([CH3:22])[CH3:14])[CH:27]=[CH:26][C:25]=1[O:30][CH3:31]
Reactant: COc1ccccc1F
Reactant: CC(C)CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCCC(C)C)cc1F
Temperature: 0 °C

Procedure:
14 ml of nitrobenzene are cooled in an ice-bath and then mixed in succession with 3.8 g of AlCl3 and 3.7 g of 5-methyl-hexanoyl chloride in 5 mi of nitrobenzene. The mixture is stirred and then treated with 2.7 ml of 2-fluoro-anisole. The solution is stirred overnight, then poured into ice-water and extracted with methylene chloride. The extracts are washed with water and 10% aqueous NaCl solution, and thereafter dried and concentrated and recrystallized using pentane. 5.31 g of 1-(3-fluoro-4-methoxy-phenyl)-5-methyl-hexan-l-one, MS: m/e 238 (M+), are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH:16]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Reactant: Nc1ccccc1
Product: CCOC(=O)c1cnc2cn[nH]c2c1Nc1ccccc1
Reaction time: 8 h
Yield: 67 %

Procedure:
Ethyl 7-chloro-1H-pyrazolo[4,3-b]-pyridine-6-carboxylate (370 mg, 1.6 mmol) was dissolved in aniline (3 ml) and stirred overnight. The resulting mixture was triturated with 60°-80° petrol, and the precipitated solid was collected and dissolved in aqueous ethanol. The solution was adjusted to pH 8 with saturated sodium hydrogen carbonate solution, and the precipitated solid was collected to give the title compound (310 mg, 67%) m.p. 164°-165° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 1-t-butoxycarbonylpyperidin-4-one (10.0 g) in dimethylformamide (200 mL) were added n-butylamine (6.0 mL) and triethylamine (7.0 mL) and the solution was stirred. To the reaction solution was added sodium triacetoxyborohydride (16.0 g) and the solution was stirred for 1.5 hours. After finishing the reaction, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the title compound having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=[O:14])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([O:15][CH2:30][C:27]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)=[O:14])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.5 g, 2.05 mmol) in DMF (about 5 ml), Cs2CO3 (0.804 g, 2.47 mmol) and BnBr (0.3 ml, 2.47 mmol) were added slowly portion wise at about 0° C., then the reaction was stirred at room temperature for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water, brine and dried over Na2SO4. The solvent was evaporated and purified by silica gel column (60-120 mesh, elution 4% EtOAc in hexane) to afford title compound as a pale yellow syrup. Wt: 0.35 g; Yield: 51%; 1H NMR (300 MHZ, CDCl3): δ 7.39-7.28 (m, 5H), 5.12 (Brs, 2H), 4.60 (Brs, 1H), 3.88-3.79 (m, 1H), 2.65-2.53 (m, 1H), 2.38-2.27 (m, 1H), 2.01-1.99 (m, 1H), 1.43 (s, 9H), 1.28 (s, 3H), 0.86 (s, 3H); IR (KBr, cm−1): 3387, 2962, 1710, 1523, 1456, 1366, 1253, 1173, 1079, 1009, 979, 746, 698.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20]C(C)C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29]O.[BH4-].[Li+].Cl.O1C[CH2:37][CH2:36][CH2:35]1>O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH:20]([CH3:29])[CH2:35][CH2:36][CH3:37])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: C1CCOC1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Product: CCCC(C)Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.070 g, 0.16 mmol) in tetrahydrofuran (mL) and methanol (0.013 mL, 0.32 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.12 mL, 0.24 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 99:1 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (m, 6 H) 1.30 (m, 4 H) 3.25 (m, 1 H) 5.74 (d, J=3.68 Hz, 1 H) 7.13 (d, J=5.15 Hz, 1 H) 7.19 (d, J=8.09 Hz, 1 H) 7.26 (t, J=7.54 Hz, 1 H) 7.54 (dd, J=8.09, 1.47 Hz, 1 H) 7.65 (d, J=7.72 Hz, 1 H) 7.73 (d, J=5.52 Hz, 1 H) 15.94 (s, 1 H). MS (ESI−) m/z 431 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13].CC(C)=O>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[C:4]([NH2:5])=[N:12][NH:13]2
Reactant: N#Cc1c(F)cccc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: Nc1n[nH]c2cccc(Cl)c12
Temperature: 90 °C
Reaction time: 19 h
Yield: 67.2 %

Procedure:
To a solution of 2-chloro-6-fluorobenzonitrile (ABCR) (3 g, 19 mmol) in anhydrous ethanol (50 mL) was added hydrazine hydrate (3.74 mL, 77 mmol). The reaction was heated at 90° C. under a nitrogen for 3.5 hours. The reaction mixture was cooled to room temperature, treated with acetone (20 mL) and left to stand for 19 hours. The mixture was evaporated in-vacuo to yield an orange/brown solid, which was partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The organic layer was passed through a hydrophobic frit and evaporated in-vacuo to yield a brown solid, which was absorbed onto Florisil (60-100 mesh), applied to a 100 g silica SPE cartridge and purified by chromatography on Flashmaster II using a 0-10% methanol in dichloromethane gradient over 60 min. Fractions 24-29 were combined and the solvent was evaporated in-vacuo to yield the title compound as a yellow solid (2.14 g, 66%) LCMS (System B) RT=1.58 min, ES+ve m/z 168 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:41]([N:60]1[CH:64]=[C:63]([C:65]2[CH:66]=[C:67]([CH:69]=[CH:70][CH:71]=2)[NH2:68])[N:62]=[CH:61]1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[O:1]=[C:2]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:68][C:67]4[CH:69]=[CH:70][CH:71]=[C:65]([C:63]5[N:62]=[CH:61][N:60]([C:41]([C:54]6[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=6)([C:48]6[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=6)[C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)[CH:64]=5)[CH:66]=4)=[O:18])=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: O=C(O)c1ccc2nc3n(c2c1)CCCNC3=O
Reactant: Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1)c1ccc2nc3n(c2c1)CCCNC3=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxylic acid (Intermediate B, 59 mg, 0.15 mmol) and TBTU (52 mg, 0.16 mmol) in DMF (2 mL) is stirred for 20 min at room temperature. 3-(1-Tritylimidazol-4-yl)-aniline (Intermediate O, 36 mg, 0.15 mmol) and triethylamine (15 mg, 0.15 mmol) are added and the solution stirred at room temperature for 4 h. DMAP (5 mg, 0.04 mmol) is added and the solution is heated at 60° C. overnight. The reaction is cooled to room temperature and H2O was added. The resulting precipitate is filtered off and purified via flash column chromatography using a gradient elution of 0-10% CH2Cl2/methanol, containing 1% NH4OH to afford the title compound as an oil (67 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1[nH]c2ccccc2c1Oc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Solvent: CCO
Product: COC(=O)c1c(Oc2ccc(Cl)cc2[N+](=O)[O-])c2ccccc2n1Cc1ccccc1

Procedure:
In the same way as described in example 5, methyl-3-[2-nitro-4-chlorophenoxy]-indole-2-carboxylate was alkylated with benzyl bromide. Analytical material was obtained by recrytallization from ethanol, mp. 120°-1°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([N:19]2[CH2:28][CH2:27][C:22]3([CH2:25][CH:24]([OH:26])[CH2:23]3)[CH2:21][CH2:20]2)=[N:9][N:8]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([N:19]2[CH2:28][CH2:27][C:22]3([CH2:25][C:24](=[O:26])[CH2:23]3)[CH2:21][CH2:20]2)=[N:9][N:8]=1
Reactant: COc1ccc(CNc2nnc(N3CCC4(CC3)CC(O)C4)c3ccc(C#N)cc23)cc1Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nnc(N3CCC4(CC3)CC(=O)C4)c3ccc(C#N)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
500 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazine carbonitrile was suspended in 20 ml dichloromethane and 10 ml tetrahydrofuran, then 690 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxsol-3(1H)-one was added thereto, and the mixture was stirred at room temperature for 15 min. Ethyl acetate, 30 ml saturated aqueous sodium bicarbonate and 2 ml saturated aqueous sodium thiosulfate 5H2O were added thereto. The organic layer was recovered and the aqueous layer was extracted with ethyl acetate. The extracted solutions were combined, washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated and the resulting residue was purified by silica gel column chromatography, crystallized from ethanol, and the resulting crystals were collected filtration by adding hexane thereto to give 420 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-oxo-7-azaspiro[3.5]non-7-yl)-6-phthalazine carbonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH3:8][I:9]>C1(C)C=CC=CC=1>[I-:9].[CH3:7][C:4]1[CH:5]=[CH:6][N+:1]([CH3:8])=[CH:2][CH:3]=1
Reactant: CI
Reactant: Cc1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc[n+](C)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 ml three-neck flask, fitted with a stirrer, thermometer, and condenser, was charged with 9.3 g (0.1 mol) of 4-picoline and 21.6 g (0.11 mol) of methyl iodide in toluene. The solution was stirred at room temperature for 4 hours, and then refluxed for 30 minutes. After cooling, the solution was filtered, and the pale yellow solid, 4-methyl-N-methylpyridinium iodide, was washed with ethyl ether and dried under vacuum. Yield 21.2 g (90%); 1H-NMR (DMSO-d6): δ 2.56 (s, 3H), 4.20 (s, 3H), 7.0 (d, 2H), 8.90 (d, 2H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[NH:16][C:15](=O)[CH2:14][CH2:13][CH2:12][C:11]=3[CH:18]=2)[CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[NH:16][C:15](=[S:28])[CH2:14][CH2:13][CH2:12][C:11]=3[CH:18]=2)[CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCCc2cc(-c3cccnc3)ccc2N1
Solvent: Cc1ccccc1
Product: S=C1CCCc2cc(-c3cccnc3)ccc2N1
Temperature: 25 °C

Procedure:
The title compound from Example 2 Step D (0.200 g, 0.839 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane2,4-disulfide (0.255 g, 0.629 mmol) were suspended in toluene (1.7 mL) and then heated to reflux for several hours. The reaction solution was then cooled to room temperature and concentrated. Purification by flash chromatography on silica gel (0-10% methanol in ethyl acetate) provided the title compound: LCMS m/z 255.03 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.81 (s, 1H), 8.48-8.47 (m, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.58-7.56 (m, 2H), 7.42 (dd, J=4.8, 7.9 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 2.74-2.71 (m, 2H), 2.68-2.65 (m, 2H), 2.26-2.20 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][OH:12].I([O-])(=O)(=O)=[O:14].[Na+].CC#N.O>[Ru](Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]([OH:14])=[O:12]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: OCc1c(F)cc(F)c(F)c1F
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=C(O)c1c(F)cc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
(2,3,4,6-Tetrafluorophenyl)methanol (1.50 g, 8.33 mmol), sodium periodate (8.91 g, 41.6 mmol) and ruthenium (III) chloride (345 mg, 1.67 mmol) was added to a mixture of MeCN (20 mL), water (10 mL) and carbon tetrachloride (20 mL). The reaction was stirred at room temperature for 6 hours, then filtered through arbocel (eluting with EtOAc) and the filtrate evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with EtOAc to afford the title compound as a colourless oil (1.60 g, 99% yield):