Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Yield: 47.2 %

Procedure:
Using a method similar to Intermediate 1, using 5-hydroxy-1-indanone (2.44 g 16.5 mmol), 6-chloronicotinamide (2.34 g, 15.0 mmol) and K2CO3 (3.11 g, 22.5 mmol) gives the title compound (1.90 g) as a yellow solid. Mass spectrum (ion spray): m/z=269 (M+1); 1HNMR (DMSO-d6): 8.63 (s, 1H), 8.30 (d, 1H), 8.06 (s, 1H), 7.68 (d, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 7.19 (d, 1H), 7.17 (d, 1H), 3.07 (t, 2H), 2.64 (t, 2H).
Reaction SMILES: [BrH:1].N[C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1.N([O-])=O.[Na+].[OH-].[Na+]>Br.O.CCO>[Br:1][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: Br
Reactant: CCOC(=O)c1csc(N)n1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1csc(Br)n1
Temperature: 0 °C

Procedure:
To a well stirred suspension of ethyl 2-aminothiazole-4-carboxylate hydrobromide (29.99 g, 0.17 mol) in 16% HBr(aq) (400 mL) at 0° C., a solution of NaNO2 (12.49 g, 0.18 mol) in H2O (22 mL) was added dropwise. The mixture was maintained at 0° C. for an additional 35 min then CuBr (28.23 g, 0.20 mol) and an additional volume of 16% HBr(aq) (150 mL) were added. The ice bath was removed and the suspension heated to 70° C. for 1 hr. The mixture was filtered hot. The filtrate was saturated with NaCl then extracted with EtOAc (2×400 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude brown oil/solid residue was used directly in the next step. A solution of the brown residue in EtOH (100 mL) and 1M NaOH (aq) (367 mL, 0.36 mol) was stirred and heated at reflux for 1 h. The reaction mixture was filtered then extracted with EtOAc (100 mL). The aqueous layer was separated and concentrated under reduced pressure to remove the remaining EtOH. The aqueous solution was acidified to pH 1 with 2N HCl(aq). The solid was filtered off and air dried to yield the title compound as a beige amorphous solid. MS m/z: 208 (M+H) 210 (M+3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][N:20]([CH2:23][O:24]CC[Si](C)(C)C)[C:18]=3[N:19]=2)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][N:20]([CH2:23][OH:24])[C:18]=3[N:19]=2)[CH2:12][CH2:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(N3CCN(c4ccccc4F)CC3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(N2CCN(c3ccccc3F)CC2)nc2c1ccn2CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
A solution of 2-(4-(2-fluorophenyl)piperazin-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (30 mg, 67.6 μmol) in methylene chloride (3.38 mL) was treated dropwise with trifluoroacetic acid (1.13 mL). The reaction was stirred at room temperature for 2 h, and was then concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 40-80% ethyl acetate/hexanes) afforded 2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-7-hydroxymethyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a light grey solid (11.2 mg, 48.2%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.97-3.15 (m, 4H) 3.71 (d, J=5.08 Hz, 4H) 5.32 (d, J=7.42 Hz, 2H) 6.28 (d, J=3.52 Hz, 1H) 6.31-6.39 (m, 1H) 6.85 (d, J=3.52 Hz, 1H) 6.93-7.21 (m, 4H) 10.89 (s, 1H). LC-MS calcd. for C17H19FN5O2 [(M+H)+] 344, obsd. 344.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[(1-tert-Butoxycarbonyl-4-piperidinyl)oxy]benzonitrile (D21) (6.83 g) was dissolved in DCM (30 ml) and TFA (30 ml) was added. The reaction was stirred at rt for 1 h and then evaporated to give the title compound (D22) as a yellow oil (7.15 g—TFA salt plus 1.3 equivalents of TFA).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16].[OH-].[Na+]>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccccc1CN
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1CNc1ncccc1C(=O)O
Temperature: 25 °C
Yield: 74.5 %

Procedure:
7.00 g (44.2 mmol) of 2-chloronicotinic acid and 12.13 g (88.4 mmol) of 2-methoxybenzylamine were heated at 140° C. for 4 hours. The mixture was left to cool to room temperature, and then a 10% aqueous solution of sodium hydroxide was added to the reaction mixture. The resulting mixture was washed with chloroform. Concentrated hydrochloric acid was added to the aqueous phase to adjust the aqueous phase to pH 6 to 7, and a solid precipitated therefrom was separated by filtration and dried. Thus, 8.50 g (yield: 74%) of the title compound was obtained as a pale yellow powder.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S([CH:14]([CH2:18][C:19](O)=O)[C:15](O)=O)(O)(=O)=O>O>[CH2:1]([O:9][CH2:15][CH2:14][CH2:18][CH2:19][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: O=C(O)CC(C(=O)O)S(=O)(=O)O
Solvent: O
Product: CCCCCCCCOCCCCCCCC
Reaction time: 7 h

Procedure:
206 kg (1581.8 moles) of n-octanol were heated to 190°-210° C. together with 2.94 kg of sulfosuccinic acid (70% by weight). The water of reaction formed was distilled off. After 7 hours, 10.3 g of 50% by weight sodium hydroxide were added to the cooled reaction mixture for neutralization, after which the crude product was washed until neutral and then distilled.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(piperazin-1-yl)-quinoline.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:15][C:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:17]([Cl:19])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[Cl:19][C:17]1[N:18]=[C:14]([C:11]2[CH2:10][CH2:9][N:8]([C:6]3[C:27]([C:29]([F:32])([F:31])[F:30])=[CH:11][CH:10]=[CH:9][N:8]=3)[CH2:13][CH:12]=2)[NH:15][C:16]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nc(Cl)c(-c3ccc(F)cc3)[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2[nH]c(C3=CCN(c4ncccc4C(F)(F)F)CC3)nc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[4-chloro-5-(4-fluoro-phenyl)-1H-imidazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester from step (b) above in 30% TFA in DCM (5 mL) was stirred at RT for 1 h. The solvents were removed, and the residue was stirred with sat. aqueous solution of NaHCO3 (10 mL) at RT for 0.5 h. The reaction mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over MgSO4 and filtered. The filtrate was evaporated in vacuo to give the title compound, which was directly used in the next step without additional purification. MS (ESI, positive ion) m/z: 278 (M+1).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH2:3][C:4]#[N:5].[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C.O>[OH:17][N:16]=[C:3]([C:2](=[O:1])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)[C:4]#[N:5]
Reactant: N#CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(=NO)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 15 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 30.0 g of the title compound of Step A in 200 mL of glacial acetic acid was added dropwise a solution of 11.7 g of sodium nitrite in 35 mL of water while maintaining the reaction temperature at about 15° C. with external cooling. Following addition, the external cooling was removed and the suspension was stirred at room temperature overnight and then poured into excess water (about 400 mL). The aqueous suspension was acidified by dropwise addition of concentrated hydrochloric acid (until red to litmus paper) and then extracted with methylene chloride. The organic solution was dried (MgSO4), filtered and concentrated to give 32.5 g of the title compound of Step B as an oil. 1H NMR (CDCl3): δ 8.3 (s,1H), 8.2 (m,1H), 7.9 (m,1H), 7.65 (m,1H); IR (neat) 1670.2 cm-1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl-].[K+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([OH:24])[CH:18]=1>CN(C)C=O>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:18]=[C:19]([O:24][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:20]=[C:21]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:22]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCBr
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)OC)c1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
To a 1 L round bottom flask (RBF), while stirring with a magnetic stir bar, 1-bromodecane (54.3 mL, 0.262 mol), dimethylformamide (DMF) (200 mL), and potassium chloride (49.3 g, 0.357 mol) were added. Methyl-3,5-dihydroxybenzoate (20.0 g, 0.119 mol) was dissolved in DMF (100 mL) and the solution was added to the 1 L RBF. The solution gradually changed from an opaque pale yellow to an opaque light grey. The reaction vessel was sealed with a rubber septum and was stirred overnight. After stirring for approximately 20 hours, the contents of the RBF changed to a dark grey color and solidified. The RBF was gently heated with a heat gun until the contents liquefied. After cooling to just above room temperature, the contents of the RBF were transferred into a 2 L Erlenmeyer Flask that contained 1 L of 30/70 ice/distilled H2O mixture. A white precipitate formed on contact with H2O. Vacuum filtration was used to isolate the precipitate. The white precipitate was recrystallized from absolute ethanol (800 mL) and allowed to cool slowly overnight. The contents were then vacuum filtered yielding fine bright white fibrous crystals. The filtrate was concentrated under reduced pressure to approximately 300 mL. The concentrated filtrate was warmed and then left in refrigerator for approximately 18 hours. A second crop of fine bright white fibrous crystals was isolated from the solution upon vacuum filtration. The remaining pale yellow colored filtrate was discarded. This gave a total of 51.5 g yield or a 96.5% yield of the derivative. The NMR characterization data for this derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.6, 6H, CH2CH3), 1.27-1.44 (m, 28H, CH2(CH2)7), 1.80 (p, J=6.9, 4H, OCH2CH2), 3.89 (s, 3H, OCH3), 3.93 (t, J=6.6, 4H, OCH2CH2), 6.63 (t, J=2.2, 1H, ArH), 7.15 (d, J=2.5, 2H, ArH). 13C NMR (75 MHz, CDCl3): 14.22, 22.78, 26.10, 29.26, 29.42, 29.45, 29.65, 31.99, 52.27, 68.37, 77.31, 106.61, 107.65, 131.86, 160.21, 167.08.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[CH3:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH2:9][CH2:10]2
Reactant: O=Cc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: [H][H]
Solvent: CCO
Product: Cc1ccc2c(c1)CCN2
Temperature: 25 °C
Yield: 84.9 %

Procedure:
Into a 200 mλ pressure resistant reactor (autoclave) equipped with a stirrer, 20 g (0.084 mol) of 1-benzyl-5-formylindoline and 100 mλ of ethanol were charged, and the interior of the reactor was flushed with nitrogen. 2 g of 10% Pd/C was introduced, and the reactor was closed, whereupon hydrogen was introduced from a hydrogen supply pipe and reacted at 80° C. for 6 hours while adjusting the initial pressure of hydrogen in the reactor to be 6 2 kg/cm. Upon confirming the ceasing of absorption of hydrogen, the reaction was terminated. Then, the reaction solution was cooled to room temperature, and the hydrogen was released, and the palladium catalyst (10% Pd/C) was collected by filtration, and ethanol was distilled off under reduced pressure to obtain a colorless liquid as the residue. The obtained liquid was subjected to vacuum distillation to obtain 9.5 g of 5-methylindoline having a boiling point of from 56 to 57° C./0.3 mmHg. The yield was 85% (based on 1-benzyl-5-formylindoline).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:16][CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1.C(OCC)C.[ClH:40]>CO>[ClH:40].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N(CCN[C@H](CC(=O)O)Cc1c[nH]c2ccccc12)CCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(O)C[C@H](Cc1c[nH]c2ccccc12)NCCNCCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Combine 2-[(S)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino]-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine (4.77 g, 10 mmol) and diethyl ether (50 mL). Cool to 0° C. in an ice-bath. Slowly pass hydrogen chloride gas through the solution for 30 minutes. Stir for 4 hour at 0° C. Warm to ambient temperature and stir for 1 hour. Evaporate in vacuo to give a residue. Dissolve the residue in methanol and triturate the residue with diethyl ether to form a solid. Filter and dry under vacuum to give the title compound. Elem. Anal. calculated for C22H27N3 O2 . 0.50 H2O: C, 59.06; H, 6.76; N, 9.39. Found: C, 58.90; H, 7.01; N, 9.18.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7](Br)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH2:24]([OH:26])[CH3:25]>[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([O:26][CH2:24][CH3:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1OCC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52 %

Procedure:
1-Bromo-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (30 mg, 0.09 mmol) obtained in Example 18 was dissolved in ethanol (3 mL), silver nitrate (15.50 mg, 0.09 mmol) was added thereto, stirred for 3.5 hrs at RT, and filtered. The organic layer was separated, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 16 mg of the titled compound (yield: 52%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([Sn:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>>[O:25]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:16][CH2:17][CH2:18][CH3:19])[O:1][C:2]1[CH:15]=[CH:14][C:5]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:16][CH2:17][CH2:18][CH3:19])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CCCC[Sn](=O)CCCC
Product: CCCC[Sn](CCCC)(Oc1ccc(C(=O)c2ccccc2)cc1)O[Sn](CCCC)(CCCC)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
In a bulb-to-bulb distillation apparatus (“Kugelrohr”) 3 g (15.1 mmol) of 4-hydroxy-benzophenone and 1.9 g (7.6 mmol) of dibutyltin oxide are slowly heated to 150° C. in high vacuum (0.009 mbar). The mixture begins to melt and at 200° C. the distillation starts and is finished after about 10 minutes. After cooling the colorless distillate is identified as 4-hydroxy-benzophenone by 1H-NMR spectrum. The residue (about 3.3 g) is crystallized several times from hot toluene. 2.0 g of the title product are obtained as white crystals melting at 150-159° C. The structure is further confirmed by 1H-NMR and 13C-NMR spectra.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C1C(=O)N([I:20])C(=O)C1>CN(C=O)C.CCOC(C)=O>[I:20][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
5-nitro-1H-indazole (2 g, 12.26 mmol) was taken up in DMF (40 mL) and NIS (5.52 g, 24.52 mmol) was added. The reaction was stirred at room temperature for 72 h. The reaction mixture was diluted with EtOAc and washed with saturated sodium bisulfite solution, water, and then 2× with brine. The organic layer was dried over Na2SO4, filtered and concentrated to give 3-iodo-5-nitro-1H-indazole (3.4 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[OH:11][CH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20](B(O)O)[C:15]=2[O:14][C:13]1([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:20]2[C:15]3[O:14][C:13]([CH3:24])([CH3:25])[CH:12]([OH:11])[C:16]=3[CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1
Reactant: CC1(C)Oc2c(B(O)O)cccc2C1O
Reactant: N#Cc1nc(Br)cnc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)Oc2c(-c3cnc(N)c(C#N)n3)cccc2C1O

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 4, using 1.6 grams (0.008 mole) of 2-amino-3-cyano-5-bromopyrazine, 2.5 grams (0.012 mole) of 2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-ylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-5-(2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-yl)pyrazine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30](F)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])=[CH:21][CH:22]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCN(C)CC4)cc32)cc1
Yield: 77.5 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.17 mL, 1.5 mmol), triethylamine (0.2 mL, 1.5 mmol), and 1-(4-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example C-1, 0.20 g, 0.5 mmol) provided 0.19 g of the title compound as a solid.
Reaction SMILES: [N:1]#[C:2]Br.C[N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:7][CH2:6]1.O>CS(C)=O>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([N:8]2[CH2:7][CH2:6][N:5]([C:2]#[N:1])[CH2:10][CH2:9]2)=[N:12]1
Reactant: N#CBr
Reactant: CN1CCN(c2n[nH]c3ccccc23)CC1
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCN(c2n[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of cyanogen bromide (5.3 g, 0.05 mol), K2 CO3 (7.1 g) and dimethylsulfoxide (40 ml) was added, dropwise, 3-(4-methyl-1-piperazinyl)-1H-indazole (1 1.0 g 0.051 mol) dissolved in dimethylsulfoxide (60 ml). The reaction was stirred at ambient temperature for 1 hour, and then it was poured into water. The aqueous suspension was extracted with ethyl acetate, the ethyl acetate was washed (H2O), dried (MgSO4), and concentrated to afford 7.8 g (67%) of a ye llow solid. This sample was combined with another and recrystallized twice from toluene to afford analytically pure 4-(1H-indazol-3-yl)-1-piperazinecarbonitrile as a white solid, m.p.=12°-122° C.
Reaction SMILES: [P:1](Cl)([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([O:3][CH3:4])=[O:2].[OH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[C:24](=[O:26])[CH2:23][CH2:22]2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[C:24](=[O:26])[CH2:23][CH2:22]2)([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C1CCc2cccc(O)c21
Reactant: COP(=O)(Cl)Sc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COP(=O)(Oc1cccc2c1C(=O)CC2)Sc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Methyl S-(3-nitrophenyl) chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product O-methyl S-(3-nitrophenyl) O-indan-1-on-7-yl thiophosphate.