Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[N:3]=1.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[OH-].[Na+]>ClC(Cl)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)[N:3]=1
Reactant: Nc1ncnc2c1c(I)nn2C1CCCNC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CN1CCCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
To a mixture of 3-iodo-1-(3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.4 g, 0.00116 mol) and sodium triacetoxyborohydride (0.34 g, 0.00162 mol) in dichloroethane (30 mL) was added formaldehyde solution (37% in water, 0.035 mL, 0.00128 mol, 1.1 eq.) at room temperature. The mixture was stirred at room temperature under an atmosphere of nitrogen for 18 hours. Additional formaldehyde solution (37% in water, 0.035 mL, 0.00128 mol, 1.1 eq.) was added, and the mixture was stirred at room temperature for 2 hours. A 5 N aqueous solution of sodium hydroxide (5 mL) was added to the mixture. The solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure, and the mixture was lyophilized to yield 3-iodo-1-(1-methyl-3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.41 g, 0.0011 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 6.0 min. MS: MH+ 359
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2].[CH3:33][C:34]1([CH3:40])[O:38][C:37](=[O:39])[N:36]=[CH:35]1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:36]3[CH2:35][C:34]([CH3:40])([CH3:33])[O:38][C:37]3=[O:39])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2]
Reactant: CC1(C)C=NC(=O)O1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Product: CC(=O)N1CCN(c2cc(N3CC(C)(C)OC3=O)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Yield: 11.3 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (653 mg) described in Preparation Example 126 and 5,5-dimethyloxazolin-2-one (165 mg) described in Preparation Example 43, the title compound (86.5 mg) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1
Reactant: OCc1ccc(CCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: OCc1ccc(CCI)cc1
Temperature: 25 °C

Procedure:
To 60.0 g (352 mmol) [4-(2-chloro-ethyl)-phenyl]-MeOH (preparation 1a) in 280 mL of acetone is added 105 g (703 mmol) sodium iodide. The reaction mixture is refluxed overnight and cooled to RT. After filtration, the residue is elutriated in DCM, filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([O:20]C)=O)=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>>[CH3:22][O:23][CH2:24][CH2:25][NH:26][C:18]([C:15]1[CH:14]=[CH:13][C:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[CH:17][N:16]=1)=[O:20]
Reactant: COCCN
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2ccc(F)cc2)cn1
Product: COCCNC(=O)c1ccc(NS(=O)(=O)c2ccc(F)cc2)cn1

Procedure:
0.5 g (1.61 mmol) of methyl 5-[(4-fluorophenylsulfonyl)amino]pyridine-2-carboxylate (compound from Example 4a) is stirred at 70° C. for 3 h in 5 ml of 2-methoxyethylamine. The mixture is concentrated, the residue is dissolved in water, the solution is acidified with conc. HCl, the solid is filtered off with suction and washed with water and 0.53 g of the title compound is obtained in the form of colorless crystals, M.p. 154° C.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH2:10]([O:17][CH2:18]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(C(C)=O)C(C)C.COCCOCCN(CCOCCOC)CCOCCOC>[CH2:10]([O:17][CH2:18][N:5]1[C:6](=[O:8])[CH2:7][NH:3][C:4]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCOCc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C1CNC(=O)N1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
In 5 ml of methyl isobutyl ketone were suspended 216 mg (3.85 mmoles) of potassium hydroxide and 73 mg (0.226 mmoles) of tris[2-(2-methoxyethoxy)ethyl]-amine followed by addition of 900 mg (8.99 mmoles) of imidazolidine-2,4-dione, and the mixture was stirred at room temperature for 10 minutes. Then, 704 mg (4.50 mmoles) of benzyloxymethyl chloride was added dropwise at 0° C. and the mixture was stirred at room temperature for 3 hours. To this reaction mixture was added water and the organic layer was separated and washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel chromatography (eluent: hexane:ethyl acetate =1:1) to give 687 mg (3.12 mmoles) of 3-benzyloxymethylimidazolidine-2,4-dione. Yield 70% (based on benzyloxymethyl chloride) 1H-NMR, δ(CDCl3): 3.90 (2H, s), 4.60 (2H, s), 5.05 (2H, s), 6.00-6.20 (1H, brs, -NH), 7.20-7.45 (5H, m)
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>C1COCC1>[F:13][C:14]1[C:19]([F:20])=[C:18]([B:21]([OH:26])[OH:22])[CH:17]=[CH:16][N:15]=1
Reactant: Fc1cccnc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1ccnc(F)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of THF and hexanes (6 mL, 1:1 v:v), and diisopropyl amine (0.681 mL, 4.78 mmol) was cooled to −78° C. BuLi (2.5 M in hexanes, 2.00 mL, 5.00 mmol) was added to the cooled mixture, followed by addition of 2,3-difluoropyridine after about 15 minutes. The mixture was stirred for 1 hour at −78° C. before being transferred to a 3 mL THF solution of triisopropyl borate (1.11 mL, 4.78 mmol) at −78° C. via a cannula. The resulting solution was stirred at −78° C. for 1 hour, slowly warmed up to ambient temperature and then quenched with 2 M NaOH solution (20 mL). The two layers were separated and the aqueous phase was washed once with ether. The aqueous phase was then acidified with HCl to pH 5 and extracted three times with EtOAc. The organic layers were combined, dried over sodium sulfate and concentrated to yield the product as a light yellow solid, which was used in the next step without purification. LCMS (m/z): 159.9 (M+H), retention time=0.35 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[C:12]([F:15])([F:14])[F:13])[CH2:26][CH2:25]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of crude 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (13.33 mmol, 75% pure) in DCM (10 mL) was added Et3N (1.4 mL, 10 mmol) and 1-methylpiperazine (1.1 mL, 10 mmol). Afetr stirring for 3 h at rt, aq. NaHCO3 was added, and the mixture was extracted with DCM. The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 10% MeOH/DCM) to provide 2.21 g of product as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[NH:13][N:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.I[C:64]1[N:68]2[CH:69]=[CH:70][C:71]([C:73]3[CH:78]=[CH:77][C:76]([S:79]([CH3:82])(=[O:81])=[O:80])=[CH:75][CH:74]=3)=[CH:72][C:67]2=[N:66][CH:65]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1.CCOC(C)=O.CS(C)=O>[C:17]([C:15]1[CH:16]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([C:64]3[N:68]4[CH:69]=[CH:70][C:71]([C:73]5[CH:74]=[CH:75][C:76]([S:79]([CH3:82])(=[O:80])=[O:81])=[CH:77][CH:78]=5)=[CH:72][C:67]4=[N:66][CH:65]=3)=[CH:3][CH:4]=2)=[O:10])[NH:13][N:14]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Br)cc2)[nH]n1
Reactant: CS(=O)(=O)c1ccc(-c2ccn3c(I)cnc3c2)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)[nH]n1
Yield: 18 %

Procedure:
To a round bottomed flask, add 1-(4-bromo-phenyl)-3-(5-tert-butyl-2H-pyrazol-3-yl)-urea (0.41 g, 1.2 mmol), tricyclohexylphosphine (24 mg, 0.07 equiv.), potassium acetate (0.36 g, 3 equiv.), bis(pinacolato)diboron (0.34 g, 1.1 equiv.) and DMSO (5 mL). Deoxygenate this mixture thoroughly with N2 then add tris(dibenzylideneacetone)-di-palladium (0) (33 mg, 0.03 equiv.) and heat to 100° C. overnight. Dilute the reaction with EtOAc and wash with water then saturated aqueous saturated sodium chloride. Pass the organic layer thru a Celite® plug then dry over magnesium sulfate, filter and concentrate to a residue (0.72 g). MS (ES), m/z 385.4 (M+1) is present. Add to this residue 3-iodo-7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine (0.25 g, 0.62 mmol), potassium carbonate (0.26 g, 1.86 mmol), dioxane (10 mL), and water (5 mL). Deoxygenate this mixture thoroughly with N2 then add dichloro-bis(triphenylphosphine) palladium (II) (13 mg, 0.03 equiv.) and reflux the reaction overnight under N2. Concentrate the reaction to dryness and slurry in acetone and filter to remove insolubles. Concentrate the filtrate then purify by silica column (1:1 Hex:EtOAc to 1:2 Hex:EtOAc to EtOAc to 5% MeOH:DCM) to give crude product. Triturate from DCM to give a pale yellow solid (0.059 g, 18%). MS (ES), m/z 529 (M+1).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=1[OH:32]>C(O)C>[Cl:28][C:26]1[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]([OH:32])=[C:22]([N:21]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]3[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]3=[O:20])=[CH:15]2)[CH:27]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(-c3cc(Cl)c([N+](=O)[O-])cc3O)cc2n(C)c1=O
Yield: 42.2 %

Procedure:
In a 10 mL round bottom flask was placed 4a (200 mg, 595 mmol) (see Example 2 for synthesis of 4a), 2-amino-4-chloro-5-nitrophenol (236 mg, 1.25 mmol), and ethanol (5 mL). The reaction was stirred at reflux for 5 h, then cooled and placed in a freezer. After several hours yellow crystals formed, which were filtered and rinsed with cold ethanol to give 5f (225 mg, 89%). 1H NMR (600 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.79 (s, 1H), 7.44 (s, 1H), 7.30 (s, 5H), 7.10 (s, 1H), 3.33 (s, 3H), 3.20 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 158.98, 152.39, 150.82, 147.31, 134.14, 131.79, 130.50, 130.32, 129.23, 128.96, 128.33, 127.48, 113.90, 112.93, 105.91, 102.66, 31.55, 27.51. MS (ES+) (m/z): [M+1]+ calculated for C20H16ClN4O5, 427.08. found 427.12.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].[CH2:22]([C@H:24]1[O:26][CH2:25]1)Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>[CH2:1]([O:19][CH2:22][C@H:24]1[CH2:25][O:26]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO
Reactant: ClC[C@@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC[C@H]1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 mL rb flask was charged with magnetic stirbar, tetrabutyl ammonium bromide (TBAB, 2.72 g, 8.4 mmol), linoleyl alcohol (225 g, 884 mmol), and sodium hydroxide (50.7 g, 1.2 mol), then cooled in an ice bath. The (S)-epichlorohydrin (156 g, 1.69 mol) was added slowly over 2 hours and then warmed to ambient temperature and stirred overnight. 259 mL of hexane was added and allowed to stir for 15 mins, then mixture was filtered and organic layer was concentrated in vacuo. The product was purified using 0-10% ethyl acetate/hexane gradient on 330 g silica column to give (2R)-2-{[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}oxirane. 1H NMR (CDCl3, 300 mHz) δ 0.90-0.86 (m, 3H), 1.29 (s, 16H), 1.55-1.64 (m, 2H), 2.00-2.07 (m, 4H), 2.58-2.61 (m, 1H), 2.74-2.80 (m, 3H), 3.12-3.15 (m, 1H) 3.34-3.52 (m, 3H), 3.67-3.72 (dd, J=12 Hz, 1H) 5.30-5.35 (m, 4H); HRMS (m+1) calcd 323.2872. Found 323.2951.
Reaction SMILES: [NH:1]([C:3]1[N:12]([CH2:13][CH2:14][CH3:15])[C:11](=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:17][CH2:18][C:19](Cl)=O.O.C(OCC)(=O)C>CN(C)C=O.ClCCl>[Cl:17][CH2:18][C:19]1[N:4]2[C:5]3[C:10]([C:11](=[O:16])[N:12]([CH2:13][CH2:14][CH3:15])[C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: CCCn1c(NN)nc2ccccc2c1=O
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCn1c(=O)c2ccccc2n2c(CCl)nnc12
Yield: 73.3 %

Procedure:
156 g of 2-hydrazino-3-n-propylquinazolin-4(3H)-one (0.72 mole) were suspended in 500 ml of dimethylformamide and 90 g of chloroacetyl chloride (0.80 mole) were added in portions with cooling in an ice bath. When the addition was complete, the mixture was heated on a hot water bath for three hours until TLC (SiO2EtOAc) indicated no starting material or intermediate remaining. The resultant mixture was poured into one liter of water and one liter of ethyl acetate and 500 ml of dichloromethane and the organic and aqueous layers were separated. The aqueous layer was extracted twice more with 500 ml of ethyl acetate and the combined organic layers were extracted twice with 500 ml of water, dried over MgSO4, filtered and evaporated to dryness. The crystalline residue was triturated with ether, filtered, washed with ether and dried under vacuum over P2O5 to obtain 146 g (74% yield) of the 1-chloromethyl-4-n-propyl[1,2,4]triazolo[4,3-a]-quinazolin-5(4H)-one melting at (capillary) 141°-145° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Reactant: NCCCN1CCOCC1
Solvent: Cc1ccccc1
Product: Clc1cc2nc(NCCCN3CCOCC3)c(-c3ccccn3)nc2cc1Cl
Yield: 83.2 %

Procedure:
A solution of 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.50 g) and N-(3-aminopropyl)-morpholine (0.46 g) in toluene (25 mL) was refluxed under nitrogen for 16 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give a yellow solid. Recrystallization from methanol and water gave the product as yellow crystals (0.56 g); mp 119-121° C.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[K+].BrC1C=[N:9][C:10]([Cl:15])=[C:11]([CH:14]=1)[C:12]#[N:13].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.OO>O1CCOCC1.C(Cl)Cl.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>[Cl:15][C:10]1[N:9]=[CH:2][C:1]([OH:4])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CC(=O)[O-]
Reactant: N#Cc1cc(Br)cnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(O)cnc1Cl
Temperature: 85 °C
Yield: 70.3 %

Procedure:
In a 300 mL sealed tube under N2 were dissolved potassium acetate (20 g, 207 mmol), 5-bromo-2-chloronicotinonitrile (15 g, 69 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (21 g, 83 mmol) and PdCl2(dppf)-CH2Cl2 Adduct (1.7 g, 2.1 mmol) in 150 mL of p-dioxane then stirred and heated at 85° C. for 2 hrs. After completion, the reaction was cooled to 0° C. and treated with hydrogen peroxide (31.5%) (22 ml, 207 mmol) then stirred at rt for 1 hr. The reaction mixture was diluted with DCM (100 mL) then water was added (200 mL). The aqueous phase was extracted 3 times with DCM (100 mL), then the organic layer was washed with saturated sodium thiosulfate solution (300 mL). The organics were then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude 2-chloro-5-hydroxynicotinonitrile (7.5 g, 70% yield) was carried through crude to the next step.
Reaction SMILES: [SH:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:4][N:3]=1.[OH-].[K+].[CH3:15]I>O.CCOCC.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][S:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:4][N:3]=1
Reactant: Sc1n[nH]c(-c2cccnc2)n1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CSc1n[nH]c(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 20 g (0.100 mol) of 65 and 7.5 g (0.150 mol) of potassium hydroxide in 100 ml of water was mixed with a solution of 10 ml (0.160 mol) of methyl iodide in 100 ml of ether. After addition of 1 g of tetrabutylammonium hydrogen sulphate the mixture was stirred overnight at room temperature. The ether phase was separated and the aqueous phase extracted with 3×100 ml of ether. The combined organic phases were dried over magnesium sulphate. Removal of the solvent in vacuo gave a colorless solid, 66. Yield: 17.0 g (0.089 mol, 89%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=[O:32])[O:18][C:19](=O)[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:8]1)(=O)C.C[N:34](C=O)C>N>[OH:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=[O:32])[NH:34][C:19](=[O:18])[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:8]1
Reactant: CC(=O)OCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Product: Cn1cc(C2=C(c3cn(CCO)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 1.6 g of 3-[1-(2-acetoxyethyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 4 ml of DMF and 8 ml of 33% aqueous ammonia was heated to 160° C. for 4 hours. The precipitate was filtered off and dried to give 1.04 g of 3-[1-(2-hydroxyethyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 250°-252° C.
Reaction SMILES: [CH:1]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[NH:16][CH:15]=1)([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.C([Li])CCC.[CH:29]([S:31]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44]C)=[O:43])=[CH:36][CH:35]=1)(=[O:33])=[O:32])=[CH2:30]>C1COCC1>[CH:1]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[N:16]([CH2:30][CH2:29][S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=2)(=[O:32])=[O:33])[CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CS(=O)(=O)c1ccc(CCC(=O)OC)cc1
Reactant: Clc1ccc2c(C(c3ccccc3)c3ccccc3)c[nH]c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(S(=O)(=O)CCn2cc(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 3-benzhydryl-6-chloro-1H-indole (1.0 eq) in THF (0.1 M), at −78° C., was added a 2.5 M solution of n-butyllithium (1.0 eq). After 0.5 h, the solution was warmed to room temperature and then treated with methyl 3-[4-(vinylsulfonyl)phenyl]propanoate (1.2 eq). The mixture was stirred for 3 h, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic solution was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The crude material was chromatographed with silica gel to give the desired product in 84% yield.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[N:16]=[CH:15]3)=[C:7]([CH:10]=1)[CH2:8][NH2:9].[C:22]([O-:25])(O)=O.[Na+]>CCOC(C)=O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[N:16]=[CH:15]3)=[C:7]([CH:10]=1)[CH2:8][NH:9][CH2:8][C:7]1[CH:10]=[CH:3][C:4]([O:25][CH3:22])=[CH:5][CH:6]=1
Reactant: Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(CNCc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)cc1

Procedure:
Intermediate (5t) (136 mg, 0.442 mmol; prepared as in Example 106, Step A) was dissolved in EtOAc (100 mL) and neutralized with saturated NaHCO3 then washed with brine, dried over MgSO4 and evaporated under reduced pressure to obtain the free amine. The free amine was dissolved in 1,2-dichloroethane (5 mL) and p-anisaldehyde was added to the solution at room temperature. After 2 hours of stirring, the solution was evaporated under reduced pressure. The residue was dissolved in MeOH (5 mL) and cooled to 0° C. Sodium borohydride was added to the solution at 0° C. After 40 minutes of stirring at 0° C., the reaction mixture was quenched with several drops of acetic acid at 0° C., then the reaction mixture was evaporated under reduced pressure. The residue was diluted with EtOAc (50 mL) and neutralized with saturated NaHCO3 and washed with brine, dried over MgSO4 and evaporated to obtain a crude oil, which was purified on silica gel with EtOAc/hexane (1:1) with 1% Et3N to afford compound (29t) as a color less oil (139 mg, 80% yield). 1HNMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.34 (d, J=9.4 Hz, 1H), 7.28 (d, J=7.0 Hz, 1H), 7.23-7.15 (m, 2H), 7.13-7.06 (m, 2H), 6.92-6.85 (m, 2H), 6.84-6.78 (m, 2H), 4.61 (s, 1H), 4.06 (s, 3H), 3.82 (s, 2H), 3.77 (s, 3H), 3.72 (s, 2H) ppm.