Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@H:6]1[C:10]2[NH:11][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[N:22]=[C:21]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:20]([CH3:29])[C:19]4=[O:30])=[CH:13][C:9]=2[C:8](=[O:31])[NH:7]1)=[N+]=[N-].CP(C)C>C1COCC1.O>[NH2:1][CH2:4][CH2:5][C@@H:6]1[C:10]2[NH:11][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[N:22]=[C:21]([NH:24][C:25]([CH3:28])([CH3:26])[CH3:27])[N:20]([CH3:29])[C:19]4=[O:30])=[CH:13][C:9]=2[C:8](=[O:31])[NH:7]1
Reactant: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](CCN=[N+]=[N-])NC4=O)cccc2c1=O
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](CCN)NC4=O)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To a solution of (R)-8-(6-(2-azidoethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrolo-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (504a, 200 mg, 0.476 mmol) in THF (7 mL) at RT was added trimethylphosphine (1.0 M in THF, 0.71 mL, 0.71 mmol) followed by 3 drops of water. It was stirred at RT for 30 min then the reaction mixture was concentrated and the crude residue was purified on the ISCO Combiflash RF (24 g Redisep column, using a gradient of 0-20% 2M NH3/MeOH in DCM) affording (R)-8-(6-(2-aminoethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (504, 65 mg, 0.166 mmol, 35% yield) as a light yellow amorphous solid after drying under vacuum. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.00 (1H, dd, J=8.0, 1.4 Hz), 7.93 (1H, dd, J=7.5, 1.5 Hz), 7.21 (1H, t, J=7.7 Hz), 6.75 (1H, s), 4.73 (1H, dd, J=7.6, 4.1 Hz), 3.56 (3H, s), 2.74-2.93 (2H, m), 2.12-2.26 (1H, m), 1.85-1.98 (1H, m), 1.57-1.67 (9H, s). m/z (ESI, +ve) 395.0 (M+1)+.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:12][C:5]=2[C:6](=[O:11])[C:7]=1[NH:8][CH:9]=[O:10].O.Cl.[CH3:30][N:31](C)C=O>>[C:30]([C:2]1[O:3][C:4]2[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:12][C:5]=2[C:6](=[O:11])[C:7]=1[NH:8][CH:9]=[O:10])#[N:31]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)Nc1cc2oc(Br)c(NC=O)c(=O)c2cc1Oc1ccccc1
Agent: Cl
Solvent: O
Product: CS(=O)(=O)Nc1cc2oc(C#N)c(NC=O)c(=O)c2cc1Oc1ccccc1
Reaction time: 2 h
Yield: 55.3 %

Procedure:
4.25 g of 2-bromo-3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 50 ml of N,N-dimethylformamide. 1.97 g of cuprous cyanide was added thereto, and the resulting mixture was stirred for 2 hours at 85°-90° C. The reaction mixture was introduced into 300 ml of water, adjusted to pH 4 with 4N hydrochloric acid, and extracted with two 200-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The resulting residue was recrystallized from acetonitrile to obtain 2.05 g (yield: 55.3%) of 2-cyano-3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 229°-230° C.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([C:28]1[CH:49]=[CH:48][C:31]([O:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([F:42])[CH:40]=3)[N:35]([CH2:43][C:44]([OH:46])=[O:45])[C:34]=2[CH3:47])=[CH:30][CH:29]=1)([OH:27])=O.[CH3:50]CN(C(C)C)C(C)C.CN.Cl>CN1C(=O)CCC1.C1COCC1>[F:42][C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:43][C:44]([O:46][CH3:50])=[O:45])[C:34]([CH3:47])=[C:33]2[O:32][C:31]1[CH:30]=[CH:29][C:28]([C:25]([NH:2][CH3:1])=[O:27])=[CH:49][CH:48]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(Oc2ccc(C(=O)O)cc2)c2cc(F)ccc2n1CC(=O)O
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Oc2c(C)n(CC(=O)OC)c3ccc(F)cc23)cc1
Reaction time: 20 h

Procedure:
HATU (294 mg) was added to a solution of the product from Example 9 (208 mg) and Hunig's base (0.3 ml) in NMP (1.2 ml). After 10 min a solution of methylamine in THF (0.4 ml, 2M) was added and stirred for 20 h. 2M HCl (1 ml) was added and the mixture was extracted with ethyl acetate. The organic extracts were dried (MgSO4), evaporated, re-dissolved in methanol and treated with a solution of trimethylsilyldiazomethan (1 ml, 2M in ether). Evaporation and purification by chromatography (silica, petrol—acetone as eluent) gave the sub-title compound (177 mg).
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH:6]2[CH2:13][C:14]3[C:19]([CH:5]12)=[CH:18][C:17]([CH3:21])(C)[CH:16]([O:22]C)[CH:15]=3)(=O)[CH3:2].B(Br)(Br)Br.[OH2:28].Cl[CH2:30]Cl>>[C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C@H:6]2[CH2:13][C:14]3[C:19]([C@@H:5]12)=[CH:18][C:17]([CH3:21])=[C:16]([OH:22])[C:15]=3[CH3:30])(=[O:28])[CH3:2]
Reactant: COC1C=C2CC3c4ccccc4N(C(C)=O)C3C2=CC1(C)C
Reactant: ClCCl
Reactant: O
Agent: BrB(Br)Br
Product: CC(=O)N1c2ccccc2[C@H]2Cc3c(cc(C)c(O)c3C)[C@H]21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under anhydrous conditions a solution of 5-acetyl-4b,5,9b,10-tetrahydro-2-methoxy-3,3-dimethylindeno[1,2-b]indole (109 mg, 0.35 mmol) in dichloromethane (1 cm3) was cooled to -78° C., and a solution of boron tribromide in dichloromethane (0.7 cm3 of 1M solution) added. The reaction was allowed to warm to room temperature, and stirred for 90 minutes, where-upon water (5 cm3) was cautiously added. After stirring for a further 10 minutes, the mixture was diluted, and extracted with dichloromethane. The combined dichloromethane extracts were dried (Na2SO4) and filtered through a pad of "flash" silica eluting further with 30% EtOAc/60°-80° petrol. Removal of solvent yielded a colourless solid. Yield: 96 mg, 94%. M.p. 205° C. (dec). 1H NMR (CDCl3) δ: [mixture of E/Z isomers] 8.06 (1/2H, d, J=7.1 Hz), 8.05-7.00 (41/2H, m), 4.23 and 5.75 (1H, d, J=8.1 and 7.5 Hz), 4.6 (1H, br), 4.22-4.08 (1H,2×ddd), 3.45-3.26 (1H, m), 3.25-3.05 (1H, 2×dd), 2.63 and 2.52 (3H, s), 2.20 and 2.17 (3H, s), 2.13 and 2.11 (3H, s).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:13]3[NH:14][C:15](=[O:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1.[CH3:26]I.O>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:13]3[N:14]([CH3:26])[C:15](=[O:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1
Reactant: O=C1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 35 mg) in dry N,N-dimethylformamide (5 ml) was added a solution of 2-(4-fluorophenyl)-5-oxo-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (250 mg) in dry N,N-dimethylformamide (3 ml) dropwise under ice cooling. The mixture was stirred for 30 minutes and to the mixture was added a solution of methyl iodide (125 mg) in dry N,N-dimethylformamide (2 ml). The mixture was stirred at ambient temperature for 2 hours and poured into water. The separated oil was extracted with dichloromethane and the solution was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained crude solid was recrystallized from a mixture of dichloromethane and diisopropyl ether to give 2-(4-fluorophenyl)-4-methyl-5-oxo-3-(pyridin-4-yl)-4,5,6,7 -tetrahydropyrazolo[1,5-a]pyrimidine (180 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6]([P:8](=[O:11])([OH:10])[OH:9])=O>>[CH2:2]([NH:1][CH2:6][P:8]([OH:11])([OH:10])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: O=CP(=O)(O)O
Reactant: NCC(=O)O
Product: O=C(O)CNCP(=O)(O)O
Yield: 65 %

Procedure:
The electrochemical reductive alkylation of glycine by formylphosphonic acid was carried out as described in Example 27 except the reaction was carried out in an undivided cell. A 65% yield of glyphosate was found.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[C:8]3[N:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:19])=[O:18])[N:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1.C(Cl)Cl.[O-:27]S([O-])(=S)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>>[NH2:1][C:2]1[N:7]2[C:8]3[N:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:19])(=[O:27])=[O:18])[N:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)c1nccc(-c2c3cccnc3n3c(N)nccc23)n1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1nccc(-c2c3cccnc3n3c(N)nccc23)n1
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 9-Amino-5-(2-methanesulfinylpyrimidin-4-yl)-pyrido[3′,2′:4,5]-pyrrolo[1,2-c]pyrimidine (50 mg, 0.16 mmol) in CH2Cl2 (15 ml) mCPBA (88 mg, 0.36 mmol) was added at room temperature. The mixture was stirred for 2 h. A saturated aq. Na2S2O3 solution was added (1 ml) and was basified with saturated aq. Na2CO3. The organic layer was separated and the aqueous layer extracted with CH2Cl2. The organic solutions were evaporated together and 9-Amino-5-(2-methanesulfonylpyrimidin-4-yl)pyrido[3′,2′:4,5]-pyrrolo[1,2-c]pyrimidine (50 mg, 91%) as a light orange solid was obtained.
Reaction SMILES: [Br-:1].O([CH2:9][CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.[CH3:30][NH2:31]>C(O)C>[Br-:1].[CH3:30][NH:31][CH2:9][CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(OCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CN
Agent: [Br-]
Solvent: CCO
Product: CNCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The required β-methylaminoethyltriphenylphosphonium bromide was prepared by heating a mixture of β-phenoxyethyltriphenyl phosphonium-bromide (46.2 g.) dissolved in ethanol (80 ml.) and 33% ethanolic methylamine (130 ml.) in an autoclave at 100° C for 3 hours. After cooling, the produce was precipitated by addition of dry ether (2 l.) filtered, washed with ether and dried, and had a melting point of 226° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li]CCCC.[C:12](=[O:14])=[O:13].CC(C)=O>C1COCC1>[C:12]([OH:14])(=[O:13])[C:3]1[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCC
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
After the inside of a 2-liter four-necked flask equipped with a magnetic stirrer, dropping funnel, 3-way cock and thermometer was replaced with nitrogen gas, the flask was charged with 117 ml (0.55 mol) of HN(Si(CH3)3)2 and 200 ml of TFE. After cooling in dry ice/acetone bath, 328 ml (0.525 mol) of 1.6 N hexane solution of n-BuLi was added dropwise over 45 minutes so that the solution temperature did not exceed −50° C. Further after stirring for 30 minutes, thereto was added dropwise over 45 minutes a solution prepared by dissolving, in 200 ml of THF, 136 g (0.5 mol) of benzoic acid (1,1,1,3,3,3-hexafluoro-2-propyl) obtained by usual preparation process so that the solution temperature did not exceed 50° C., followed by 30-minute stirring. 300 Gram of ice and 150 ml of concentrated hydrochloric acid were put in a 3-liter beaker, followed by stirring, and to the obtained slurry was added the reaction solution gradually. Then an organic layer was separated in the dropping funnel and water layer was extracted two times with 300 ml of n-hexane. The organic layer obtained by two extractions was washed with saturated brine, followed by drying with MgSO4, concentrating with an evaporator and refining by distillation under reduced pressure. Thereby 107.3 g of benzoic acid (1,1,1,3,3-pentafluoro-2-propenyl) was synthesized (boiling point: 71° to 73° C./24 mmHg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CCCCCC.CS(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
60% sodium hydride (0.26 g, 6.5 mmol) was washed with hexane, and suspended in dry DMSO (10 mL). To the suspension was added a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) in dry DMSO (10 mL). The mixture was stirred at room temperature for 1 hour and at 60° C. for 1 hour, and cooled to room temperature. To the reaction mixture was added 2-bromopyridine (0.62 mL, 6.5 mmol), and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added water (50 mL), and the mixture was extracted with diethyl ether. The extract was washed with water and saturated aqueous solution of sodium hydrogen carbonate, successively, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (50 g, ethyl acetate-hexane 1:5) to give the titled compound as colorless crystals (928 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:35]([F:38])([F:37])[F:36])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([C:31]([F:34])([F:33])[F:32])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[F:41][C:42]([F:47])([F:46])[CH2:43][CH2:44]I.CC#N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:35]([F:36])([F:37])[F:38])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:44][CH2:43][C:42]([F:47])([F:46])[F:41])[CH2:26]4)=[O:24])=[C:19]([C:31]([F:33])([F:34])[F:32])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Reactant: FC(F)(F)CCI
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1CCC(F)(F)F
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]imidazolidin-4-one (80 mg, 0.14 mmol, 1.00 equiv) in N,N-dimethylformamide (5 ml), sodium hydride (11 mg, 0.28 mmol, 2.00 equiv, 60%), 1,1,1-trifluoro-3-iodopropane (153 mg, 0.68 mmol, 5.00 equiv). The resulting solution was stirred overnight at r t. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 17.8 mg (19%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a light yellow solid. (ES, m/z): [M+CH3CN]+ 711.0; 1H NMR (300 MHz, CD3OD): δ8.12-8.22 (m, 2H), 7.99 (s, 1H), 7.89 (d, J=5.4 Hz, 2H), 7.71 (d, J=5.1 Hz, 1H), 5.12 (s, 1H), 4.70 (s, 1H), 4.16-4.47 (m, 3H), 3.86 (s, 1H), 3.57-3.74 (m, 2H), 2.39-2.67 (m, 2H).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[H-].[Na+].Br[CH2:14][C:15]1[N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>CN(C=O)C>[C:24]1([C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)(=[O:32])=[O:31])[C:15]=2[CH2:14][N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][C:9]=3[NH2:10])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ncnc2[nH]cnc12
Reactant: Cc1ccc(S(=O)(=O)n2c(CBr)c(-c3ccccc3)c3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(Cn3cnc4c(N)ncnc43)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a stirred mixture of 9H-purin-6-ylamine (130 mg, 0.976 mmol) in DMF (5 mL) under an argon atmosphere was added NaH (60% in mineral oil, 40 mg, 0.976 mmol). After stirring for 10 min at RT, 2-bromomethyl-3-phenyl-1-(toluene-4-sulfonyl)-1H-indole (430 mg, 0.976 mmol) in DMF (10 mL) was added and stirring was continued for 15 min. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) affording 9-((3-phenyl-1-tosyl-1H-indol-2-yl)methyl)-9H-purin-6-amine as a white solid (370 mg, 77%). LCMS: RT 3.16 min [M+H]+ 495.1
Reaction SMILES: [S:1]1[C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]2[S:1][C:2]3[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=3[CH:4]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(O)c2cc3ccccc3s2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cc2cc3ccccc3s2)cc1

Procedure:
2-(4-methoxybenzyl)-benzo[b]thiophene was prepared by the method of Example 47B with α-(2-benzo[b]thienyl)-4-methoxybenzyl alcohol (1.9 mmoles) 0.50 g), triethylsilane (2.0 mmoles, 0.32 mls), CH2Cl2 (20 ml) and TFA (3.7 mmoles, 0.30 ml). Recrystallization with hexanes and chloroform provided 0.40 (85%) of a pink solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[C:19]2[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].O>ClCCl>[NH2:25][C:20]1[C:19]([C:11]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:46]([NH:45][C:42]4[CH:43]=[CH:44][C:39]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:40][CH:41]=4)=[O:47])=[CH:9][CH:8]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: NCc1ccc(-n2c(-c3cccnc3N)nc3cccnc32)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)NCc2ccc(-n3c(-c4cccnc4N)nc4cccnc43)cc2)cc1
Yield: 14.2 %

Procedure:
3-(3-(4-(aminomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine HCl salt (63 mg, 0.2 mmol) was suspended in dichloromethane (2 mL). Diisopropylethylamine (0.07 mL, 0.4 mmol) was added. After everything went into solution 1-tert-butyl-4-isocyanatobenzene (32 mg, 0.2 mmol) were added. After 20 min water (10 mL) was added and diluted with dichloromethane (10 mL). The organic phase was separated and dried over Na2SO4. After filtration the solvent was removed under reduced pressure and it was purified by silica gel chromatography (0-20% methanol in dichloromethane) to yield the desired product (14 mg, 15% yield). Mp. 210-212° C.; 400 M Hz 1H NMR (CD3OD) δ: 8.32 (dd, J=0.8 Hz and 2.4 Hz, 1H), 8.19 (dd, J=0.6 Hz and 3.8 Hz, 1H), 7.98-7.94 (m, 1H), 7.55-7.49 (m, 2H), 7.45-7.37 (m, 3H), 7.35-7.24 (m, 5H), 6.48-6.23 (m, 1H), 4.48 (s, 2H), 1.29 (s, 9H); LCMS [M+H]: 492.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][C:6]([C:14]#[N:15])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1.CN1CCOCC1.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>O1CCCC1.C(OCC)(=O)C>[Br:23][C:19]1[CH:18]=[C:17]([NH:16][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:31](=[O:34])[CH:32]=[CH2:33])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:14]#[N:15])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1N
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: C=CC(=O)Nc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cc1OC
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of 1.5 g (4.06 mmol) of 6-Amino-4-[(3-bromophenyl)amino]-7-methoxy-3-quinolinecarbonitrile and 0.45 ml of N-methylmorpholine in 30 ml of tetrahydrofuran was added at 0° C., under nitrogen, with stirring, 0.42 g (4.7 mmol) of acryloyl chloride of a 15 minute period. After 1 hour at 0° C., the solution was diluted with 200 ml ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution and then dried over magnesium sulfate. The solvent was removed. The residue was chromatographed on silica gel eluted with chloroform-ethyl acetate mixtures to give 0.5 g of the tide compound as a light yellow solid powder: mass spectrum (electrospray, m/e): M+H 423.1,425.1
Reaction SMILES: C([O:8][C:9](Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=O.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH:30]=[C:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[N:23]=1>C(Cl)Cl>[CH3:13][N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([N:34]1[CH2:35][CH2:36][C:31](=[CH:30][C:29]#[C:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[N:23]=2)[CH2:32][CH2:33]1)=[O:8]
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNc1ccccc1
Solvent: ClCCl
Product: Cc1cccc(C#CC=C2CCN(C(=O)N(C)c3ccccc3)CC2)n1
Reaction time: 0.67 h
Yield: 242.2 %

Procedure:
To a solution of ditrichloromethyl carbonate (43.6 mg, 0.147 mmol) in CH2Cl2 (1 mL) stirred at r.t., was added dropwise a solution of N-methylaniline (48.2 μL, 0.445 mmol) and DEA (168 μL, 0.98 mmol) in 1.5 mL of CH2Cl2 over 30′. After 40 min., was added a solution of the Compound of Example 3 (94.4 mg, 0.445 mmol) and 168 μL of DEA in 2 mL di CH2Cl2. After 24 h, the reaction mixture was evaporated to dryness in vacuo, taken up with water and extracted with EtOAc. The residue from extraction was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc gradient from 4:6 to 2:8 to afford the title compound (123 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:30]2[CH2:31][CH2:32][N:27]([C:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:26])[CH2:28][CH2:29]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Reactant: O=C(c1ccccc1)N1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 25 °C
Yield: 1362.5 %

Procedure:
A solution of N-benzyl-5-bromo-2-nitrobenzenamine (50 mg, 0.16 mmol) and phenyl(piperazin-1-yl)methanone (93 mg, 0.48 mmol) in NMP (1 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish (4-(3-(benzylamino)-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (520 mg, 2.18 mmol), 92% yield. 1H NMR (500 MHz, CDCl3) d (ppm) 8.85 (m, 1H), 8.14 (d, J=9.5 Hz, 1H), 7.51-7.3 (m, 10H), 6.24 (dd, J=2.5 Hz, 10 Hz, 1H), 5.88 (d, J=2.5 Hz, 1H), 4.55 (d, J=5 Hz, 2H) 3.9-3.2 (m, 8H).+ESI HRMS (calcd for C24H24N4O3Na, M+Na) 439.1746, found 439.1741