Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[NH:8][C:9]([C:11]3[N:16]=[C:15]([C:17]4[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]5[O:24][C:23]([C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=6)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=5[CH:36]=4)[CH:14]=[CH:13][C:12]=3[OH:43])=[CH:10][C:3]=12.[C:44]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[C:3]2[CH:10]=[C:9]3[C:11]4[N:16]=[C:15]([C:17]5[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:39])=[O:40])=[CH:19][C:20]6[O:24][C:23]([C:25]7[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=7)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=6[CH:36]=5)[CH:14]=[CH:13][C:12]=4[O:43][CH2:44][N:8]3[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(-c4cc5c(F)cncc5[nH]4)n3)cc12
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cncc5n3CO4)cc12
Yield: 28.7 %

Procedure:
To a stirring solution of 5-(6-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-2-yl)-5-hydroxypyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.17 mmol) and Cs2CO3 (108 mg, 0.33 mmol) in DMF (3 mL) was added chloroidomethane (35 mg, 0.2 mmol) dropwise at 100° C. under N2. The mixture was heated for 8 hours. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine and dried over Na2SO4. The crude product was purified using prep-HPLC to obtain the product of Compound 46 (30 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 8.61 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.95 (t, J=6.0 Hz, 2H), 7.65 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.53 (d J=8.0 Hz, 1H), 7.25˜7.19 (m, 3H), 6.10 (s, 2H), 5.99 (s, 1H), 3.37 (s, 3H), 3.00 (d, J=4.0 Hz, 3H), 2.80 (s, 3H). MS (M+H)+: 616.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[S:17]([NH:20][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=1)(=[O:19])=[O:18].C(OCC)(=O)C>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[S:17]([N:20]([C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=1)[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])(=[O:18])=[O:19]
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cnccc1Cl
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cnccc1Cl
Temperature: -5 °C

Procedure:
2-(Trimethylsilyl)ethoxymethyl chloride (0.22 ml) was added dropwise over 5 minutes to a stirred solution of 4-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.306 g) and N,N-diisopropylethylaminc (0.21 ml) in dry DMF (1 ml) at -15° C. The resultant solution was allowed to warm to -5° C. over 40 minutes then ethyl acetate (30 ml) was added and the mixture was washed with 2M hydrochloric acid (30 ml), water (30 ml) and saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 30-50% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 4-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.266 g) as an oil; 1H NMR (d6 -DMSO): -0.1 (s, 9 H), 0.7 (t, 2 H), 2.45 (s, 3 H), 3.6 (t, 2 H), 3.85 (s, 3 H), 5.2 (s, 2 H), 7.8 (d, 1 H), 8.0 (s, 1 H), 8.8 (d, 1 H), 9.1 (s, 1 H); mass spectrum (+ve FAB, DMSO/Glycerol): 445 (M+H)+.
Reaction SMILES: B(Br)(Br)[Br:2].[Cl:5][C:6]1[C:7]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][C:9]([O:15]C)=[C:10]([CH2:12][CH2:13]O)[CH:11]=1>C(Cl)Cl>[Br:2][CH2:13][CH2:12][C:10]1[CH:11]=[C:6]([Cl:5])[C:7]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][C:9]=1[OH:15]
Reactant: BrB(Br)Br
Reactant: COc1cc(C2CCCCC2)c(Cl)cc1CCO
Solvent: ClCCl
Product: Oc1cc(C2CCCCC2)c(Cl)cc1CCBr
Reaction time: 5 h

Procedure:
20 ml of boron tribromide are added slowly at 0° with stirring to 11 g of 2-(5-chloro-4-cyclohexyl-2- methoxyphenyl)-ethanol in 300 ml of dry methylene chloride. The mixture is then stirred for 5 hours at 22°.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:23]=[CH:22][O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+].CCOC(C)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:24]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:23]=[CH:22][O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:8]1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(-c3ccon3)cc2)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(-c3ccon3)cc2)C(=O)O1
Temperature: 60 °C

Procedure:
[(5R)-3-(4-Isoxazol-3-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate (Intermediate 7,400 mg, 1.18 mmol), sodium azide (99 mg, 1.53 mmol), 18 crown-6 (23.6 mg, 0.089 mmol) and tetrabutylammonium iodide (28.2 mg, 0.076 mmol) were combined in DMF (5 ml) and heated to 60° C. for 4 hours. EtOAc (20 ml) was added and the organic layers were washed with brine (3×20 ml), dried over Na2SO4 and concentrated under vacuum to yield (5R)-5-(azidomethyl)-3-(4-isoxazol-3-ylphenyl)-1,3-oxazolidin-2-one. (5R)-5-(Azidomethyl)-3-(4-isoxazol-3-ylphenyl)-1,3-oxazolidin-2-one (300 mg, 1.045 mmol) was added to CH2Cl2:MeOH:THF:H2O 10:10:10:2 and then polystyrene triphenylphosphine resin (2650 mg, 4.18 mmol) was added. The reaction was allowed to stir overnight and then the resin was filtered and washed multiple times with dichloromethane and methanol. The filtrate was concentrated in vacuo and then dissolved in dichloromethane (10 ml) followed by addition of 2N HCl in ether (0.5 ml). The precipitate was collected and washed with ether (2×20 ml) and then dried under vacuum to yield the title product (300 mg).
Reaction SMILES: [F:1][C:2]1([F:52])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:39]=[N:40][N:41](CC3C=CC(OC)=CC=3)[CH:42]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:52][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:42]=[N:41][NH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(Cn2cc([C@H]3CCC(F)(F)C[C@@H]3Oc3cc(F)c(S(=O)(=O)N(Cc4ccc(OC)cc4OC)c4ccncn4)cc3C)cn2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CC(F)(F)CC[C@@H]1c1cn[nH]c1
Yield: 96.3 %

Procedure:
A solution of the 4-({(1S,2R)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (0.15 g, 0.20 mmol) prepared in Example 143f, triethylsilane (0.16 mL) and trifluoroacetic acid (0.20 mL) in dichloromethane (2.0 mL) was stirred at 140° C. for 1 hour under microwave irradiation. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (ethyl acetate) to yield the title compound (90 mg, 94%) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CCCCCC>C(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]2=[O:20])=[O:27])=[CH:24][CH:23]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (100 mg, 0.37 mmol) and p-chlorobenzoyl chloride (52 μl, 0.41 mmole) were combined at room temperature in 5 ml of methylene chloride. The resulting solution was protected from moisture and stirred at room temperature overnight. The reaction mixture was diluted with 70 ml of methylene chloride and washed with sodium bicarbonate solution (sat.) and brine. The organic extracts were dried (MgSO4) and concentrated to give 150 mg of crude product. Chromatography on silica gel (chloroform - methanol - ammonia, 95:5:0.5 v/v) and trituration with hexane yielded the analytical product as a white powder, m.p. 258°-259° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([OH:17])=[O:16]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(COc2cncc(Cl)c2)cc1
Yield: 53.6 %

Procedure:
To a suspension of 5-chloro-3-hydroxypyridine (0.6 g, 4.6 mmol) and potassium carbonate (1.27 g, 9.2 mmol) in acetone (10 mL) was added 4-carboxybenzylbromide (1.0 g, 4.6 mmol). The reaction was heated at reflux for 18 hours. After cooling, the reaction mixture was partitioned between EtOAc (80 mL) and saturated aqueous ammonium chloride solution (140 mL). The organic layer was dried over magnesium sulfate and evaporated in vacuo to afford the title compound (0.65 g, 53%), which was used in the next step without further purification.
Reaction SMILES: CSC.B.[NH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:9]=2[O:8][N:7]=1>COCCOC>[NH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][NH2:16])=[CH:14][C:9]=2[O:8][N:7]=1
Reactant: N#Cc1ccc2c(N)noc2c1
Agent: B
Solvent: COCCOC
Solvent: CSC
Product: NCc1ccc2c(N)noc2c1
Reaction time: 0.5 h

Procedure:
Borane methylsulfide complex (2 M in THF, 1.98 mL) was added to a stirred refluxing solution of 3-amino-6-cyano-1,2-benzisoxazole (210 mg, 1.32 mmol) in DME (10 mL). After 45 min excess methyl sulfide was evaporated and the reaction mixture was cooled and quenched with 1M HCl solution (10 mL). The mixture was stirred for 30 min and then was neutralised with sodium bicarbonate solution and concentrated to dryness. The residue was triturated with 5% methanol/chloroform, filtered and the filtrate evaporated in vacuo. The residue was purified by chromatography on silica (5% methanol, chloroform/ammonia) to give the title compound as a yellow solid:
Reaction SMILES: [NH2:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:37][CH3:38])[C:20]([Cl:39])=[CH:19][N:18]=1>>[Cl:39][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:37][CH3:38])=[N:22][C:17]([NH:1][C:2]2[C:13]([O:14][CH3:15])=[CH:12][C:5]3[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: COc1cc2c(cc1N)CCNC(=O)C2
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)CCNC(=O)C2

Procedure:
The title compound was prepared from 7-Amino-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.012 g, 15%). MP: 208-213° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.14-8.10 (m, 2H), 8.03-8.02 (m, 1H), 7.44 (s, 2H), 6.64-6.62 (m, 1H), 6.58-6.56 (m, 1H), 6.54-6.49 (m, 1H), 5.70 (br s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.56-3.50 (m, 2H), 3.23-3.18 (m, 4H), 3.00-2.96 (m, 2H), 2.64-2.59 (m, 4H), 2.38 (s, 3H). MS: 538 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.[CH3:15][NH:16][O:17][CH3:18]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([N:16]([O:17][CH3:18])[CH3:15])=[O:8]
Reactant: CNOC
Reactant: COc1cc(Br)cc(C(=O)Cl)c1Cl
Agent: Cl
Solvent: ClCCl
Product: COc1cc(Br)cc(C(=O)N(C)OC)c1Cl
Reaction time: 18 h
Yield: 78.2 %

Procedure:
To a solution of acid chloride 59 (3.41 g, 14.3 mmol) in CH2Cl2 (70 mL) was added dropwise N,O-dimethylhydroxylamine hydrochloride (4.18 g, 42.9 mmol) at 0° C. under an atmosphere of nitrogen. Then, TEA (12.0 mL, 85.8 mmol) was added to the mixture at 0° C. After being stirred for 18 hours, the mixture was partitioned between EtOAc (150 mL) and water (100 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the product 60 (3.45 g, 80%) as a white solid.
Reaction SMILES: C=O.[CH:3](O)=O.[F:6][C:7]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(=O)([O-])O.[Na+]>O>[F:6][C:7]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH3:3])[CH2:12]1
Reactant: O=CO
Reactant: O=[N+]([O-])c1ccc(OCC2CCCNC2)c(F)c1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCCC(COc2ccc([N+](=O)[O-])cc2F)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
38% aqueous formaldehyde (1.00 ml) and formic acid (1.00 ml) were added to 3-(2-fluoro-4-nitrophenoxymethyl)piperidine (compound of Reference Example 53; 0.300 g, 1.18 mmol), and the mixture was stirred at 90° C. for 1 hour. The reaction mixture was adjusted to pH=8 by addition of saturated aqueous sodium hydrogencarbonate, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel to give the title compound (0.275 g, 87%) as a yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][CH:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].[NH3:30]>CN1CCCC1=O>[CH:1]([O:4][C:5](=[O:29])[NH:6][CH:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:26]([NH2:30])=[N:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)NC1Cc2c(n(Cc3nccnc3Cl)c3ccc(C#N)cc23)C1
Reactant: N
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)NC1Cc2c(n(Cc3nccnc3N)c3ccc(C#N)cc23)C1
Temperature: -78 °C
Reaction time: 72 h
Yield: 28 %

Procedure:
In a screw-cap vial, dissolve (±)-[4-(3-chloro-pyrazin-2-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (30 mL, 0.073 mmol) in 1-methyl-2-pyrrolidinone (NMP) (0.5 mL) and cool to −78° C. Condense NH3 into the reaction mixture (1 mL), seal the reaction vessel, and warm to room temperature over 24 h. Heat the reaction up to 50° C. for 18 h, then at 80° C. for 72 h. Cool the reaction in a dry ice bath. Carefully open the reaction vessel and allow the liquid NH3 to evaporate. Dissolve the residue in EtOAc (50 mL) and wash the organics with water (3×20 mL). Dry the organics (MgSO4), filter, and concentrate to give 27 mg crude product as a colorless film. Purify on 4 g silica gel [50-100% EtOAc/(1:1 CH2Cl2/hexanes)] to give 8 mg (28%) of the title compound as a colorless film. LCMS 100% @ 4.23 min m/z 391 (M+H), 389 (M−H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.[I-].[K+].[CH3:30][NH:31][CH:32]([CH3:34])[CH3:33]>CC(N(C)C)=O.C(OCC)(=O)C>[CH:32]([N:31]([CH3:30])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1)([CH3:34])[CH3:33]
Reactant: CNC(C)C
Reactant: CCNC(=O)c1ccc(C)c(-n2ccc3ccc(OCCCl)cc3c2=O)c1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCNC(=O)c1ccc(C)c(-n2ccc3ccc(OCCN(C)C(C)C)cc3c2=O)c1
Temperature: 150 °C
Yield: 63.3 %

Procedure:
3-[7-(2-Chloroethoxy)-1-oxoisoquinolin-2(1H)-yl]-N-ethyl-4-methylbenzamide (150 mg), potassium iodide (129 mg) and methylisopropylamine (244 μL, 2.34 mmol) were stirred in DMA (3 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using initially 10% methanol/ethyl acetate and then a 99:1 mixture of 10% methanol/ethyl acetate and aqueous ammonia solution gave 3-[7-[2-(Isopropylmethylamino)ethoxy]-1-oxoisoquinolin-2(1H)-yl]-N-ethyl-4-methylbenzamide as a foam (104 mg); NMR Spectrum: (DMSO d6) 0.97 (d, 6H), 1.12 (t, 3H), 2.11 (s, 3H), 2.23 (s, 3H), 2.75 (t, 2H), 2.83 (m, 1H), 3.29 (m, 2H), 4.13 (m, 2H), 6.73 (d, 1H), 7.23 (d, 1H), 7.41 (m, 1H), 7.51 (d, 1H), 7.67 (d, 1H), 7.72 (d, 1H), 7.78 (d, 1H), 7.89 (m, 1H), 8.51 (t, 1H); Mass Spectrum: M+H+ 422.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[O:5][C:4]1=[O:14].[CH2:15](Br)[CH2:16][CH2:17][CH3:18]>CC(N(C)C)=O>[CH2:15]([N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[O:5][C:4]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCn1c(=O)oc(=O)c2cccnc21
Reaction time: 1 h
Yield: 32.7 %

Procedure:
A suspension of sodium hydride (95%, 0.96 g, 40 mmol) in dimethylacetamide (60 mL) at 10° C. under nitrogen was reacted with the product of Example 1A (5.7 g, 34.7 mmol) with stirring for 1 hour then treated with n-butylbromide (5.2 g, 38 mmol) and stirred for an additional 16 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash column chromatography with silica gel eluting with hexane and ethyl acetate (3:1) to give the title compound as a white solid, (2.5 g, 33% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.92 (t, J=7.35 Hz, 3H), 1.36 (m, 2H), 1.65 (m, 2H), 4.13 (m, 2H), 7.38 (dd, J=7.72, 4.78 Hz, 1H), 8.39 (dd, J=7.72, 1.84 Hz, 1H), 8.77 (dd, J=5.15, 1.84 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:52][N:53]([CH3:59])[CH2:54][CH2:55][CH2:56][CH2:57][NH2:58]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:58][CH2:57][CH2:56][CH2:55][CH2:54][N:53]([CH3:59])[CH3:52])=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: CN(C)CCCCN
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C)CCCCNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 30 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (210 mg, 0.58 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (242 mg, 0.63 mmol) and 4-dimethylaminobutyl amine (139 mg, 1.2 mmol); (67 mg, 30% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.7 (m, 2H), 8.0 (d, 1H), 7.6–7.8 (m, 4H), 7.4 (m, 2H), 3.3–3.6 (m, 4H), 2.3 (s, 6H), ES-MS (m/z) 377 [M+1]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:27])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=2[CH3:21])[NH:12][C:11]1=[O:28].Cl[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:27])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=2[CH3:21])[N:12]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:11]1=[O:28]
Reactant: CCOC(=O)CCl
Reactant: CCOC(=O)c1c(C)cc2[nH]c(=O)n(-c3ccccc3Cl)c(=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(-c2ccccc2Cl)c(=O)c2c(C)c(C(=O)OCC)c(C)cc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A portion (50 mg) of sodium hydride suspension (50%) in mineral oil was added to a stirred solution of 3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-2,4-(1H,3H)-quinazolinedione (373 mg) in dried dimethylformamide (20 ml). After addition of ethyl chloroacetate (123 mg), the mixture was stirred at 70° C. for one hour. The solvent was evaporated at reduced pressure, and the residue was extracted with CHCl3, and the CHCl3 extract was washed with water, dried over anhydrous MgSO4 and concentrated. The residue was recrystallized from ethanol to give 3-(2-chlorophenyl)-1-ethoxycarbonylmethyl-6-ethoxycarbonyl-5,7-dimethyl-2,4(1H,3H)-quinazolinedione (287 mg, 62.6%) melting at 158°-159° C. MS: m/e, 458(M+), 423. NMR: δ (ppm, CDCl3), 1.28 (3H, t), 1.39 (3H, t), 2.40 (3H, s), 2.74 (3H, s), 4.28 (2H, q), 4.42 (2H, q), 4.92 (2H, s), 6.74 (1H, s), 7.41 (4H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.[H-].[Na+]>CN(C=O)C>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH:18]=3)[CH:14]=[CH:15]2)[CH:25]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3cc[nH]c3c2)c1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2ccc3ccn(-c4cc(Cl)ncn4)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.7 %

Procedure:
6-(3-Nitrophenyl)-1H-indole (2 g, 8.39 mmol) and 4,6-dichloropyrimidine (1.25 g, 8.39 mmol) were dissolved in DMF (20 mL) and sodium hydride (60% in mineral oil, 671 mg, 16.78 mmol) was added at 0° C. 1 hour later, ice was added to the reaction solution and the mixture solution was added to ice water. The mixture solution was stirred at room temperature for 12 hours. Thus prepared solid was filtered, washed with water, and dried in the air. 1-(6-Chloropyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (2.61 g) was yielded as yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:13]([CH2:20][CH2:21][NH:22][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:22][CH2:21][CH2:20][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: NCCOc1ccccc1
Product: c1ccc(OCCNc2ccc3nc(NCCOc4ccccc4)ccc3c2)cc1

Procedure:
The title compound, MS: m/e=400.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline and 2-phenoxyethylamine.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][CH:10]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:24][O+](C)C>C(Cl)Cl>[CH3:24][O:18][C:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:9][CH:8]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:17]=1
Reactant: O=C1CCCCCC(CC=Cc2ccccc2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(CC=Cc2ccccc2)CCCCC1

Procedure:
The product of Example 68 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.