Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH2:16])=[CH:5][CH:4]=1.Cl[CH2:18][C:19]([NH2:21])=[O:20].C(=O)(O)[O-].[Na+].CCOCC.CCCCC>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH:16][CH2:18][C:19]([NH2:21])=[O:20])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccccc2CN)cc1
Reactant: NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCCCC
Solvent: CCOCC
Product: COc1ccc(-c2ccccc2CNCC(N)=O)cc1

Procedure:
A reaction vessel was charged with 800 mg (3.8 mmole) of [(4-methoxyphenyl)phenyl]methylamine dissolved in 30 ml of absolute ethanol together with 340 mg (3.7 mmole) of chloracetamide and 330 mg (4 mmole) of sodium bicarbonate. The suspension was brought to reflux and held at reflux for 3 days. Solvent was evaporated and the residue was dissolved in dichloromethane and water. The organic phase was dried over potasium carbonate and the solvent evaporated under reduced pressure. The oil obtained was solidified by stirring in an ether pentane mixture. The solid was crystallized in cyclohexane with a few drops of ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:4]([O:21][CH3:22])[CH:3]=1.FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:39](=[O:54])[C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:41]=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:39](=[O:54])[C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:43]=[C:42]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:41]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1NCCS(C)(=O)=O
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 4-(4-fluoro-2-methoxyphenyl)-N-(2-(methylsulfonyl)ethyl)pyridin-3-amine (0.08 g, 247 μmol, example 192, intermediate a) and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (177 mg, 617 μmol, example 223, intermediate d) in CH2Cl2 (2 mL) was added DIPEA (128 mg, 172 μL, 987 μmol) and the clear solution was stirred at room temperature for 19 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (0.075 g; 52%). MS (ESI): m/z=575.09 [M+H]+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[O:24]N)([O-:14])=[O:13]>O1CCCC1>[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24])([O-:14])=[O:13].[NH2:12][N:5]1[CH:6]=[CH:7][C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][CH2:4]1
Reactant: CCOC(=O)c1ccncc1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C1=CCN(N)C=C1
Product: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Yield: 99.7 %

Procedure:
Ethyl isonicotinate (10.0 g) was dissolved in tetrahydrofuran (100 ml), and O-(2,4-dinitrophenyl)hydroxylamine (11.9 g) was added at room temperature, which was followed by refluxing under heating for 2 hr. The solvent was evaporated under reduced pressure, and the obtained residue was washed with diethyl ether and ethyl acetate to give the objective compound (10.5 g) as an amber-colored powder.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:21][C:22]([F:45])([F:44])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]2[CH2:34]OS(=O)(=O)[N:31]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:25][CH:24]=1>CN(C=O)C.CCOCC>[Br:1][C:2]1[S:3][C:4]([N:7]([CH2:34][C@@H:30]([NH:31][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:44])[F:45])=[CH:28][CH:27]=2)[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccc(C(F)(F)F)cc2)COS1(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1cnc(Br)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a 250 mL round-bottomed flask was added tert-butyl 2-bromothiazol-5-ylcarbamate (0.75 g, 2.69 mmol), DMF (26.9 mL, 2.69 mmol), and cesium carbonate (1.75 g, 5.37 mmol). The mixture was warmed to 50° C. and 1,1-dimethylethyl 4-((4-(trifluoromethyl)phenyl)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.13 g, 2.96 mmol, Scheme 1) was added slowly in 10 mL DMF. After 1 hour, the mixture was cooled, diluted with ether (100 mL) and washed with brine (3×50 mL). The organic layer was dried over sodium sulfate, evaporated onto a plug of silica gel and purified by chromatography through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 20% to 100% EtOAc in hexane, to provide the product (1.42 g, 91% yield) as a white amorphous solid. LCMS (API-ES) m/z (%): 582 (100%, M+H).
Reaction SMILES: N[C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:8]=[C:9]([Cl:11])C=1)[C:5]([OH:7])=[O:6].C[Si]([CH:18]=[N+:19]=[N-])(C)C.[C:21]1(C)C=CC=CC=1>CO>[NH2:19][C:18]1[C:9]([Cl:11])=[CH:8][C:4]([C:5]([O:7][CH3:21])=[O:6])=[C:3]([O:12][CH3:13])[CH:2]=1
Reactant: Cc1ccccc1
Reactant: COc1c(N)cc(Cl)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4 amino-5-chloro-2-methoxybenzoic acid (1.008 g, 5.0 mmol) in a mixture of toluene (9 mL) and methanol (1 mL) at 0° C. was added (trimethylsilyl)diazomethane (2.0 M in hexane, 3.0 mL, 6.0 mmol) dropwise. The reaction mixture was then warmed to room temperature and stirred for 16 h. Excess (trimethylsilyl)diazomethane was quenched by adding acetic acid until the bright yellow color of the reaction mixture disappeared. The mixture was then concentrated in vacuo to give the title compound as an off-white solid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]([N:14]1[CH:18]=[CH:17]N=[CH:15]1)(N1C=CN=C1)=[O:8].[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][NH:26][C:27]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)CNCC2)=[O:28].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:14]1[CH2:15][CH2:36][C:37]2[C:17](=[CH:31][CH:30]=[C:29]([C:27]([NH:26][O:25][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][O:19]3)=[O:28])[CH:38]=2)[CH2:18]1)=[O:8]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Reactant: COCCCN
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COCCCNC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Reaction time: 8 h

Procedure:
A mixture of 0.074 ml 3-methoxyproylamine in 4 ml DMF is treated under an inert gas atmosphere is treated with 117 mg carbonyldiimidazole. After 2 h at ambient temperature the resulting mixture is treated with 200 mg of N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide and 10 mg DMAP. The reaction mixture is stirred overnight. After addition of 2 ml water the mixture is extracted twice with dichloromethane and the combined organic phases are dried and evaporated. The residue is purified by silica gel flash chromatography. 180 mg of yellowish oil are obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C([O-])=O.[Na+].[O:12]=[C:13]1[C:21]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])([NH:22][C:23]([CH:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][NH:26]2)=[O:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)=O>[CH:1]([N:26]1[CH:25]([C:23]([NH:22][C:21]2([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:13]2=[O:12])=[O:24])[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:3]
Reactant: CCCCCN1C(=O)C(CCC(=O)OCC)(NC(=O)C2Cc3ccccc3CN2)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Product: CCCCCN1C(=O)C(CCC(=O)OCC)(NC(=O)C2Cc3ccccc3CN2C=O)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A mixture of 0.66 g of formic acid and 1.35 g of acetic acid anhydride was heated at 50° C. for 15 minutes. After cooling by dilution with 15 ml of anhydrous methylene chloride, 0.68 g of sodium formate and 15 ml of a methylene chloride solution of 1.70 g of ethyl 3-[2,3-dihydro-2-oxo-1-pentyl-3-(1,2,3,4-tetrahydro-3-isoquinolinyl)carbonylamino-1H-indol-3-yl]propionate were added to this mixed anhydride solution. The whole was stirred at room temperature overnight. The reaction mixture was neutralized with an aqueous saturated sodium hydrogen carbonate solution and then extracted with chloroform. The extract was washed, dried, filtered and then evaporated in vacuo to afford 1.72 g of ethyl 3-[3-(2-formyl-1,2,3,4-tetrahydro-3-isoquinolinyl)carbonylamino-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3- yl]propionate as a pale yellow amorphous solid. IR (Nujol) (cm-1): 3280, 1720, 1655, 1610, FAB-MS (m/z): 506 (MH+) 160 (base).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22][CH3:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCCl)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCN3CCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 2-(butyloxy)-9-(6-chlorohexyl)-8-(methyloxy)-9H-purin-6-amine and pyrrolidine.
Reaction SMILES: Br[C:2]1[C:23]([O:24][CH3:25])=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=4.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH:35]=[C:36]([C:2]2[C:23]([O:24][CH3:25])=[CH:22][C:5]3[C:6]([CH3:21])([CH3:20])[C:7]4[NH:8][C:9]5[C:14]([C:15]=4[C:16](=[O:17])[C:4]=3[CH:3]=2)=[CH:13][CH:12]=[C:11]([C:18]#[N:19])[CH:10]=5)[CH2:37][CH2:38]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1cc2c(cc1Br)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1C1=CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 80 °C
Reaction time: 1.33 h

Procedure:
To 9-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E3-1-1, 300 mg, 0.759 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (282 mg, 0.911 mmol, 1.2 eq.), Pd(PPh3)2Cl2 (26.6 mg, 0.0379 mmol, 0.05 eq.) and sodium carbonate (241 mg, 2.28 mmol, 3.0 eq.), DME (5 ml) and water (1 ml) were added. The mixture was subjected to reduced pressure under ultrasonication treatment, followed by flushing with nitrogen gas. This procedure was repeated five times and then degassed. The mixture was stirred at 80° C. for 80 min under nitrogen atmosphere. Pd(PPh3)2Cl2 (26.6 mg, 0.0379 mmol, 0.05 eq.) was added and the mixture was further stirred at 80° C. for 20 min. Then, the mixture was cooled to room temperature, and added with water and ethyl acetate. The insoluble matters were filtered through Celite. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to obtain the title compound as a crude product (gray powder).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33][C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:49]=[CH:48][C:47]([CH2:50]O)=[CH:46][CH:45]=1)=[O:35]>>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:50][C:47]2[CH:46]=[CH:45][C:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH2:37][NH:36][C:34]([NH:33][CH3:32])=[O:35])=[CH:49][CH:48]=2)[C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)cc1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC[C@@H](C)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-[2(R)-benzyloxypropyl]amino-3-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step C) and 2'-[[(methylamino)carbonyl]amino]methyl-1,1'-biphenyl-4-methanol, methanesulfonate ester (Example 48, Step I) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CD3OD): δ 1.10 (s, 3H), 1.12 (s, 3H), 1.18 (d, 6 Hz, 3H), 1.95 (m, 1H), 2.12-2.39 (m, 3H), 2.40-2.63 (m, 3H), 2.63 (s, 3H), 3.70 (m, 1H), 4.13 (s, 2H), 4.42 (dd; 12, 8 Hz; 1H), 4.46 (d, 12 Hz, 1H), 4.59 (d, 12 Hz, 1H), 4.93 (d, 15 Hz, 1H), 5.23 (d, 15 Hz, 1H), 7.02-7.40 (m, 17H). FAB-MS: calculated for C41H49N5O4 675; found 676 (M+H, 100%).
Reaction SMILES: C(S(C1C=C(C2C=CC(O)=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C.[CH2:27]([S:29]([C:32]1[CH:33]=[C:34]([C:38]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C@H:49]([OH:51])[CH3:50])=[C:43]3[C:39]=2[C:40]2[CH:55]=[C:54]([CH3:56])[CH:53]=[N:52][C:41]=2[NH:42]3)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:28]>>[CH2:27]([S:29]([C:32]1[CH:33]=[C:34]([C:38]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C@@H:49]([OH:51])[CH3:50])=[C:43]3[C:39]=2[C:40]2[CH:55]=[C:54]([CH3:56])[CH:53]=[N:52][C:41]=2[NH:42]3)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH3:28]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OC[C@@H](C)O)c3[nH]c4ncc(C)cc4c23)c1
Agent: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OC[C@H](C)O)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 157 using an analogous procedure to the procedure described for the preparation of Compound 233. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.33 Hz, 3H) 1.25 (d, J=6.06 Hz, 3H) 2.27 (s, 3H) 3.41 (q, J=7.33 Hz, 2H) 3.94 (m, 1H) 4.09-4.16 (m, 2H) 4.97 (d, J=4.04 Hz, 1H) 7.07-7.14 (m, 2H) 7.57 (s, 1H) 7.85 (t, J=7.71 Hz, 1H) 7.96-8.00 (m, 2H) 8.09 (s, 1H) 8.28 (d, J=1.52 Hz, 1H) 11.94 (s, 1H); [M+H] calc'd for C23H25N2O4S, 425.2; found, 425.3.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:14]=23)=[C:8]([F:30])[CH:7]=1)=[O:4].[Cl:33]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.O.ClCCl>[Cl:33][C:21]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][C:13]=2[CH2:12][C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:31])[F:32])=[CH:7][C:8]=2[F:30])[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cc3ccc(NC(=O)C(F)(F)F)cc3F)ccnc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(Cl)c2c(Cc3ccc(NC(=O)C(F)(F)F)cc3F)ccnc21

Procedure:
550 mg (1.07 mmol) of 2,2,2-trifluoro-N-{3-fluoro-4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl]phenyl}acetamide and 143 mg (1.07 mmol) of N-chlorosuccinimide in 23 ml of carbon tetrachloride are heated at reflux for 20 min. After cooling, the mixture is diluted with water in dichloromethane and extracted. The organic phase is separated off, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (mobile phase: dichloromethane with increasing amounts of methanol).
Reaction SMILES: Cl[P:2]1(Cl)[N:7]=[P:6](Cl)(Cl)[N:5]=[P:4](Cl)(Cl)[N:3]=1.[CH:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([OH:22])[CH:14]=1.[OH-:23].[K+]>>[N+:19]([C:18]1[CH:17]=[CH:16][C:15]([O:22][P:2]2([O:22][C:15]3[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=3)[N:7]=[P:6]([O:22][C:15]3[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=3)([O:23][C:15]3[CH:14]=[CH:13][C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=3)[N:5]=[P:4]([O:22][C:15]3[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=3)([O:22][C:15]3[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=3)[N:3]=2)=[CH:14][CH:13]=1)([O-:21])=[O:20]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Agent: [K+]
Product: O=[N+]([O-])c1ccc(OP2(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccc([N+](=O)[O-])cc3)(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccc([N+](=O)[O-])cc3)(Oc3ccc([N+](=O)[O-])cc3)=N2)cc1

Procedure:
This material is prepared according to the method of Kober et al., Inorganic Chemistry, Vol. 5, p. 2239 (1966), which is incorporated herein by reference, by treatment of hexachlorocyclotriphosphazene with p-nitrophenol and potassium hydroxide. Hexakis(4-nitrophenoxy)-cyclotriphosphazene having a melting point of 261°-264° C. is obtained (lit. m.p. 264° C.). The infrared spectrum (in KBr), (cm-1) is 1589 (aromatic), 1522 and 1348 (asymmetrical and symmetrical nitro group stretching) and 1203, 1182 and 1163 (cyclotriphosphazene P=N).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][S:11]([CH3:13])=[O:12]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH3:6])=[CH:4][CH:3]=1.[C:10]1([S:11]([C:13]2[CH:6]=[CH:5][CH:8]=[CH:9][CH:2]=2)=[O:12])[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: CS(C)=O
Reactant: O=Cc1ccc(Br)cc1
Product: Cc1ccc(Br)cc1
Product: O=S(c1ccccc1)c1ccccc1

Procedure:
The yield of p-bromobenzaldehyde is 66%. Compared with the reaction with DMSO as sulphoxide, the yield is thus higher by a factor of 1.94. The difference between the ionisation potentials is 0.2 eV in this case.
Reaction SMILES: CON(C)[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][CH:6]=1.[C:22]([Mg]Br)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[CH3:23][C:22]([CH3:25])([CH3:24])[C:4]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[O:13][N:12]=2)=[CH:9][CH:10]=1)=[O:20]
Reactant: CC(C)(C)[Mg]Br
Reactant: CON(C)C(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Yield: 7 %

Procedure:
Prepared from N-Methoxy-N-methyl-4-(5-trifluoromethyl-isoxazol-3-yl)-benzamide and a 1.7 N THF solution of tert-butylmagnesium bromide as described in Example 5. Chromatographed on silica gel with EtOAc/hexanes (5 then 10%) as eluant to afford product as a colorless solid (21 mg, 7%). 1H NMR (CDCl3) 1.37 (s, 9H), 7.05 (s, 1H), 7.79 (d, J=8.4, 2H), 7.87 (d, J=7.9, 2H). 19F NMR −64.6. LC/MS 7.28 min, [M+1]+ 298.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>CS(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1cnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCOc1cnc(Cl)c2ccccc12
Temperature: 25 °C

Procedure:
1-chloro-4-hydroxyisoquinoline (50 mg, 0.28 mmol, 1.0 equiv), Cs2CO3 (454 mg, 1.39 mmol, 5.0 equiv.), and tert-butyl (2-bromoethyl)carbamate (2-2) (94 mg, 0.42 mmol, 1.5 equiv.) were suspended in anhydrous DMSO (2 mL) and stirred at room temperature. When LCMS indicated the reaction was complete, the crude reaction mixture was purified with reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA present) to yield the product (2-3). LRMS m/z (M+H) 323.1 found, 323.1 required.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3]1)[CH2:14][CH2:13][CH2:12][CH2:11]3.CC(C)([O-])C.[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.O>[CH2:27]([N:7]1[C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3][CH:2]([CH3:1])[C:8]1=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Oc2cccc3nc4c(c(c23)N(Cc2ccccc2)C1=O)CCCC4
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (5.0 g) in dry dimethylformamide (60 ml) was added potassium t-butoxide (3.15 g), with stirring. After 15 mins, benzyl bromide (2.66 ml) was added, and the reaction mixture was stirred for two hrs. The reaction mixture was diluted with water (300 ml), extracted twice with 100 ml-portions of diethyl ether, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was adhered to silica and flash chromatographed (10-30% ethyl acetate/hexane). The mixed fractions were flash chromatographed (3% ethyl acetate/dichloromethane), and the appropriate fractions were combined, and concentrated. Trituration of the residue with (1/1-diethyl ether/pentane) gave 4.58 g (68%) of 1-benzyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13](=O)[CH2:14][CH3:15])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][O:28][CH3:29].Cl.N1C=CC=CC=1>CCO>[CH3:29][O:28][N:27]=[C:13]([C:11]1[CH:10]=[CH:9][C:8]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=1)[CH2:14][CH3:15]
Reactant: CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCC(=NOC)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure P, 1-[6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-propan-1-one (Compound 78), (24 mg, 0.07 mmol), NH2OMe—HCl (23 mg, 0.25 mmol) and pyridine (21 mg, 0.28 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid.