Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([CH2:36][O:37][CH3:38])[CH2:33][C@H:32]1[C:39]([OH:41])=[O:40])=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH3:38][O:37][CH2:36][C@@H:34]1[CH2:35][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:30])[C@H:32]([C:39]([O:41][CH2:2][C:3](=[O:4])[C:5]2[CH:6]=[CH:7][C:8]3[C:17]4[CH:16]=[C:15]5[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]5=[CH:13][C:12]=4[O:11][CH2:10][C:9]=3[CH:23]=2)=[O:40])[CH2:33]1
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
3-(2-Bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (7.47 g, 20.1 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (5.22 g, 20.1 mmol) were suspended in 2-Me-THF (75 mL) and treated with Cs2CO3 (3.27 g, 10.1 mmol). After stirring 4 h at RT, the reaction mixture was diluted with DCM. The organic layer was washed with H2O. The aqueous layer was then back extracted 2× with DCM. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 50% EtOAc/DCM) to afford (2S,4S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.73 g, 70%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15]([O:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]Br)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[CH3:16]
Reactant: Oc1ccccc1I
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)CCCCOc1ccccc1I
Yield: 38.1 %

Procedure:
Under the conditions of example 2A, 3 g of 2-iodophenol in the presence of 8.9 g of cesium carbonate is reacted with 2.84 g of 5-bromovaleric acid ethyl ester, worked up, and 1.8 g of 5-(2-iodophenoxy)valeric acid ethyl ester with a boiling point of 210° C./0.4 mbar is obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[NH:4][N:3]=1.[B-](F)(F)(F)[F:11].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(O)(=O)C.[B-](F)(F)(F)F.[B-](F)(F)(F)F.C[N+]12CC[N+](F)(CC1)CC2>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[C:6]([F:11])=[C:5]([C:7]([OH:9])=[O:8])[NH:4][N:3]=1
Reactant: F[B-](F)(F)F
Reactant: O=C(O)c1cc(Cl)n[nH]1
Agent: C[N+]12CC[N+](F)(CC1)CC2
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1[nH]nc(Cl)c1F

Procedure:
3-chloro-1H-pyrazole-5-carboxylic acid (200 mg, 1.37 mmol) was suspended in acetonitrile (3 mL) followed by the addition Selectfluor 11(550 mg, 1.55 mmol) and acetic acid (500 g, 8.33 mmol). The mixture was submitted to microwave irradiation, maintaining the temperature at 100 C for 2 h. An additional 550 mg of Selectfluor II was added and the reaction returned to the microwave where the temperature was maintained at 100 C for 1 h. The reaction mixture was diluted with 3 mL of EtOAc then washed with water (5 mL) three times. The solvent was stripped in vacuo and 3-chloro-4-fluoro-1H-pyrazole-5-carboxylic acid was isolated by semi prep HPLC (ACN/water+0.05% TFA).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][CH:26]=[O:27])[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2].CC(=CC)C.Cl([O-])=[O:40].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][C:26]([OH:40])=[O:27])[CH2:23][CH2:24]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC=O)CC4)cc3)oc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC(=O)O)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension (partially dissolved) of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-oxoethyl)cyclohexyl]methyl}benzamide (50 mg, 0.113 mmol, EXAMPLE 43, Step B) in t-butanol (4 ml) was added 2-methyl-2-butene (0.060 ml, 0.570 mmol), and then a solution of sodium chlorite (25 mg, 0.276 mmol) and sodium dihydrogen phosphate (27 mg, 0.225 mmol) in water (1 ml). The mixture was stirred overnight at room temperature (the mixture remained a finely divided suspension), at which point LC/MS analysis showed no starting material. The mixture was diluted with 10 ml of water and 10 ml of ethyl acetate. The phases were separated and the aqueous phase was acidified to pH 4 and extracted with 2×10 ml of ethyl acetate. The combined organics were washed with 10 ml of brine, dried (sodium sulfate), and concentrated to provide the title compound (52 mg, 0.113 mmol, 100% yield). Mass spectrum (ESI) 459.8 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:23]([O-:25])=[O:24])=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:5][CH2:4]1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][C:37]3([CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:36][CH:35]=2)O1>>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:23]([O-:25])=[O:24])=[C:13]([C:34]3[CH2:39][CH2:38][C:37]4([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]4)[CH2:36][CH:35]=3)[CH:14]=2)[CH2:5][CH2:4]1
Reactant: COC1CCN(c2ccc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)c2)CC1
Reactant: CC1(C)OB(C2=CCC3(CCCCC3)CC2)OC1(C)C
Product: COC1CCN(c2ccc([N+](=O)[O-])c(C3=CCC4(CCCCC4)CC3)c2)CC1
Yield: 111.6 %

Procedure:
Trifluoromethanesulfonic acid 5-(4-methoxypiperidin-1-yl)-2-nitrophenyl ester (2.0 g, 5.43 mmol) prepared in Example (7c) was used as the starting material. 4,4,5,5-Tetramethyl-2-spiro[5.5]undec-2-en-3-yl-[1,3,2]dioxaborolane (1.65 g, 5.97 mmol) prepared in Example (39b) was used instead of 4-t-butylcyclohex-1-enyl-(4,4,5,5-tetramethyl)-[1,3,2]dioxaborolane for reaction in a manner similar to Example (7e) and treated in a similar manner, to give 2.331 g of the title compound as an orange oil.
Reaction SMILES: [C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(C(NC2C=C(C(F)(F)F)C=C(N3C=C(C)N=C3)C=2)=O)=CC=1NC1N=C(C2C=NC=CC=2)C=CN=1>C(OCC)(=O)C>[C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)([O-])c1ccccc1
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CCOC(C)=O
Product: O=S(=O)(O)c1ccccc1

Procedure:
The seventh embodiment of the present invention is directed to the benzene sulfonate salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide. This salt is reproducibly produced from ethyl acetate when one equivalent benzene sulfonic acid is used. The weight loss (room temperature to 250° C.) is about 0.63%, and the sample melts with decomposition at about 260° C. Its crystal structure ranges from poor to good. The XRPD pattern for the benzene sulfonate salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide is shown in FIG. 7.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.C([Li])(C)(C)C.[F:25][C:26]([F:40])([F:39])[C:27]([C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([CH3:38])[CH:30]=1)=[O:28]>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:6]2[C:5]3[CH:18]=[CH:19][C:2]([C:27]([OH:28])([C:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]([CH3:38])[CH:30]=4)[C:26]([F:25])([F:40])[F:39])=[CH:3][C:4]=3[N:8]([CH3:9])[C:7]2=[O:10])=[CH:12][CH:13]=1
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccccc21
Reactant: Cn1c(=O)n(-c2ccc(F)cc2)c2ccc(Br)cc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(O)(c2ccc3c(c2)n(C)c(=O)n3-c2ccc(F)cc2)C(F)(F)F)c2ccccc21
Reaction time: 0.02 h
Yield: 12.8 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-3-methyl-1,3-dihydro-benzimidazol-2-one (80 mg, 0.25 mmol) in anhydrous THF (3 mL) was added tert-butyllithium (0.2 mL of 1.7 M solution in heptane, 0.34 mmol). After 1 minute, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone (57 mg, 0.25 mmol) in anhydrous THF (1 mL) was added. After 10 minutes, the mixture was quenched with ammonium chloride solution and extracted with three 15 mL portions of methylene chloride. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a brownish oil. The residue was purified by column chromatography over silica gel eluting with 0-10% ethyl acetate in methylene chloride to afford 15 mg of the title compound as a white powder. MS m/z 470 (MH+).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([SH:11])[CH:7]=[CH:8]2)=[CH:3][CH:2]=1.F[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O>[CH:5]1[C:4]2[C:9](=[CH:10][CH:1]=[CH:2][CH:3]=2)[CH:8]=[CH:7][C:6]=1[S:11][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: Sc1ccc2ccccc2c1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: O=Cc1ccccc1Sc1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-thionaphthol (5.29 g; 33 mmol), 2-fluorobenzaldehyde (3.73 g; 33 mmol) and potassium carbonate (4.57 g; 33 mmol) in 28 mL of iso-propanol was heated to reflux for 12 h. The mixture was cooled to r.t., diluted with water and filtered. The solution was diluted with EtOAc and washed with water, brine and dry over MgSO4. The crude product (7.9 g) was used as is for the next step.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[CH2:18]([NH2:20])[CH3:19].[OH-].[Na+]>>[O:8]1[CH2:9][CH2:10][CH:6]([CH2:5][NH:20][CH2:18][CH3:19])[CH2:7]1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCNCC1CCOC1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
A mixture comprising 4.09g of (tetrahydro-3 -furanyl)methyl tosylate, 17 ml of 70% aqueous ethylamine solution and 8.2 ml of 2 N aqueous sodium hydroxide solution was stirred at 75° C. for 6 hours. The reaction fluid was concentrated under a reduced pressure to obtain crude N-{(tetrahydro-3-furanyl)methyl}-N-ethylamine. To this were added 2.00 g of 1,1-bis(methylthio)-2-nitroethylene and 20 ml of acetonitrile. The resulting mixture was refluxed for 3 hours. The reaction fluid was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/2) to obtain 0.81 g of 1-[N-{(tetrahydro-3-furanyl)methyl}-N-ethylamino]-1-methylthio-2-nitroethylene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:32])[C:9]=1[N:10]1[C:18]2[CH:17]=[CH:16][NH:15][C:14](=[O:19])[C:13]=2[C:12]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:11]1)[C:5]#[N:6].CS(C)=[O:35].C(=O)([O-])[O-].[K+].[K+].OO>O>[F:32][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[N:10]1[C:18]2[CH:17]=[CH:16][NH:15][C:14](=[O:19])[C:13]=2[C:12]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[N:11]1)[C:5]([NH2:6])=[O:35]
Reactant: N#Cc1cc(F)c(-n2nc(-c3ccc(N4CCOCC4)cc3)c3c(=O)[nH]ccc32)c(F)c1
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1cc(F)c(-n2nc(-c3ccc(N4CCOCC4)cc3)c3c(=O)[nH]ccc32)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-difluoro-4-(3-(4-(morpholin-4-yl)phenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile (120 mg) obtained in Step D of Example 244 in a mixed solvent of DMSO (3 mL) and water (0.25 mL) were added potassium carbonate (45.9 mg) and aqueous hydrogen peroxide (concentration 30 w/v %, 0.085 mL), and the mixture was stirred overnight at room temperature. The precipitate was collected by filtration, and washed with DMSO and water to give the title compound (64 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][N:8]=2)[CH:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])=[O:22]>>[CH3:32][O:31][C:24]1[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:23]=1[C:21](=[O:22])[CH2:20][N:9]1[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8]1
Reactant: CCOC(=O)c1cc(-c2cccnc2)n[nH]1
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Reaction time: 8 h

Procedure:
To a flame dried flask equipped with a stirbar cooled under argon was added ethyl 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (0.02 grams, 0.092 mmol, 0.1 M in THF). While stirring at room temperature NaH (0.0055 grams, 1.8 mmol, 60% in mineral oil, purchase from Aldrich) was added. After fifteen minutes 2-bromo-1-(2,5-dimethoxyphenyl)ethanone (0.047 grams, 0.14 mmol, purchased from Aldrich) was added as a solid. The reaction was stirred overnight. The next day, the reaction was quenched with 0.1M HCl and the organic material extracted using ethyl acetate. The aqueous layer was salted out using sodium chloride and washed twice with ethyl acetate. The combined organic material was then dried with sodium sulfate, filtered, and concentrated. Purification was done on preparative thin layer chromatography using hexanes/ethyl acetate (1:2) to afford the desired compound. Yield, 10%. 1H-NMR δ9.07 (bs, 1H), 8.58 (bs, 1H), 8.13 (d, 1H), 7.47 (d, 1H), 7.31 (bs, 1H), 7.29 (s, 1H), 7.14 (dd, 1H), 7.00 (d, 1H), 6.03 (s, 2H), 4.32 (q, 2H), 3.99 (s, 3H), 3.79 (s, 3H), 1.35 (t, 3H). Calculated mass for C21H21N3O5, 395.15, observed, 396.3 (M+1).
Reaction SMILES: I[Si](C)(C)C.C(OC(=O)[NH:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([NH:23][C:24]3[O:25][C:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=4[F:39])=[CH:27][N:28]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14]1)(C)(C)C>C(Cl)Cl>[F:39][C:30]1[CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[CH:33]=[CH:34][C:29]=1[C:26]1[O:25][C:24]([NH:23][C:16]2[C:15]3[CH2:14][CH:13]([NH2:12])[CH2:22][CH2:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)=[N:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4F)o3)c2C1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: NC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4F)o3)c2C1
Reaction time: 0.25 h

Procedure:
Iodotrimethylsilane (52 mg, 0.260 mmol) was added dropwise to a solution of the product of Example 22B (107 mg, 0.218 mmol) in 1 mL CH2Cl2 at ambient temperature. After 15 minutes the reaction was diluted with CH2Cl2 and quenched with 1N aq NaOH solution. The mixture was stirred 15 minutes and then poured into water. The separated organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was triturated with Et2O/hexanes and the solid collected by vacuum filtration and dried under high vacuum. The result was 36 mg (42%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 9.42 (br s, 1H), 7.75 (m, 3H), 7.52 (d, J=8.1 Hz, 1H), 7.44 (d, J=3.7 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 3.05-2.70 (m, 4H), 2.30 (m, 1H), 1.86 (m, 1H), 1.70 (br s, 2H), 1.43 (m, 1H); MS (ESI+) m/z 392 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5](=[O:13])[C:6]1[C:11]([Br:1])=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(N)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Bromine (1.78 ml, 34.8 mmol) was added dropwise over an hour to a stirred solution of 2-amino-isonicotinic acid methyl ester (5.13 g, 33.75 mmol) in chloroform (350 ml) at room temperature and the orange solution stirred at room temperature overnight. A 2N solution of sodium thiosulfate (300 ml) was added to the reaction and stirred for ten minutes. The two layers were separated and the aqueous extracted with chloroform (100 ml). The combined organics were dried (MgSO4) and concentrated under reduced pressure. The desired isomer was purified by flash column chromatography using ethyl acetate 2/3 hexane as eluent to afford 2-amino-5-bromo-isonicotinic acid methyl ester as a yellow solid (1.79 g, 23%). 1H NMR (CDCl3): 8.21 (1H, s, py); 6.79 (1H, s, py); 4.53 (2H, br s, NH2); 3.88 (3H, S, CO2CH3).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C=O)C.[C:10]1([S:16]([N:19]2[C:31]3[CH:30]=[C:29]([CH:32](O)[CH3:33])[CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[C:10]1([S:16]([N:19]2[C:31]3[CH:30]=[C:29]([CH:32]([Cl:3])[CH3:33])[CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(O)c1ccc2c3ccccc3n(S(=O)(=O)c3ccccc3)c2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Cl)c1ccc2c3ccccc3n(S(=O)(=O)c3ccccc3)c2c1

Procedure:
Thionyl chloride (0.26 ml, 3.54 mmol) and catalytically effective amount of DMF were added at room temperature to a solution of 9-benzenesulfonyl-2-(1-hydroxyethyl)carbazole (0.621 g, 1.77 mmol) in methylene chloride, and the mixture was heated under reflux for 1.5 hours. After evaporation of the solvent under reduced pressure, the thus obtained residue was mixed with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order, the organic layer was dried over magnesium sulfate and then the solvent was evaporated under reduced pressure to obtain 9-benzenesulfonyl-2-(1-chloroethyl)carbazole.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][N:13]=[C:12]2[O:17]C(=O)C1C(Cl)=CC=CC=1Cl)=[O:5].N1C=CN=C1.O>CN1CCN(C)C1=O>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[NH:15][CH:14]=[N:13][C:12]2=[O:17])=[O:5]
Reactant: O=C(Nc1cccc2c(OC(=O)c3c(Cl)cccc3Cl)ncnc12)c1c(Cl)cccc1Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=C(Nc1cccc2c(=O)nc[nH]c12)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-4-(2,6-dichlorobenzoyloxy)quinazoline (40 mg) and imidazole (53.7 mg) in 1,3-dimethyl-2-imidazolidinone (0.6 ml) was stirred for 1 hour at ambient temperature. Cold water was added to the mixture, and the resulting precipitates were collected by filtration to give 8-(2,6-dichlorobenzoylamino)-1,4-dihydro-4-oxoquinazoline (23 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[C:10]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[O:21])=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)=[O:21])=[C:9]([CH:32]([CH3:33])[CH3:34])[N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc([N+](=O)[O-])cc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccc1

Procedure:
General Procedure S. A solution of 1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-nitro-1H-indole-3-carboxamide (Compound 124, 300 mg, 0.65 mmol) in EtOAc (5 ml) was treated with 10% Pd—C (6.8 mg, 0.065 mmol) and hydrogen gas under atmospheric pressure at room temperature for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N+:8]([CH3:13])[CH:7]=[CH:6]2.C(=O)([O-])[O-].[Na+].[Na+].O[CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([O-:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(#N)C.CCOCC>[O:23]1[CH2:24][CH2:25][CH:21]([O:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[N+:8]([CH3:13])[CH:7]=[CH:6]3)[CH2:22]1.[C:26]1([CH3:36])[CH:27]=[CH:28][C:29]([S:32]([O-:35])(=[O:33])=[O:34])=[CH:30][CH:31]=1
Reactant: OC1CCOC1
Reactant: C[n+]1ccc2cc(O)ccc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Solvent: CCOCC
Product: C[n+]1ccc2cc(OC3CCOC3)ccc2c1

Procedure:
6-Hydroxy-2-methylisoquinolinium bromide (2.4 g.), sodium carbonate (5 g.) and 3-hydroxytetrahydrofuran, p-toluenesulphonate (5 g.) in acetonitrile (100 ml) were heated under reflux for 60 hours. The mixture was cooled and diluted with ether. The solid that crystallised was collected and had m.p. 144°-146°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: O=C1COc2ccccc2N1
Reactant: BrCCCCBr
Product: O=C1COc2ccccc2N1CCCCBr

Procedure:
The procedure is as for Example 53, Step A, using as substrate 4H-benzo[1,4]oxazin-3-one and 1,4-dibromobutane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](S(OCCC=CC=C)(=O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([NH2:32])[C:26]1C=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>C(#N)C>[CH2:1]([NH:32][CH2:25][CH2:26][CH:27]=[CH:28][CH:29]=[CH2:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC=CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CC=CCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
A solution of hexa-3,5-dien-1-yl 4-methylbenzenesulfonate (1.90 g, 7.53 mmol) and triethylamine (1.39 mL, 10.0 mmol) in acetonitrile (70 mL) was treated with benzylamine (2.45 mL, 22.5 mmol), and the mixture was stirred at room temperature for 16 hours. The solution was then heated to reflux for 3 hours, cooled, and treated with 1.0 N aqueous sodium hydroxide. The mixture was extracted three times with ethyl acetate. (A portion of the extracts were lost due to spillage). The combined organic phases were dried over magnesium sulfate and concentrated to provide a pale yellow oil. The yellow oil was purified by radial thin-layer chromatography, eluting with 25% ethyl acetate/hexane, to provide a colorless oil (628 mg, 45%). 1H NMR (300 MHz, CDCl3) δ7.32 (m, 4H), 7.26 (m, 1H), 6.32 (td, J=17, 10 Hz, 1H), 6.12 (dd, J=15, 10 Hz, 1H), 5.68 (td, J=15, 7 Hz, 1H), 5.12 (d, J=17 Hz, 1H), 5.00 (d, J=10 Hz, 1H), 3.80 (s, 2H), 2.71 (t, J=7 Hz, 2H), 2.32 (q, J=7 Hz, 2H), 1.52 (broad s, 1H). Mass spec (ES+) m/z 188.4 (M+H+, 100%).