Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:32]1[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:34][CH2:33]1)=[O:20])=[N:5]2
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(F)c(F)cc4nc3OC)CC2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 76.7 %

Procedure:
Ethyl N-(6,7-di fluoro-2-methoxyquinoxalin-3-yl)carbamate (25 mg, 0.088 mmol) and 1-(3-methoxy phenyl)piperazine (35 mg, 0.18 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (28 mg, 0.18 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (1:1) mixture and concentration gave 29 mg of the titled compound (yield, 76%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.76-3.77 (m, 4H), 3.81 (s, 3H), 4.12 (s, 3H), 6.48-6.49 (m, 2H), 6.56-6.58 (m, 1H), 7.20-7.23 (m, 1H), 7.29-7.30 (m, 1H), 7.50-7.53 (m, 1H), 7.60-7.62 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([F:26])=[C:19]([N:21]([CH3:25])[C:22](=[O:24])[CH3:23])[CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:26][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[N:1]=[CH:11][CH:12]=2)=[CH:20][C:19]=1[N:21]([CH3:25])[C:22](=[O:24])[CH3:23]
Reactant: N#Cc1cn[nH]c1N
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C#N)cnn23)ccc1F
Yield: 80.8 %

Procedure:
A mixture of 0.041 g (0.38 mmol) of 5-amino-1H-pyrazole-4-carbonitrile and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. Dichloromethane (15 mL) and a saturated sodium bicarbonate solution (10 mL) were added to the resulting residue. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 95 mg of N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 81%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH2:22][CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH:26]=3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:32])([F:33])[C:28]([F:30])([F:31])[F:29])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(C3=CCNCC3)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.5 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[2-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-4-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 190, triethylamine (42.0 uL, 0.30 mmol) and methanesulfonyl chloride (7.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])=[O:2].[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC=CC=1.C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:16][CH2:17][O:18][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: OCCO
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C2OCCO2)c([N+](=O)[O-])c1
Yield: 78.3 %

Procedure:
To a solution of methyl 4-formyl-3-nitrobenzoate (9.0 g, 43.0 mmol) in toluene (150 mL) was added ethylene glycol (7.20 mL, 129 mmol) followed by p-TsOH (0.409 g, 2.152 mmol) and the reaction mixture was heated at reflux temperature with azeotropic removal of H2O using a Dean-Stark trap for 4 h. The reaction mixture was then cooled and diluted with DCM. The DCM layer was then washed with sat. aq. NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated to yield a residue. The residue was dissolved in minimal quantity of DCM and purified by silica gel chromatography to yield 5A (8.53 g, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.27 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 6.38 (s, 1H), 4.00 (dt, J=3.8, 1.9 Hz, 2H), 3.94 (dt, J=3.8, 1.9 Hz, 2H), 3.91 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1.C(Cl)(Cl)Cl>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=3[F:1])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: COc1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)c(F)c1

Procedure:
From 2-fluoro-4-methoxybenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+19.4° (c=1.02, CHCl3), ES-MS m/e (%): 419 (M+H+, 100).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]([CH3:31])([CH3:30])[CH2:12][C:13]1[N:14]([CH2:27][CH2:28][CH3:29])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[NH2:26].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:26][C:17]1[C:16]2=[N:15][N:14]([CH2:27][CH2:28][CH3:29])[C:13]([CH2:12][C:11]([NH:10][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])([CH3:31])[CH3:30])=[C:25]2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
Cyclohexanecarbonyl chloride (401 μL, 3.00 mmol) was added to a 0° C. stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 892 mg, 3.00 mmol) and triethylamine (627 μL, 4.5 mmol) in dichloromethane (26.7 mL). After 3 hours at 0° C., the solution was stirred for 2 days at ambient temperature. More triethylamine (697 μL) and cyclohexanecarbonyl chloride (602 μL) was added. After 30 minutes, 2 M aqueous sodium carbonate was added to the solution. The mixture was extracted with chloroform four times. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Methanol (20 mL) and concentrated hydrochloric acid (2 mL) were added. The solution was heated at reflux for 4 hours, then left to stand at ambient temperature overnight, then heated at reflux again for brief periods of time during the next 2 days. In all, the solution was heated at reflux for a total of 7 hours. After cooling to ambient temperature, 2 M aqueous sodium carbonate was added to adjust the mixture to pH 10-11. The mixture was concentrated under reduced pressure to remove the methanol. Water was added and a solid was isolated from the mixture by filtration. The solid was washed with water. Chloroform was added to the solid, and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by IFC. The appropriate fractions were combined and concentrated to a white solid that was recrystallized from 50% ethyl acetate/hexanes. The crystals were isolated by filtration and dried to yield 896 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]cyclohexanecarboxamide as a white solid, mp 190-191° C.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[I-:34].[Na+]>CC(=O)CC>[I:34][CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Yield: 85 %

Procedure:
A solution of Compound 3 (200 mg) and sodium iodide (200 mg) in 2-butanone (4 mL) was heated at 80° C. for 24 hours. Solvent was removed under reduced pressure and directly purified on a silica gel using 1% ethanol in dichloromethane to obtain the required product in 85% yield (200 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:3]=1.[Cl:29]N1C(C)(C)C(=O)N(Cl)C1=O.O>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:3]=1[Cl:29]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)cc(N)c2F)c1F
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: O
Solvent: CC#N
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Temperature: 25 °C
Yield: 228.3 %

Procedure:
Benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (2.07 g, 5.12 mmol) was slurried in acetonitrile (20 mL) in a scintillation vial. 1,3-Dichloro-5,5-dimethylhydantoin (554 mg, 2.181 mmol) was added as a solid, and the reaction mixture was stirred at reflux for 1 h. After cooling to room temperature, water (40 mL) was added to precipitate the product. The solid was collected on a Buchner funnel and washed with water. Drying under vacuum at 55° C. gave a white solid (2.187 g, 97%): 1H NMR (400 MHz, CDCl3) δ 7.50-7.41 (m, 2H, aromatic), 7.41-7.20 (m, 5H, aromatic), 5.42 (s, 2H, CH2Ph), 4.92 (br s, 2H, NH2), 3.97 (d, J=1.2 Hz, 3H, OMe); 19F{1H} NMR (CDCl3) δ −128.19 (d, J=33.9 Hz, F2′), −137.79 (d, J=33.8 Hz, F5).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[NH2:28][C:29]1[CH:33]=[C:32]([CH3:34])[N:31]([CH2:35][CH:36]([O:38][C:39](=[O:41])[CH3:40])[CH3:37])[N:30]=1>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:33]=[C:32]([CH3:34])[N:31]([CH2:35][CH:36]([O:38][C:39](=[O:41])[CH3:40])[CH3:37])[N:30]=2)=[O:15])[C:9](=[O:11])[CH:10]=1
Reactant: O=C(O)C(CC1CCOCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(=O)OC(C)Cn1nc(N)cc1C
Product: CC(=O)OC(C)Cn1nc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)cc1C

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 32) and acetic acid 2-(3-amino-5-methyl-pyrazol-1-yl)-1-methyl-ethyl ester (Intermediate 98) afforded acetic acid 2-{3-[2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-5-methyl-pyrazol-1-yl}-1-methyl-ethyl ester as a mixture of diastereomers (180 mg, 39%); ES+-HRMS m/e calcd for C27H31N5O6F2 [M+H+] 560.2315 found 560.2313. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.45 (m, 4H), 1.17, 1.18 (2×d, J=6.4 Hz, 3H), 1.45-1.58 (m, 2H), 1.77-1.92 (m, 1H), 1.94, 1.95 (2×s, 3H), 2.22 (s, 3H), 3.09-3.28 (m, 2H), 3.73-3.86 (m, 2H), 3.97-4.14 (m, 2H), 5.01-5.18 (m, 1H), 5.53 (dd, J=10.7, 3.2 Hz, 1H), 6.04 (d, J=2.3 Hz, 1H), 6.21 (s, 1H), 7.33-7.43 (m, 2H), 7.44-7.54 (m, 1H), 8.29 (d, J=2.3 Hz, 1H), 10.75, 10.77 (2×s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[CH2:17]([Li])CCC.C([CH:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)CC.Cl>O.CCCCCC.C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2([C:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=3)[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][CH2:11]2)[CH2:6][CH2:5]1
Reactant: CCCC1CCC(=O)CC1
Reactant: COC[C@H]1CC[C@H](c2ccc(I)cc2)CC1
Reactant: [Li]CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: COC[C@H]1CC[C@H](C2(C3=CCCCC3)C=CC(C)=CC2)CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Into a 500 ml three-neck flask were placed the compound (VI) (21 g, 0.064 mol) obtained at the fourth step and dry toluene (40 ml) in dry nitrogen atmosphere, followed by dissolving with stirring. To the solution was dropwise added a commercially available 1.67N hexane solution (42.7 ml) of n-butyllithium (0.067 mol) over about 10 minutes at a liquid temperature kept at 20° to 25° C. After completion of the addition, the mixture was kept at 25° C. for 30 minutes, and then cooled to 5° C., followed by dropwise adding 4-propylcyclohexanone (11.2 g, 0.08 mol) over 20 minutes while the temperature was kept at 5° to 10° C., further keeping the temperature at 45° C. for 30 minutes, dropwise adding water (20 ml), further dropwise adding 6N-HCl (40 ml) while the temperature was kept at 30° C. or lower, separating off the resulting organic layer, adding potassium hydrogen sulfate (KHSO4) (2 g), distilling off the solvent on heating, concentrating until the liquid temperature reached 110° C., during which dehydration reaction proceeded, cooling, transferring into a separating funnel, washing the resulting organic layer with water, distilling off the solvent, recrystallizing the residue from ethyl alcohol (10 c.c.) to obtain trans-4-methyloxymethyl-1-(4'-methyl-1-cyclohexenylphenyl)cyclohexane (VII) (5.3 g) having a melting point (C-S point) of 64° C., a S-N point of 93.4° C. and a clearing point (N-I point) of 14.3° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[C:15]1([S:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([S:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCCSc1ccccc1
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccccc3)cc21

Procedure:
Prepared analogously to Example 5 from 6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-phenylmercaptobutylbromide (B.p. 0.03 mb : 95°-104° C.).
Reaction SMILES: N1C=NC=N1.CN(C)C=O.[H-].[Na+].ClC(C1C=CC(Cl)=CC=1)[C:15]1[CH:16]=[CH:17][C:18]2[N:22]=[N:21][N:20]([CH3:23])[C:19]=2[CH:24]=1>O>[CH3:23][N:20]1[C:19]2[CH:24]=[CH:15][CH:16]=[CH:17][C:18]=2[N:22]=[N:21]1
Reactant: Cn1nnc2ccc(C(Cl)c3ccc(Cl)cc3)cc21
Agent: [H-]
Agent: [Na+]
Agent: c1nc[nH]n1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 28.4 parts of 1H-1,2,4-triazole in 135 parts of N,N-dimethylformamide were added 11.4 parts of a sodium hydride dispersion 80% under nitrogen atmosphere. After stirring for 1 hour at room temperature, a solution of 40 parts of 6-[chloro(4-chlorophenyl)-methyl]-1-methyl-1H-benzotriazole in 90 parts of N,N-dimethylformamide was added to the mixture. The whole was stirred for 1 hour at 60° C. The reaction mixture was diluted with 50 parts of water and the whole was evaporated. The residue was extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off and dried, yielding 13 parts (29.2%) of 6-[(4-chlorophenyl)-1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole; mp. 178.9° C. (compound 64).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:7][CH2:6]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29](Cl)=[O:30])[CH:24]=1>Cl.O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:2][CH2:3][CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:7][CH2:6]2)=[O:30])[CH:24]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: NCCC1CCN(S(N)(=O)=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccn2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
To a mixture of 1.95 g. (0.008 mole) of 4-(2-aminoethyl)-1-piperidinesulfonamide hydrochloride and 2.22 ml. (0.016 mole) of triethylamine in 15 ml. of dry tetrahydrofuran, there were added 1.41 g. (0.008 mole) of 4-chloropicolinoyl chloride dissolved in 15 ml. of tetrahydrofuran. The initial addition step was slightly exothermic (~40° C.) and after completion of same, the resulting reaction mixture was stirred at ambient temperatures for a period of approximately 16 hours. At this point, the thoroughly stirred mixture was poured into 50 ml. of ice water and subsequently acidified with a few drops of 3N aqueous hydrochloric acid. The resulting crystalline precipitate was then recovered by means of suction filtration and thereafter recrystallized twice from acetonitrile to afford 0.997 g. of pure product. In this way, there was ultimately obtained a 36% of 4-[2-(4-chloropicolinamido)ethyl]-1-piperidinesulfonamide, m.p. 186°-187° C.
Reaction SMILES: S(Cl)(Cl)=O.CO.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1.[C:19]([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:13]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
Thionyl chloride (14.6 ml, 200 mmol, 3.3 equiv) was added dropwise to a solution of dry methanol (60 ml, 1453 mmol, 24 equiv) at −10° C. After stirring for 10 minutes, 3-(4-aminophenyl)propanoic acid (10.0 g, 61 mmol) was added to give a yellow suspension. The solution stirred for 1 hour and was slowly warmed to room temperature. The resulting solution was concentrated to give a yellow solid. The solid was suspended in ethyl acetate, and NaHCO3 (aq.) was added until the salt dissolved fully. Solid sodium bicarbonate was added to give pH 8.The layers were separated and the organics were washed with brine (aq.). The resulting solution was dried over MgSO4, filtered, and concentrated to give a yellow solid (10.6 g, 98%). 1H NMR (300 MHz, CDCl3) 7.00 (d, J=8.3 Hz, 2H), 6.63 (d, J=8.3 Hz, 2H), 3.67 (s, 3H), 3.59 (bs, NH2, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.58 (t, J=8.3 Hz, 2H). 13C NMR (300 MHz, CDCl3) 173.8, 144.9, 130.7, 129.3, 115.5, 51.8, 36.4, 30.4. M.S. (ESI) m/z=180.102 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[C:7]([O:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)(=[O:9])[CH3:8]>ClCCl>[C:7]([O:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:8]2[C:7](=[O:9])[O:10][C:1](=[O:5])[C:2]=2[C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([CH3:12])[CH:14]=2)=[CH:14]1)(=[O:9])[CH3:8]
Reactant: CC(=O)OCCn1ccc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)OCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)OC2=O)c2ccccc21
Reaction time: 2 h

Procedure:
2.57 ml of oxalyl chloride were added to a solution of 5.7 g of 1-(2-acetoxyethyl)indole in 70 ml of dichloromethane at 0° C. The resulting solution was stirred for 2 hours and the solvent was then evaporated. To the residue, dissolved in 210 ml of dichloromethane, were added 7.7 ml of triethylamine and 5.29 g of 1-methylindole-3-acetic acid under a nitrogen atmosphere. After stirring for 18 hours the solvent was evaporated and the residue was purified on silica gel with ethyl acetate/petroleum ether (1:2). Crystallization from ethyl acetate/hexane gave 1.87 g of 3-[1-(2-acetoxyethyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione, m.p. 198°-199° C.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:6]=2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([N:8]1[CH2:7][C:6]2[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=[C:2]([C:28]3[CH:27]=[N:26][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:30][CH:29]=3)[C:11]=2[O:10][CH2:9]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N1COc2c(Br)cc(-c3ccc(F)cc3)cc2C1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)N1COc2c(cc(-c3ccc(F)cc3)cc2-c2ccc(C(F)(F)F)nc2)C1
Temperature: 80 °C
Yield: 32.7 %

Procedure:
A mixture of 8-bromo-3-(tert-butyl)-6-(4-fluorophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (2.0 g, 5.49 mmol), 2-(trifluoromethyl)pyridine-5-boronic acid [purchased from Frontier Scientific] (1.26 g, 6.59 mmol) and potassium carbonate (1.52 g, 10.98 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (317.2 mg, 0.275 mmol) was added and the reaction mixture heated at 80° C. in a sealed vial for 17 hours. The cooled reaction mixture was partitioned between ethyl acetate (80 mL) and 1.0 M aqueous sodium hydroxide solution (80 mL), the organic phase separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an orange syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 8% methanol (containing 1% aqueous ammonium hydroxide) in dichloromethane to give 3-(tert-butyl)-6-(4-fluorophenyl)-8-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.773 g, 37% yield) as a colorless syrup.