Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccccc1
Reaction time: 16 h
Yield: 96.4 %

Procedure:
To a stirred solution of phenol (36.6 g, 0.39 mol) in DMF (250 mL) was added sodium hydride (10 g, 0.42 mol) in portions. To the resulting solution was added a solution of 2,5-dichloronitrobenzene (68 g, 0.35 mol) in DMF (500 mL), and the mixture was stirred for 16 hours. The solvent was removed under reduced pressure, and the residue was takene up in EtOAc (400 mL) and extracted with brine (saturated, 400 mL). The product was distilled to yield a yellow liquid (84.2 g, 95%), which had a boiling point of 245°-265° C./1.5 mmHg. This material was employed in Example 9 without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:27])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Cl)=[C:14]([O:25][CH3:26])[CH:13]=2)[CH2:4][CH2:3]1.[CH3:28][NH:29][CH3:30]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:27])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:29]([CH3:30])[CH3:28])=[C:14]([O:25][CH3:26])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCCl
Reactant: CNC
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCN(C)C

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl)-4-(5-chloropentyloxy)-3-methoxycinnamamide (Example 132), 100 ml of methylisobutylketone, and 150 ml of 50% aqueous dimethylamine solution, a reaction similar to that conducted in Example 107 was carried out. As a result, 3.17 g of N-(trans-4-methylcyclohexyl)-4-(5-dimethylaminopentyloxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH2:37][NH:36][CH2:35]2)([O-:31])=[O:30].FC(F)(F)C([O-])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([N:36]1[CH2:35][C:34]2[C:38](=[CH:39][CH:40]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=2)[CH2:37]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC2
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc([N+](=O)[O-])cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A solution of 2,4-bis-benzyloxy-5-isopropyl-benzoic acid (505 mg; 1.3 mmol) (Preparation B5), 5-nitroisoindoline, trifluoroacetate (360 mg; 1 equiv.), EDAC (300 mg; 1.2 equiv.), HOBt (210 mg; 1.2 equiv.) and NEt3 (270 μl; 1.5 equiv.) in DMF (10 ml) was stirred at room temperature overnight then evaporated in vacuo. The residue was partitioned between EtOAc and 2M HCl, the EtOAc layer was separated, washed with saturated NaHCO3, dried (MgSO4) and evaporated. Purification by flash column chromatography (1:4 then 1:2 then 1:1 EtOAc/P.E. as eluant) gave 460 mg of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-nitro-1,3-dihydro-isoindol-2-yl)methanone. MS: [M+H]+ 523.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([O:31]C)=[O:30])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1Cl)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:35]>>[C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([OH:31])=[O:30])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([N+:25]([O-:27])=[O:26])[C:19]=1[OH:35])(=[O:17])=[O:16])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(CCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl)NC(=O)OC(C)(C)C
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O)C(=O)O
Yield: 75.7 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-[5-(tert-butoxycarbonylamino)-5-methoxycarbonylpentyl]-2,6-dichloro-3-nitrobenzenesulfonamide (1.2 g, 2.33 mmol), 60% NaH (379 mg, 9.32mmol) and water (84 μL, 4.66 mmol) were reacted to form the desired product (850 mg, 76%). 1H NMR (MeOD-d4): δ 8.05 (d, 1H), 7.22 (d, 1H), 4.00 (m, 1H), 3.01 (t, 2H), 1.72 (m, 2H), 1.50-1.65 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.C([O-])(=O)C.[Na+].[CH2:15]([O:17][C:18](=[O:30])[C:19](=[N:28]O)[C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16].ClCCl>C(O)(=O)C.[Zn]>[CH3:5][C:3]1[NH:28][C:19]([C:18]([O:17][CH2:15][CH3:16])=[O:30])=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]=1[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)C(=NO)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A mixture of ethyl acetoacetate (72.5 g, 0.56 mol), zinc dust (98 g, 1.51 mol) and anhydrous sodium acetate (102 g, 1.21 mol) in glacial acetic acid (110 mL) was heated to 60° C. Ethyl-2-hydroxyimino-3-oxo-3-phenyl-propanoate (110 g, 0.5 mol) was added as a solution (some precipitation on standing) in glacial acetic acid (550 mL) in 3 portions with vigorous stirring over a period of 1 h. The temperature increased to 90° C. during the addition and the reaction was then maintained at 60-75° C. for 3 h. Additional zinc dust (49 g, 0.75 mol) was added over 15 min, again causing a temperature rise, and then the reaction mixture was then stirred at 60 to 75° C. for 1 h. After cooling to room temperature the mixture was filtered and the filtrate was evaporated in vacuo to give a residue which was azeotroped with toluene (2×200 mL) to remove residual acetic acid. Water (2 L) and ethyl acetate (300 mL) were added to the residue and the mixture was stirred until two clear phases were obtained. The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×200 mL). The combined organic phases were washed successively with water (2×250 mL), saturated bicarbonate solution (2×250 mL), water (2×100 mL), brine (2×100 mL), dried over anhydrous sodium sulfate and then concentrated to give a gummy residue. A mixture of dichloromethane and petroleum ether (175 mL; 1:6) was added to the solid and it was stirred for 15 min. The resulting free-flowing solid was filtered off and washed with chilled petroleum ether (100 mL) to afford diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (85 g, 57%) as an off-white solid.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:33][C:34]4[CH:43]=[C:42]5[C:37]([CH:38]=[CH:39][N:40]=[CH:41]5)=[CH:36][CH:35]=4)=[N:18][CH:19]=[C:20]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH:21]=3)[N:10]=2)=CC=1.S(O)(C(F)(F)F)(=O)=O.FC(C(O)=O)(F)F>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:33][C:34]3[CH:43]=[C:42]4[C:37]([CH:38]=[CH:39][N:40]=[CH:41]4)=[CH:36][CH:35]=3)=[N:18][CH:19]=[C:20]([CH2:22][N:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:28]3)[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4ccncc4c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2Nc2ccc3ccncc3c2)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a 25 mL, round-bottomed flask was added N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)isoquinolin-7-amine (150 mg, 0.201 mmol) and 5% TfOH-TFA (5 mL). The reaction mixture was stirred at 70° C. for 30 minutes and cooled to room temperature. After removal of TFA in high vacuum, the residue was treated with saturated NaHCO3, the obtained suspension was filtered to provide the crude product as a yellow solid. After air drying, the solid was treated with MeOH-DCM-ether and filtered to provide N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)isoquinolin-7-amine (100 mg, 98% yield) as a yellow solid. m/z (ESI positive ion): 506 (M+H)+. 1H NMR (400 MHz, DMSO-d6): 6 ppm 2.88 (s, 3H) 3.09-3.16 (m, 4H) 3.29-3.36 (m, 7H) 3.56 (s, 2H) 7.74 (d, J=5.67 Hz, 1H) 7.83 (br s, 1H) 7.93 (d, J=8.80 Hz, 2H) 8.07 (dd, J=8.90, 2.05 Hz, 1H) 8.36 (d, J=5.67 Hz, 1H) 8.40 (d, J=2.15 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 8.87 (d, J=1.56 Hz, 1H) 9.21 (s, 1H) 12.42 (s, 1H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:46]=[C:47]([CH2:49][NH:50]C(OC(C)(C)C)=O)[CH:48]=1)[C:13]([NH:15][C@H:16]([B:33]1[O:41]C2C(C)(C3CC(C2)C3(C)C)[O:34]1)[CH2:17][C:18]1[C:19](OC)=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([O:23]C(C)(C)C)=[O:22])=[O:14])=O)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:50][CH2:49][C:47]1[CH:46]=[C:12]([CH:11]=[C:10]([CH2:9][NH2:8])[CH:48]=1)[C:13]([NH:15][C@H:16]1[CH2:17][C:18]2[CH:30]=[CH:29][CH:28]=[C:20]([C:21]([OH:23])=[O:22])[C:19]=2[O:34][B:33]1[OH:41])=[O:14]
Reactant: COc1c(C[C@H](NC(=O)c2cc(CNC(=O)OC(C)(C)C)cc(CNC(=O)OC(C)(C)C)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NCc1cc(CN)cc(C(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)c1

Procedure:
Prepared from tert-butyl 3-((2R)-2-(3,5-bis((tert-butoxycarbonylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 370 (MH)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([CH2:30][O:23][C:19]1[CH:18]=[C:17]([C:15](=[O:16])[CH2:14][CH2:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:22]=[CH:21][CH:20]=1)=[O:32])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(CCC(=O)c2cccc(O)c2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCC(=O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc1OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 8228.3 %

Procedure:
A 60% mineral oil suspension of NaH (279 mg, 6.98 mmol) in anhydrous DMF (10 mL) was cooled to 0° C. in an ice bath and solid 3-(3,4-Dimethoxyphenyl)-1-(3-hydroxyphenyl)propan-1-one (7) (2 g, 6.98 mmol) added in one portion. The resulting yellow solution was stirred for 5 min after which time tert-butylbromoacetate (1.18 mL, 7.33 mmol) was added. Stirring was continued at 0° C. for 15 min after which time the reaction mixture was warmed to room temperature and partitioned between diethyl ether (50 mL) and water (50 mL). The organic layer was washed with a saturated NaCl solution (2×50 mL), dried over MgSO4, filtered, evaporated, and flash chromatographed (silica gel, 30% EtOAc/hexanes) to afford 230 g (82%) of a clear colorless oil: IR (neat) 2980, 1750, 1685, 1590, 1515, 1260, 1155 cm−1; 1H NMR (CDCl3, 300 MHz) 7.59 (d, J=7.7 Hz, 1H), 7.49 (s, 1H), 7.39 (app t, J=8.0 Hz, 1H), 7.14 (dd, J=8.2, 2.6 Hz, 1H), 6.81-6.79 (m, 3H), 4.58 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.28 (t, J=7.3 Hz, 2H), 3.02 (t, J=7.8 Hz, 2H), 1.51 (s, 9H); 13C NMR (CDCl3, 75 MHz) 199.2, 168.0, 158.6, 149.3, 147.8, 138.7, 134.2, 130.1, 121.8, 120.6, 113.5, 112.2, 111.8, 108.1, 83.0, 66.1, 56.2, 41.1, 30.2, 28.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[CH3:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)(=O)C>[CH3:16][C:17]1[S:21][C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:19][C:18]=1[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OCCc3nc(-c4ccccc4)sc3C)ccc2[nH]1
Reaction time: 48 h
Yield: 53 %

Procedure:
A solution of ethyl 5(hydroxy)-1H-indole-2-carboxylate (991 mg, 4.83 mmol) and 2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethanol (1.06 g, 4.83 mmol) in tetrahydrofuran (30 +5 mL rinse) was added to a stirred mixture of triphenylphosphine (1.3 g, 4.9 mmol) and 1,1′-(azodicarbonyl)dipiperidine (1.2 g, 4.9 mmol) in tetrahydrofuran (10 mL). The reaction was stirred for 48 h and then diluted with ethyl acetate (200 mL). This solution was washed successively with water, 10% hydrochloric acid, and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 25% ethyl acetate/hexane gave 1.04 g (53%) of the desired product. The product had: 1H NMR (300 MHz, acetone-D6) □ 10.40-10.55 (br s, 1 H), 7.89-7.95 (m, 2 H), 7.38-7.49 (m, 4 H), 7.19 (d, 1 H), 7.06-7.09 (m, 1 H), 6.95 (dd, 1 H), 4.30-4.40 (m, 4 H), 3.20 (t, 2 H), 2.51 (s, 3 H), 1.35 (t, 3 H); mass spectrometry gave MH+=407.1 (calc'd exact mass for C23H22N2O3S=406.14).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([CH3:28])[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[S:33][CH:34]=1.CC(C)([O-])C.[K+]>COCCOC.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[S:33][CH:34]=[C:30]([CH3:29])[CH:31]=4)=[CH:3][C:4]=3[CH3:28])(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1C
Reactant: Cc1csc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-methylbenzenesulfonamide (E102) (120 mg, 0.26 mmol) and (4-methyl-2-thienyl)boronic acid (73 mg, 0.51 mmol) in DME (3 ml) was added potassium tert-butoxide (263 mg, 2.34 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E108). MS (ES+) m/e 486 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[O:19][N:18]=[C:17]([O:20][CH2:21][C:22](O)=[O:23])[CH:16]=3)=[N:9][C:8]=2[N:7]([CH2:25][CH2:26][CH3:27])[C:5]1=[O:6])[CH2:2][CH3:3].[CH2:28]1[O:37][C:36]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=2[O:29]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:27][CH2:26][CH2:25][N:7]1[C:5](=[O:6])[N:4]([CH2:1][CH2:2][CH3:3])[C:13](=[O:14])[C:12]2[C:8]1=[N:9]/[C:10](/[N:11]=2)=[C:15]1/[CH:16]=[C:17]([O:20][CH2:21][C:22]([NH:33][C:32]2[CH:34]=[CH:35][C:36]3[O:37][CH2:28][O:29][C:30]=3[CH:31]=2)=[O:23])[NH:18][O:19]/1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)no3)nc2n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=N/C(=C1/C=C(OCC(=O)Nc3ccc4c(c3)OCO4)NO1)N=2

Procedure:
Condensation of 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yloxy]acetic acid (0.5 mmol) and 3,4-methylenedioxyaniline (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.
Reaction SMILES: [I:1]I.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:10]1[CH:11]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1I
Yield: 60.6 %

Procedure:
2-iodo-4-(trifluoromethyl)aniline was prepared according to method D Step I with iodine (1.58 g; 6.21 mmol), silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40 mL). The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to afford 1.08 g (61%) of 2-iodo-4-(trifluoromethyl)aniline as a red oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[K].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][CH:10]=1)([O-:8])=[O:7]>CN(C)C=O>[Br:1][CH2:2][CH2:3][N:15]([C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1)[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18]
Reactant: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccccc2)cc1
Reactant: BrCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N(CCBr)S(=O)(=O)c2ccccc2)cc1
Temperature: 92.5 °C
Reaction time: 4 h

Procedure:
1,2-Dibromoethane (2.26 kg, 12 mol) mixed with 4 L of dimethylformamide was brought to 80° C. 1.264 kg (4 mol) of the potassium salt of N-(4-nitrophenyl)benzenesulfonamide (5) was added in portions and the mixture was stirred at 90-95° C. for 4 hours. The resulting mixture was filtered while hot and a KBr salt was formed, which was washed with dimethylformamide. The filtrate was poured onto 20 kg of ice in 20 kg of water. A yellow precipitate formed, which was filtered off by suction, reslurried three times in hot 1N sodium hydroxide, and then reslurried in water to neutral pH. The crude product (1.2 kg wet) obtained was recrystallized from 3 L of acetic acid. This mixture was filtered while boiling and the filtrate was cooled to 20° C. A white precipitate formed, which was filtered off by suction, washed with acetic acid and then with petroleum ether, and then dried under vacuum. 773 g product with a melting temperature of 168° C. were isolated.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[CH3:25][P:26]([C:29]1[CH:30]=[CH:31][C:32]([O:36][CH3:37])=[C:33]([CH:35]=1)[NH2:34])([CH3:28])=[O:27]>>[CH3:28][P:26]([C:29]1[CH:30]=[CH:31][C:32]([O:36][CH3:37])=[C:33]([NH:34][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=2)[CH:35]=1)([CH3:25])=[O:27]
Reactant: COc1ccc(P(C)(C)=O)cc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Product: COc1ccc(P(C)(C)=O)cc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)c(C(F)(F)F)cn1

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 5-(Dimethylphosphoryl)-2-methoxyaniline.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1cnc(Br)cn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cnc(Br)cn2)CC1

Procedure:
A mixture of 5-bromopyrazin-2-ol B4a (525 mg, 3 mmol), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.117 g, 4 mmol), 18-crown-6 (79 mg, 0.3 mmol), K2CO3 (829 mg, 6 mmol) in butan-2-one (19 mL) is subjected to microwave irradiation at 130° C. for 15 min. The solids are filtered off, washed with ethyl acetate and purified by flash chromatography (hexanes/ethyl acetate gradient) to afford tert-butyl 4-(5-bromopyrazin-2-yloxy)piperidine-1-carboxylate B4b as a white solid: MS calcd. For C14H21BrN3O3 ([M+H]+): 358.1, found: 358.1.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:22])[C:9]([O:11][CH2:12][C:13](=[O:21])OC2C=CC=CC=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:1]1([CH2:7][CH:8]2[O:22][C:13](=[O:21])[CH2:12][O:11][C:9]2=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(COC(=O)C(O)Cc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Product: O=C1COC(=O)C(Cc2ccccc2)O1
Temperature: 250 °C
Reaction time: 0.77 h

Procedure:
Experiment 8. 2-oxo-2-phenoxyethyl 3-phenyllactate (240 mL of a 10% w/v solution in tetrahydrofuran at 10 mL/hr) and nitrogen (240 mL/min) were passed through a 23-mm I.D. quartz tube containing 4 mL of coarsely crushed quartz on top of 4 mL of Catalyst A heated to 250° C. Contact time and WWH were 0.98 s and 0.77 hr-1, respectively. The column effluent was rotovaped, phenol was removed by distillation under reduced pressure to give crude product. Two crystallizations from anhydrous isopropanol gave 7.53 g (36.5 mmol) of 3-phenylmethyl-1,4-dioxane-2,5-dione. mp 64°-65° C. 1H NMR (300 MHz, CDCl3): δ3.28 (dd, 1H, J=5.7 and 14.6 Hz), δ3.37 (dd, 1H, J=4.6 and 14.7 Hz), δ3.89 (d, 1H, J=16.8 Hz), d 4.60 (d, 1H, J=16.8 Hz), δ5.17 (dd, 1H, J=4.6 and 5.7 Hz), and δ7.2-7.4 (phenyl, 5H). 13C NMR (75 MHz, CDCl3): 38.2, 65.0, 76.9, 128.1, 129.2, 130.1, 134.1, 163.4, and 165.1. HRMS calcd for C11H10O4 =206.0579, found 206.0574.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH2:18])[CH:11]=1>>[CH3:9][C:4]1[CH:3]=[C:2]([NH:18][CH2:17][CH2:16][C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(I)cc1C
Reactant: NCCc1cccnc1
Product: Cc1ccc(NCCc2cccnc2)cc1C

Procedure:
In analogy to the procedure described for the synthesis of example 22, step 1, the title compound was prepared from 4-iodo-o-xylene and 2-pyridin-3-yl-ethylamine (CAS: 20173-24-4). MS (m/e): 227.2 [M+H]+.