Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([Cl:30])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[CH:29]=[C:28]([Cl:30])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(Cl)sc3n2)cc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[N:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)=O)C.O.[OH-].[Na+]>O1CCCC1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([N:13]2[C:14]3[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=3)[CH:20]=[C:12]2[CH2:10][OH:9])=[CH:24][CH:25]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cc2cc(OC)ccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)cc(CO)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
Lithium aluminum hydride (1.53 mL, 1 M in tetrahydrofuran, 1.53 mmol) was diluted with tetrahydrofuran (5 mL) under N2, and 1-(4-benzyloxyphenyl)-5-methoxy-1H-indole-2-carboxylic acid ethyl ester (0.51 g, 1.27 mmol) in tetrahydrofuran (5 mL) was added dropwise. The reaction was stirred at reflux for 2 hours, then cooled to room temperature. Water (0.3 mL) was added carefully, followed by 2 N NaOH (0.3 mL) and water (0.9 mL). The solvent was evaporated, and the residue was partitioned between water and ethyl acetate. The organic was separated, dried over MgSO4, and concentrated to give 0.41 g (88% yield) of crude product. LC-MS (C23H21NO3 calc'd 359) m/z 360 (M+H).
Reaction SMILES: [Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]([C:7]([C:4]3[CH:3]=[C:2]([Br:1])[O:6][CH:5]=3)=[O:9])[C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: NC(=O)N1C(=O)Cc2ccc(Cl)cc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Product: NC(=O)N1C(=O)C(C(=O)c2coc(Br)c2)c2ccc(Cl)cc21
Yield: 11 %

Procedure:
The experimental procedure used to produce the title compound was adopted from Example 55. A 750 mg (3.93 mmole) portion of 5-bromo-3-furoic acid (prepared according to Amaral, L., et al., J.O.C., 41, 2350 (1976)) was transformed into the acyl imidazole by reaction with 690 mg (4.25 mmole) of 1,1'-carbonyldiimidazole. The intermediate 5-bromo-3-furan-(1-imidazo)carboxamide coupled directly with 689 mg (3.27 mmole) of 6-chloro-2-oxindole-1-carboxamide in the presence of 1.08 g (8.83 mmole) of 4-(N,N-dimethylamino)pyridine to give 500 mg (40% yield) of crude greenish-yellow solid. Recrystallization gave 143 mg (0.37 mmole, 11% yield) of pure title compound as a greenish solid, m.p. 232°-4° C. (acetic acid).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[CH2:35][OH:36]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][C@@H:31]4[CH2:35][OH:36])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: OC[C@H]1CCCN1
Product: OC[C@H]1CCCN1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 37 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (R)-2-pyrrolidinemethanol to give the title compound in 37% yield; NMR Spectrum: 1.49-1.53 (m, 1H), 1.60-1.66 (m, 2H), 1.77-1.82 (m, 1H), 2.33-2.36 (m, 1H), 2.58 (br s, 1H), 2.77-2.79 (m, 1H), 3.13-3.15 (m, 1H), 3.26-3.29 (m, 2H), 3.37-3.41 (m, 1H), 4.39 (t, 2H), 4.44 (br s, 1H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.56 (s, 1H), 7.58 (s, 1H), 7.87 (t, 1H), 7.93 (d, 1H), 8.29 (s, 1H), 8.40 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:7][CH:8]=1)#N.[CH3:28][C:29](N=C(N(C)C)N(C)C)([CH3:31])[CH3:30].BrCC(C)C>C(#N)C.CO>[CH3:27][C:22]1[C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([S:10]([N:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:6]3[CH:5]=[CH:4][C:3]([CH3:1])=[CH:8][N:7]=3)(=[O:12])=[O:11])=[CH:14][CH:15]=2)=[C:25]([CH3:26])[O:24][N:23]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C#N)cn2)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC(C)CBr
Solvent: CC#N
Solvent: CO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
To a solution of N-(5-cyano-2-pyridinyl)-4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonamide (23 mg, 0.060 mmol) in acetonitrile (0.5 mL) at room temperature was added N″-(1,1-dimethylethyl)-N,N,N′,N′-tetramethylguanidine (0.024 mL, 0.120 mmol). The reaction mixture was stirred at 20° C. for 1 hour, then 1-bromo-2-methylpropane (0.013 mL, 0.120 mmol) was added. The reaction was heated by microwaves to 150° C. for 30 minutes. After cooling, the reaction mixture was diluted with methanol and passed through an aminopropyl (NH2) solid phase extraction (SPE) cartridge followed by a sulphonic acid (SCX) SPE cartridge, eluting with methanol. The appropriate fractions were combined and evaporated under a stream of nitrogen to give the crude product. The crude was purified by mass directed autoprep (formic acid modifier), to provide the title compound (1.8 mg). LCMS (2 min, formic) Rt 1.25 min, m/z (ES+) 441 (M+H).
Reaction SMILES: C(O[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[N:6][NH:7][C:8]([O:10]C)=O)CC.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CO>[CH:16]1([N:22]2[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[N:6][NH:7][C:8]2=[O:10])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: CCCOC(=NNC(=O)OC)OCCC
Solvent: CO
Product: CCCOc1n[nH]c(=O)n1C1CCCCC1
Reaction time: 5 h

Procedure:
In an autoclave, 2.04 g of methyl N′-dipropoxymethylenehydrazinecarboxylate (8.9 mmol) and 3.23 g of cyclohexylamine (32.2 mmol) were initially charged in 25.8 g of methanol. After 5 hours at 110° C., the solvent was distilled off and the crude 4-methyl-5-cyclohexyloxy-2,4-dihydro-1,2,4-triazol-3-one (1.3 g) was purified by column chromatography (mobile phase: ethyl acetate). This gave 0.37 g (18%) of pure product. Melting point: 132-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][N:16]=[N:15]2)[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.ClCCl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:14]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:17][N:16]=[N:15]2)[CH2:10][CH2:11][N:29]2[CH2:30][CH2:31][C:26]([OH:25])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:27][CH2:28]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CCC(Cn1nnnc1-c1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: OC1(c2ccccc2)CCN(CCC(Cn2nnnc2-c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.03 h
Yield: 44.9 %

Procedure:
3-(3,4-Dichlorophenyl)-4-(5-phenyltetrazol-1-yl)butyraldehyde (0.200 g) in methanol (1 mL) and dichloromethane (1 mL) was added to a solution of 4-hydroxy-4-phenylpiperidine (0.147 g) and acetic acid (0.047 mL) in methanol (1 mL). After 2 minutes, sodium cyanoborohydride (52 mg) in methanol (1 mL) was added in a single portion. After being stirred overnight, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried and evaporated. The crude product was suspended in methanol/ether and filtered to give the title compound as a white solid (0.13 g); NMR: 7.57 (m,5), 7.44 (m,2), 7.36-7.18 (m,5), 6.87 (dd,1, J=1.6, 8.2), 4.98 (dd,1, J=5.2, 14.3), 4.81 (dd,1, J=10.1, 14.2), 4.71 (s,1), 3.20 (m,1), 2.54 (m,1), 2.34-2.16 (m,3), 2.09 (m,2), 1.91 (m,1), 1.75 (m,3), 1.50 (m,2); MS: m/z=522(M+1). Analysis for C28H29Cl2N5O: Calculated: C, 64.37; H, 5.59; N, 13.40; Found: C, 64.10; H, 5.56; N, 13.28.
Reaction SMILES: O.[Br:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([Br:12])[C:4]=1[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:14]#[N:15]>C1COCC1>[NH2:9][C:7]1[CH:6]=[C:5]([Br:12])[C:4]([CH:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:14]#[N:15])=[C:3]([Br:2])[CH:8]=1
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Br)cc([N+](=O)[O-])cc1Br
Solvent: C1CCOC1
Solvent: O
Product: N#CC(c1ccc(Cl)cc1)c1c(Br)cc(N)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
A solution of 15% TiCl3 in water (0.13 mol) was added dropwise at RT to a solution of (±)-2,6-dibromo-α-(4-chlorophenyl)-4-nitrobenzeneacetonitrile (0.026 mol) in THF (200 ml). The mixture was stirred at RT for 2 hours, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, washed with H2O and with K2CO3 10%, dried, filtered and the solvent was evaporated. A part of this residue (2 g) was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 1.3 g (±)-4-amino-2,6-dibromo-α-(4-chlorophenyl)benzeneacetonitrile (interm. 47).
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[N:13]([CH3:24])[N:14]=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[N:13]([CH3:24])[N:14]=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:34]3[CH:35]=[CH:36][C:37]([C:40]4([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]4)=[CH:38][CH:39]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: C[C@@H](OC(=O)Nc1c(-c2ccc(Br)cc2)nnn1C)c1ccccc1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](OC(=O)Nc1c(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)nnn1C)c1ccccc1
Temperature: 80 °C
Yield: 64 %

Procedure:
In a 20 mL vial, [5-(4-bromo-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester (Example 1, 110.3 mg, 275 μmol), N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide (112 mg, 307 μmol), DPPF (38 mg, 68.5 μmol) and PdCl2(dppf)CH2Cl2 (39 mg, 47.8 μmol) were combined with DMF (5 mL) and the mixture was bubbled with nitrogen for 20 minutes to give a light brown/red solution. To this was added 2N Na2CO3 (550 μL, 1.1 mmol, degassed with nitrogen bubbled through for 20 min), and the red mixture (looked like salt precipitated) had nitrogen bubbled through for 1 min. The vial was sealed, placed in a dry block, and heated at 80° C. for 4 hr. The reaction was diluted with ethyl acetate (75 mL) and 0.1 M HCl (100 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (75 mL). The organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and dried from DCM/hexanes to give a crude material (311 mg). The crude material was dissolved in minimal DCM and purified by flash chromatography (silica gel, 24 g Redisep, 30 mL/min, 0% to 100% EtOAc in hexanes, 0.5% AcOH). Appropriate fractions were combined, concentrated, dried from DCM/hexanes and DCM to yield {5-[4′-(1-methanesulfonylaminocarbonyl-cyclopropyl)-biphenyl-4-yl]-3-methyl-3H-[1,2,3]triazol-4-yl}-carbamic acid (R)-1-phenyl-ethyl ester (98.5 mg, 64% yield). LC/MS calcd. for C29H29N5O5S (m/e) 559, obsd. 560 (M+H, ES+). 1H NMR (DMSO-d6) δ ppm 11.16 (br. s., 1H), 9.93 (br. s., 1H), 7.80 (d, J=7.8 Hz, 2H), 7.62-7.76 (m, 4H), 7.06-7.57 (m, 7H), 5.65-5.93 (m, 1H), 3.85 (s, 3H), 3.20 (s, 3H), 1.38-1.76 (m, 5H), 1.20 (br. s., 2H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH2:13](Br)[CH:14]=[CH2:15].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([O:10][CH2:15][CH:14]=[CH2:13])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: C=CCBr
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOC1CC(C)(C)N(O)C(C)(C)C1
Temperature: 70 °C

Procedure:
A vigorously stirred two phase solution of 30.0 g (0.17 mol) 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 29.0 g (0.24 mol) of allyl bromide, 2.6 g (8 mmol) of tetrabutylammonium bromide, 100 mL of 50% aqueous sodium hydroxide and 30 mL of toluene is heated at 70° C. for 90 minutes. The mixture is partitioned between 100 mL of toluene, 100 mL of heptane and 200 mL of water. The organic phase is dried over anhydrous magnesium sulfate and concentrated to yield the title compound as a red oil after column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([O:22]C)[CH:16]=[C:15]([O:24]C)[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33].Cl.N1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([OH:22])[CH:16]=[C:15]([OH:24])[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc([N+](=O)[O-])cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccc([N+](=O)[O-])cc4Cl)oc23)[C@@H]1CO

Procedure:
A mixture of (−)-trans-2-(2-chloro-4-nitrophenyl)-8-(2-hydroxymethyl-1-methyl pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one (0.4 g, 0.8 mmol), pyridine hydrochloride (0.48 g, 4.1 mmol) and a catalytic amount of quinoline was heated at 180° C. for a period of 2 hrs. The reaction mixture was cooled and diluted with methanol (50 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.1% ammonia and 3% methanol in chloroform as eluent to yield the title compound as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)[CH2:8]OS(C)(=O)=O)(=[O:4])=[O:3].CN1C(=O)N(C)CCC1.[N-:37]=[N+:38]=[N-:39].[Na+]>CCOC(C)=O>[CH3:1][S:2]([O:5][CH2:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)[CH2:8][N:37]=[N+:38]=[N-:39])(=[O:4])=[O:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC(COS(C)(=O)=O)(c1cccc(Br)c1)c1cccc(Br)c1
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCC(CN=[N+]=[N-])(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: 110 °C
Yield: 40.1 %

Procedure:
To a solution of 2,2-bis(3-bromophenyl)propane-1,3-diyl dimethanesulfonate (3.6 g, 6.64 mmol) in DMPU (25 mL, 207 mmol) under N2 was added NaN3 (0.52 g, 7.97 mmol) with stirring. The mixture was heated to 110° C. for 5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL), and washed with water (30 mL×2) and brine (25 mL), dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with Petroleum ether: EtOAc=3:1) to afford 1.3 g of the title compound (2.66 mmol, 40%). LC/MS: [M+18]=507. 1HNMR (CDCl3), 400 MHz: δ 2.83 (s, 3H), 4.07 (s, 2H), 4.77 (s, 2H), 7.07-7.09 (m, 2H), 7.21-7.31 (m, 4H), 7.44-7.46 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:25][N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.O.ClCCl.Cl>[C:1]([O:5][C:6](=[O:32])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:25][N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CN(C)S(C)(=O)=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN(Cc1cc(CC(=O)OC(C)(C)C)ccc1Oc1ccc(C(=O)O)cc1)S(C)(=O)=O
Reaction time: 5 h
Yield: 70.6 %

Procedure:
To a stirred solution of methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-((N -methylmethylsulfonamido)methyl)phenoxy)benzoate (370 mg, 0.797 mmol) in dioxane (8 ml) was added a solution of LiOH monohydrate (43.5 mg, 1.04 mmol) in water (2 ml) (0.1 M solution 4:1 dioxane/water). The reaction was stirred for 5 hours, then diluted with dichloromethane and 2 N HCl. The aqueous phase was extracted with dichloromethane and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified by silica gel chromatography to give 4-(4-(2-tert-butoxy-2-oxoethyl)-2-((N -methylmethylsulfonamido)methyl)phenoxy)benzoic acid (0.253 g).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2S[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])[CH3:2].C(=O)([O-])O.[Na+].ClC1C=CC=C(C(OO)=O)C=1.[S:47]([O-:51])(O)(=O)=[O:48].[Na+]>ClCCl>[CH2:1]([C:3]1[C:11]2[S:47](=[O:51])(=[O:48])[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:4]=1[CH3:30])[CH3:2]
Reactant: O=S(=O)([O-])O
Reactant: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1S(=O)(=O)CC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a mixture of N-(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide (225 mg, 0.512 mmol) obtained in Example 164 and sodium hydrogen carbonate (250 mg, 0.590 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (283 mg, 1.65 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 2 hours. To the reaction solution was added an aqueous sodium hydrogensulfate solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 74 mg (yield: 28%) of the title compound. Amorphous powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(C(F)(F)F)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethyl)phenol: ESMS m/e: 603.1 (M+H)+.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>C1C=CC=CC=1.ClCCl>[C:1]([NH:5][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([C:7]([F:6])([F:17])[F:18])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 429 %

Procedure:
To N-tert-butylamine (3.50 g, 0.0048 mol) in 75 mL of benzene was added 4-trifluoromethylbenzoyl chloride (5.00 g, 0.024 mol). The temperature was maintained below 15° C. during the addition and then the reaction mixture was allowed to warm to ambient temperature and stirred for 3 hours. The solvent was then stripped and the residue was dissolved in 75 mL of dichloromethane. This solution was washed with 5% hydrochloride acid (2×75 mL), water (2×75 mL), dried over MgSO4 and then the solvent was removed in vacuo to provide 5.05 g (85-9% yield) of the title compound, m.p. 146-148° C.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].C([O-])([O-])=O.[K+].[K+].[F:18][C:19]([P:25](Cl)[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])([F:24])[C:20]([F:23])([F:22])[F:21]>C(Cl)Cl>[F:24][C:19]([P:25]([C:26]([F:31])([F:32])[C:27]([F:28])([F:29])[F:30])[O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])([F:18])[C:20]([F:23])([F:22])[F:21]
Reactant: C=CCCCCCCCCO
Reactant: FC(F)(F)C(F)(F)P(Cl)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCCCCCCCCOP(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.31 g (1.9 mmol) of 9-decen-1-ol is initially introduced in CH2Cl2 with excess K2CO3, and 0.64 g (2.1 mmol) of bis(pentafluoroethyl)phosphinous acid chloride, (C2F5)2PCl, is condensed in. After the mixture has been stirred at room temperature for 30 minutes, the precipitate is filtered off, and volatile substances are removed in vacuo. The product, 9-decenyl bis(pentafluoroethyl)phosphinite, remains as a colourless, oily liquid, which is characterised by spectroscopy.