Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]([F:28])([F:27])[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC#N>CCCCO>[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([F:17])([F:27])[F:28])[N:7]=1)([CH3:15])[CH3:14]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: NC(c1ccccc1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Solvent: CCCCO
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(NC(c2ccccc2)C(F)(F)F)n1
Temperature: 110 °C
Yield: 25.4 %

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (163 mg, 0.674 mmol), 2,2,2-trifluoro-1-phenylethanamine (624 mg, 3.56 mmol, 5.3 equiv) and p-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol, 2.5 equiv) in n-BuOH (3 mL) was heated at 110° C. for 2 h and treated with additional p-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol, 2.5 equiv), then heated at 110° C. for 1½ h. After cooling, the solid reaction mixture was treated with MeCN, sonicated and filtered. The filtrated was concentrated and purified by silica gel column chromatography (EtOAc/Heptane 0 to 30%) to give (4S)-4-isopropyl-3-(2-(2,2,2-trifluoro-1-phenylethylamino)pyrimidin-4-yl)oxazolidin-2-one (65 mg) in 25% yield. 1H NMR (400 MHz, CD3OD) δ 8.215 (d, J=6.1 Hz, 0.5H), 8.212 (d, J=6.1 Hz, 0.5H), 7.52 (t, J=7.1 Hz, 2H), 7.46 (dd, J=5.8, 3.8 Hz, 1H), 7.43-7.34 (m, 3H), 5.86 (qd, J=8.2, 4.0 Hz, 1H), 4.83-4.75 (m, 1H), 4.42-4.33 (m, 2H), 2.62 (dtd, J=14, 7.0, 3.8 Hz, 0.5H), 2.28 (br s, 0.5H), 1.02 (d, J=7.1 Hz, 1.5H), 0.91 (d, J=7.1 Hz, 1.5H), 0.88 (d, J=7.11 Hz, 1.5H), 0.73 (d, J=7.1 Hz, 1.5H); HRMS(B) m/z 381.1545 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3](O)=O.[CH2:22]([NH2:24])[CH3:23].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[CH2:22]([N:24]([CH2:3][C:2]([CH3:1])=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:25](=[O:27])[CH3:26])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CCN
Product: CCN(CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=O)C(C)=O

Procedure:
Starting materials: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid; ethylamine (70% aqueous ethylamine solution); and acetic anhydride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:25]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=2[F:26])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1cc(F)ccc1F
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 2,5-difluorobenzene boronic acid according to the general procedure B. Obtained as a yellow solid (2.85 g).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:18]3[CH2:22][CH2:21][CH2:20][N:19]3[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=O)[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].N>CO.C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:15]([C@H:24]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:23][N:19]4[CH2:20][CH2:21][CH2:22][C@H:18]43)=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)CN2CCCC2c2cccc(OCC3CCN(C(C)C)CC3)c2)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCC4CCN(C(C)C)CC4)ccc32)cc1
Yield: 70 %

Procedure:
2-{2-[3-(1-Isopropyl-piperidin-4-ylmethoxy)-phenyl]-pyrrolidin-1-yl}-(4-methoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.31 mmol scale, to give 1.04 g (70%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C27H36N2O3, 450.3; m/z found, 451.5 [M+H]+. 1H NMR (MeOH-d4): 7.84 (m, 2H), 7.20 (m, 1H), 7.01 (d, J=1.5, 1H), 6.96 (d, J=7.5, 1H), 6.92 (m, 2H), 6.81 (m, 1H), 4.89 (s, 1H), 3.96 (d, J=16.6, 1H), 3.86 (m, 5H), 3.46 (m, 3H), 3.29 (m, 3H), 2.80 (t, J=12.3, 2H), 2.33 (m, 1H), 2.18 (m, 1H), 2.02 (m, 4H), 1.87 (m, 1H), 1.75 (m, 1H), 1.64 (m, 2H), 1.28 (d, J=6.7, 6H).
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]2.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([NH:21][C@@H:5]1[C@@H:1]([OH:6])[CH2:2][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](NCc2ccccc2)[C@@H](O)C1
Yield: 85.2 %

Procedure:
A solution of the epoxide (4.6 g, 24.9 mmol) of step A and benzylamine (5.2 g, 48.6 mmol) in ethanol was stirred at 85° C. overnight. The solvent was removed by concentration under reduced pressure to give a solid. The solid was washed with a mixed solvent of 50% EtOAc/hexanes to provide 6.2 g of the desired compound. MS calculated (M+H)+ 293. found 293.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([OH:15])=[CH:3][CH:2]=1.[C:16]([OH:20])(=[O:19])[CH:17]=[CH2:18]>>[C:16]([O-:20])(=[O:19])[CH:17]=[CH2:18].[CH:10]1[CH:9]=[C:8]([CH2:7][C:5]2[C:4]([OH:15])=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:13]([OH:14])=[CH:12][CH:11]=1
Reactant: C=CC(=O)O
Agent: Oc1ccccc1Cc1ccccc1O
Product: C=CC(=O)[O-]

Procedure:
A bisphenol F-type epoxy resin (RE-404P, manufactured by Nippon Kayaku Co., Ltd., epoxy equivalent: 160 g/eq, hydrolyzed amount: 30 ppm) was reacted with acrylic acid of amount of 100% equivalent to epoxy groups, subjected to purification by liquid-separation treatment using ion exchanged water/toluene and then deprived of toluene by evaporation to obtain an acrylate of the bisphenol F-type epoxy resin. Thus obtained acrylate of the bisphenol F-type epoxy resin of 80 parts by weight, the Epoxy resin B of the Synthesis Example of 20 parts by weight, 3,6-bis(2-methyl-2-morphorinopropionyl)-9-n-octyl carbazole (Adeka Optmer N-1414, manufactured by Asahi Denka Kogyo Co., Ltd.) of 1.8 parts by weight, serving as a radical-forming photopolymerization initiator and an amino silane coupling agent (N-β(aminoethyl)-γ-aminopropyltrimethoxy silane, KBM-603, manufactured by Shin-Etsu Silicone Co., Ltd.) of 1.2 parts by weight were heated and dissolved at 90° C. to obtain a resin solution. Thus obtained resin solution was cooled to room temperature, then added with 3.3 parts by weight of isophthalic acid dihydrazide (trade name: IDH-S; prepared by finely grinding a material of jet-mill ground-grade manufactured by Otsuka Chemical Co., Ltd. using a jet mill; melting point: 224° C.; active hydrogen equivalent: 48.5 g/eq; average particle diameter: 1.7 μm; maximum particle diameter: 7 μm), 30 parts by weight of fused ground silica (Crystalite 1FF, manufactured by Tatsumori Co., Ltd., average particle diameter: 1.0 μm) and 1 part by weight of IXE-100 (a zirconium phosphate-series ion scavenger, manufactured by Toa Gosei Co., Ltd.), and kneaded using a three-roll mill to obtain a sealant for liquid crystals of the present invention. The sealant had viscosity of 400 Pa·s (25° C.) (measured by an R-type viscometer, manufactured by Toki Sangyo Co., Ltd.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:25](C=O)=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:25]1[C:24]([CH3:23])=[CH:29][C:28]([CH3:30])=[CH:27][N:26]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)NCCCNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(N(CCCNC(=O)OC(C)(C)C)C2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B, reaction of [3-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-propyl]-carbamic acid tert-butyl ester, 3,5-dimethylpyridine-2-carboxaldehyde and NaBH(OAc)3 in CH2Cl2 gave {3-[(3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-carbamic acid tert-butyl ester as a pale beige sticky solid. 1H NMR (CDCl3) δ 1.75 (m, 4H), 2.18 (br t, 1H), 2.27 (s, 3H), 2.30 (s, 3H), 2.37 (br, 1H), 2.56 (t, 1H, J=10.5 Hz), 2.83 (m, 4H), 3.38 (br, 1H), 3.68 (d, 1H, J=15.0 Hz), 3.84 (br, 1H), 4.04 (d, 1H, J=15.0 Hz), 7.13 (m, 1H), 7.26 (s, 1H), 7.41 (d, 1H, J=7.0 Hz), 8.33 (s, 1H), 8.53 (d, 1H, J=4.5 Hz). Deprotection with TFA using General Procedure F gave N′-(3,5-dimethyl-pyridin-2-yl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine as a white solid.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])[O:7][C:8](Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=C[CH:16]=[CH:15][CH:14]=1.O1CCC[CH2:20]1>>[ClH:1].[C:6](=[O:12])([O:7][CH2:8][CH2:16][CH2:15][CH2:14][NH:13][CH3:18])[O:5][CH2:2][CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCOC1
Reactant: c1ccncc1
Product: CCOC(=O)OCCCCNC
Product: Cl
Reaction time: 0.5 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.59 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 30 minutes under ice-cooling, and ethyl 4-(methylamino)butyl carbonate hydrochloride (1.27 g) obtained in Reference Synthetic Example 39 was added thereto. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 3 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and then extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). To the solution were added (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.26 g), triethylamine (0.95 mL) and 4-dimethylaminopyridine (catalytic amount), and stirred at 60° C. overnight. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give title compound as yellow amorphous solid (1.08 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].CC1(C)C(C)(C)OB(C2C=CC=CC=2C(NC2SC=CN=2)=O)O1.[CH3:38][C:39]1[CH:52]=[CH:51][C:42]([C:43]([NH:45][C:46]2[S:47][CH:48]=[CH:49][N:50]=2)=[O:44])=[CH:41][C:40]=1B1OC(C)(C)C(C)(C)O1>>[S:47]1[CH:48]=[CH:49][N:50]=[C:46]1[NH:45][C:43]([C:42]1[CH:41]=[C:40]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][C:3]=2[CH3:14])[C:39]([CH3:38])=[CH:52][CH:51]=1)=[O:44]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Agent: CC1(C)OB(c2ccccc2C(=O)Nc2nccs2)OC1(C)C
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)Nc4nccs4)ccc3C)c(C)c2)o1

Procedure:
Example 19 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[1,3,4]oxadiazole and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-N-(thiazol-2-yl)-benzamide (Intermediate 22).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH:36]3[CH2:48][O:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)[S:33][CH:34]=2)=[CH:26][CH:25]=1>CO>[ClH:1].[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH:36]3[CH2:48][O:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)[S:33][CH:34]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2csc(N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2csc(N3CCNCC3COc3cccnc3)n2)cc1
Reaction time: 1 h

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(4-(4-methoxyphenyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (199 mg, 0.280 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 44.2 mg of the free-base of the desired product. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (0.029 mL) was added. This was concentrated under reduced pressure, yielding 48.2 mg (41%) of the desired product as an off-white solid. LC-MS: RT=4.98 min, [M+H]+=383.0.
Reaction SMILES: [CH2:1]([N:19]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:20](=[O:45])[CH2:21][CH2:22][CH:23]([CH:25]1[C:41]2([CH3:42])[CH:28]([CH:29]3[CH:38]([CH2:39][CH2:40]2)[C:37]2([CH3:43])[CH:32]([CH2:33][CH:34]([OH:44])[CH2:35][CH2:36]2)[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:64](=O)([O:73]N1C(=O)CCC1=O)[O:65][N:66]1[C:70](=[O:71])[CH2:69][CH2:68][C:67]1=[O:72].C(N(CC)CC)C.C(#N)C>ClCCl>[O:72]=[C:67]1[CH2:68][CH2:69][C:70](=[O:71])[N:66]1[O:65][C:64](=[O:73])[O:44][CH:34]1[CH2:33][CH:32]2[C:37]([CH3:43])([CH:38]3[CH:29]([CH2:30][CH2:31]2)[CH:28]2[C:41]([CH3:42])([CH:25]([CH:23]([CH3:24])[CH2:22][CH2:21][C:20](=[O:45])[N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:26][CH2:27]2)[CH2:40][CH2:39]3)[CH2:36][CH2:35]1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)ON5C(=O)CCC5=O)CCC4(C)C3CCC12C
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.4 %

Procedure:
Referring to scheme 20, amide 82 (15.5 g, 17.6 mmol) was dissolved in anhydrous dichloromethane (150 mL) To the solution were added disuccinimidyl carbonate (6.76 g, 26.4 mmol), triethylamine (10 mL) and acetonitrile (50 mL) The reaction mixture was stirred at room temperature under argon for 6 h and then evaporated dryness. The residue was dissolved in dichloromethane (300 mL) It was washed with saturated NaHCO3 aqueous solution (3×100 mL) The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Compound 83 (12.3 g, 71%) was obtained as colorless powder after drying in high vacuum, which was directly used for the next step without further purification.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[C:6]([O:10][C:11](=[O:26])[NH:12][CH2:13][CH:14]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[CH3:25])[CH2:15][CH2:16][OH:17])([CH3:9])([CH3:8])[CH3:7].[NH4+].[Cl-]>C(Cl)Cl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([CH:14]([CH2:13][NH:12][C:11]([O:10][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:26])[CH2:15][CH2:16][O:17][S:1]([CH3:4])(=[O:3])=[O:2])=[C:19]([CH3:25])[CH:20]=1
Reactant: Cc1cc(Br)ccc1C(CCO)CNC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(CCOS(C)(=O)=O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Mesyl chloride (7.53 mL, 0.09726 mol) was added, at −78° C., to a solution of [2-(4-bromo-2-methyl-phenyl)-4-hydroxy-butyl]-carbamic acid tert-butyl ester (30.3 g, 0.08457 mol) in DCM (600 mL) followed by TEA (27 mL, 0.1945 mol). The reaction mixture was stirred at −78° C. for 1 hour, then allowed to reach room temperature with stirring for an additional hour. A saturated aqueous solution of NH4Cl was added, and the resulting mixture was extracted with DCM. The combined organic extracts were dried over MgSO4, filtered, and evaporated under reduced pressure to give methanesulfonic acid 3-(4-bromo-2-methyl-phenyl)-4-tert-butoxycarbonylamino-butyl ester, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O>O>[CH:6]1[C:7]2[C:2](=[N:1][C:12]3[C:11]([N:8]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Nc1ccccc1
Solvent: O
Product: c1ccc2nc3ccccc3nc2c1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
This example is similar to TMA(OH) loading Example No. 7 except that the slurry contained 262.4 gms of calcined and protonated ZSM-5, 211.4 gms. Of 25% aqueous TMA(OH) and 262 ml of deionized water. The ion exchange was conducted at 40° C. for three hours. The filter cake after ion exchange was dried using a vacuum desiccator without a nitrogen purge overnight at room temperature. The drier cake was further dried in a vacuum desiccator at 35° C. for 2.5 hours using a nitrogen purge. For a 20% target loading of TMA(OH) onto the ZSM-5, 413.8 gms of 25% aqueous TMA(OH) was added into a vessel that was connected to an assembly that was similar to a rotary evaporator. The hot water bath was maintained at about 35° C. and the drying/evaporating process was conducted for about 2.5 hours at vacuum pressures between 8 and 38 mm Hg. The dried material was removed from the vessel and transferred to a flat dish for further drying in a vacuum desiccator. The drying in the vacuum desiccator was kept at 40° C. for about 3 hours. The resulting dried material was not hard, and easy to grind and consisted of what appears to be one phase when ground. A coupling reaction test based on reacting aniline and nitrobenzene failed to produce phenazine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.C(N(CC)CC)C.[CH3:35][S:36]([Cl:39])(=[O:38])=[O:37].O>O1CCCC1>[CH3:35][S:36]([O:1][CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1)(=[O:38])=[O:37].[Cl:39][CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc2cc(C3=NCC(CCCl)S3)[nH]c12)S(=O)(=O)c1cccs1
Product: CN(c1cccc2cc(C3=NCC(CCOS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 3 h
Yield: 8 %
Yield: 54 %

Procedure:
To a solution of N-{2-[5-(2-hydroxyethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (200 mg) and triethylamine (70 μL) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (60 mg) at room temperature, and the mixture was stirred for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)ethyl methanesulfonate (126 mg, yield 54%, MS: 500 (MH+)) and N-{2-[5-(2-chloroethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (16 mg, yield 8%, MS: 440 (MH+)), as a white amorphous solid from a fraction eluted with ethyl acetate, respectively.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.O.[CH3:18][C:19]1[C:20]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:21]([O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:29][CH3:30])=[CH:24][CH:23]=2>C1COCC1>[CH3:18][C:19]1[C:20]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:21]([O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([N:1]3[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]3)=[O:37])=[CH:34][CH:33]=2)[C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:29][CH3:30])=[CH:24][CH:23]=2
Reactant: O=C(O)C1CCNCC1
Reactant: COc1ccc2c(Oc3ccc(C(=O)Cl)cc3)c(-c3ccccc3)c(C)cc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(Oc3ccc(C(=O)N4CCC(C(=O)O)CC4)cc3)c(-c3ccccc3)c(C)cc2c1
Yield: 69 %

Procedure:
To a suspension of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid (16) (0.149 g, 0.388 mmol) in toluene (3 mL) was added oxalyl chloride (0.06 mL, 0.087 g, 0.687 mmol, 1.8 eq) followed by DMF (1 drop). The reaction mixture was stirred at RT under N2 for 45 min. The reaction mixture was concentrated to give crude 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoyl chloride as a yellow oil. Isonipecotic acid (0.051 g, 0.39 mmol), triethylamine (0.12 mL, 0.087 g, 0.86 mmol) and H2O (2 mL) were combined and the solution was cooled in an ice-water bath under N2. To the cold isonipecotic acid solution was slowly added dropwise a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoyl chloride in THF (2 mL) with stirring under N2. The ice-water bath was removed and the reaction mixture was allowed to stir for 5 d. The pH of the reaction mixture was adjusted to ˜1 (litmus paper) with 1 N HCl and the acidic reaction mixture was partitioned between EtOAc and H2O. The organic phase was separated, washed with H2O (2×), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude title compound. The crude product was purified by flash chromatography over SiO2 with CH2Cl2:MeOH (94:6) to give 0.133 g (69%) of compound 17 as an amorphous solid. 1H NMR (400 MHz; DMSO-d6): δ 1.42 (m, 2H), 1.80 (m, 2H), 2.17 (s, 3H), 2.93 (br s, 2H), 3.87 (s, 3H), 6.59 (d, J=8.6 Hz, 2H), 7.09 (dd, J=2.5 Hz, 9.2 Hz, 1H), 7.15 (m, 4H), 7.25 (m, 3H), 7.35 (d, J=2.4 Hz, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.70 (s, 1H), 12.25 (br s, 1H). AP LRMS m/z 494 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].ClC([N:18](C)C)=C(C)C.N>>[NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:18])=[O:6]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: Nc1c(Cl)ccc(C(=O)O)c1F
Agent: N
Product: NC(=O)c1ccc(Cl)c(N)c1F
Yield: 69 %

Procedure:
The sub-title compound was prepared from 3-amino-4-chloro-2-fluoro-benzoic acid, (1-chloro-2-methyl-propenyl)-dimethyl-amine and conc. NH3 in analogy to step 5c.