Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([O:27]C)=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.Cl.[OH-].[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:34])[F:36])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)O)cc32)cc1
Temperature: 130 °C

Procedure:
A mixture of methyl 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido-[2,3-b][1,5]benzodiazepine-8-carboxylate (90 mg, intermediate 56), water (0.63 mL), conc. HCl (1.25 mL), and glacial acetic acid (2.0 mL) was heated at 130° C. for 2 h. After cooling to rt, 4N aqueous NaOH was added until pH=6. The reaction mixture was extracted with DCM (3×), and the extracts were dried, filtered, and concentrated to provide the title compound. LC/MS: m/e 506.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.12 (1H, s), 7.79 (1H, dd, J=8.5, 1.6 Hz), 7.49 (1H, d, J=7.5 Hz), 6.99 (3H, m), 6.79 (3H, m), 4.45-4.70 (2H, br), 1.11 (9H, s).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O>>[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[CH:15][C:14]([C:3]1[N:4]2[C:5]([S:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=32)=[N:1][CH:2]=1)=[O:16]
Reactant: O=Cc1cccc(F)c1F
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Product: O=C(C=Cc1cccc(F)c1F)c1cnc2sc3c(n12)CCCCC3

Procedure:
1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)ethanone (Formula N-4), 1.87 g and 2,3-difluorobenzaldehyde (1.39 g) were condensed by non-critical variations in PREPARATION 15 to provide 3-(2,3-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula N-5, X=2,3-difluoro), 1.35 g, m.p. 193-195°.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([O:14][CH2:21][CH3:22])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 2-(4-isobutylphenyl)-propionic acid (15.0 g) was dissolved in ethanol (200 ml), and conc. sulfuric acid (1 ml) was added, after which the solution was stirred with heating under reflux for 15 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate, and thereafter neutralized with a saturated aqueous sodium bicarbonate solution. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain ethyl 2-(4-isobutyl-phenyl)-propionate.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4CCNCC4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[N:23]1([C:29]([C@@H:31]2[CH2:36][CH2:35][C@H](O)[CH2:33][CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C@H:17]4[CH2:35][CH2:36][C@H:31]([C:29]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[O:30])[CH2:32][CH2:33]4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Reactant: O=C([C@H]1CC[C@@H](O)CC1)N1CCOCC1
Product: O=C([C@H]1CC[C@H](Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1)N1CCOCC1

Procedure:
Example 287 (E287) was prepared from 3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) and cis-4-(4-morpholinylcarbonyl)-cyclohexanol (D55) using the method described for Example 5a (E5a); MS (ES+) m/e 413 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C@@H:26]([OH:39])[CH2:27][O:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH:43]([O:45][CH2:46][CH3:47])=[CH2:44].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[CH2:1]([N:8]([CH2:25][C@@H:26]([O:39][CH:43]([O:45][CH2:46][CH3:47])[CH3:44])[CH2:27][O:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)(=[O:31])=[O:30])[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COCC
Reactant: COC(=O)C[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)C[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CN(Cc1ccccc1)[C@@H](CC(=O)OC)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl 4-methyl(2S)-2-[benzyl((2R)-2-hydroxy-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate (43.0 g, 0.0774 mol) in methylene chloride (500.0 mL, 7.800 mol) was added ethyl vinyl ether (15.0 mL, 0.157 mol) followed by pyridinium p-toluenesulfonate (4.0 g, 0.016 mol). The mixture was stirred at rt for 3 g. After concentrated to dry, the residue was purified by silical gel column (eluting with 0 to 20% EtOAc in hexane) to provide the ether compound (38.1 g, 78.4%). MS (ESI): (M+H)+=628.1.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[F:1])[CH2:6][CH2:7]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2F)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3F)CC2)cc1
Yield: 80.3 %

Procedure:
0.382 g (0.001825 mol) of 1-(2-fluoro-benzyl)-piperidin-4-ol and 0.512 ml (0.00365 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.483 ml (0.00365 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.48 g (80%) of 1-(2-fluoro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil. MS: me/e=328 (C20H23 FN02+).
Reaction SMILES: [BH4-].[Na+].[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14].O=S(Cl)[Cl:18]>>[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Cl:18])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: CNc1ccc(CO)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CCl)cc1[N+](=O)[O-]

Procedure:
4-Chloro-3-nitro-benzaldehyde is reacted with methylamine to yield 4-(methylamino)-3-nitrobenzaldehyde (8) which is then reduced by NaBH4 to N-methyl-4-hydroxymethyl-2-nitroaniline (9). Reaction of SOCl2 with 8 will give N-methyl-4-chloromethyl-2-nitroaniline (10). Structures of 8, 9 and 10 may be characterized by 1H NMR and elemental analysis. 10 is used as an electrophile to react with sodium CD alkoxide (11) to yield 2-O-(4-methylamino-3-nitro) benzyl-β-CD (12). The addition of 10 to 11 is a novel method for mono-functionalizing the 2-position of CD's (Rong, P., and D'Souza, V. T., Tetrahedron Lett., 31:4275 (1990)). 12 is hydrogenated by agents such as H2 /Pd, H2 /Pt, H2 /Ni, Sn/HCl, Fe/HCl and Zn/HCl, and then condensed with alloxan monohydrate to yield 2-flavo-CD (13). Compounds 11 and 12 can be characterized by 1H and 13C NRM. 2-Flavo-α-CD, β-CD and γ-CD may be synthesized by the same method. ##STR12##
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][CH2:12][C:13]#[CH:14])=[CH:10][C:4]=2[O:3]1.[C:16]([N:19]=[C:20]=[S:21])(=[O:18])[CH3:17]>C1COCC1>[F:15][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:12][C:13](=[CH2:14])[S:21]/[C:20]/3=[N:19]\[C:16](=[O:18])[CH3:17])=[CH:10][C:4]=2[O:3]1
Reactant: CC(=O)N=C=S
Reactant: C#CCNc1ccc2c(c1)OC(F)(F)O2
Solvent: C1CCOC1
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(C)=O)S1

Procedure:
A solution of Example 1 (1.4 g, 6.63 mmol) and acetyl isothiocyanate (0.60 mL, 6.63 mmol) in dry THF (25 mL) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue purified by column chromatography using DCM as eluant to provide the titled compound. 1H NMR (CDCl3) δ ppm 2.20 (3H), 3.73 (2H), 4.85-5.00 (2H), 7.00-7.25 (3H); MS (ESI) 313 (M+H).
Reaction SMILES: [CH3:1][N:2]=[C:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][N:5]2[C:13](=O)[CH2:14][CH2:15][CH:4]12.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][NH:2][C@@H:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][N:5]2[CH2:13][CH2:14][CH2:15][C@@H:4]12
Reactant: CN=C1c2ccccc2CN2C(=O)CCC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@@H]1c2ccccc2CN2CCC[C@@H]12
Yield: 72.3 %

Procedure:
The 10-methylimino-1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-3-one (880 mg, 4.1 mmol) was dissolved in THF (12 mL) and added dropwise to a suspension of LAH (623 mg, 16.4 mmol) in THF (12 ml) at room temperature under nitrogen. The suspension was stirred at reflux for 15 hours, cooled, and quenched by the addition of H2O(0.88 mL), NaOH (1.5 N, 0.88 mL) and additional H2O(2.6 mL). The mixture was filtered and the filtrate was concentrated in vacuo to give cis-10-methylamino-1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinoline as a dark oil (600 mg). Chromatography on silica gel with CH2Cl2/MeOH/NH4OH (95:4:1) provided the product as a dark red, viscous oil (547 mg). 1H NMR (CDCl3, 300 MHz): δ 7.52 (d, J=7.63 Hz, 1H), 7.25 (t, J=7.23, 14.47 Hz, 1H), 7.17 (t, J=7.76, 15.13 Hz, 1H), 7.09 (d, J=7.63 Hz, 1H), 4.03 (d, J=14.01 Hz, 1H), 3.79 (d, J=10.01 Hz, 1H), 3.62 (d, J=14.01 Hz, 1H), 3.17 (m, 1H), 2.58 (m, 1H), 2.47 (m, 1H), 2.41 (s, 3H), 2.28 (m, 1H), 1.87 (m, 1H0, 1.69 (m, 1H); 13C NMR (CDCl3): δ 137.24, 135.83, 126.63, 126.20 (2C), 64.92, 62.70, 55.85, 54.71, 32.33, 30.04, 21.57; IR (neat): 3285 (br), 3060, 3020, 2950, 2870, 2795, 1735-1565 (br), 1475, 1450, 1155, 1035, 920, 905, 780, 720 cm−1; MS (FAB): m/e 203 (M+H, 74.8%), 201 (74.1%), 172 (M−NHMe, 100%), 170 (85%), 133 (53.1%), 132 (27%), 118 (17.7%); HRMS (FAB): Calc for C13H18N2 202.1469, found 203.1555 (M+H).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[C:6]([O-:9])(=[O:8])[CH3:7].[Na+]>C(O)(=O)C>[C:6]([O:9][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])(=[O:8])[CH3:7]
Reactant: ClCC1CO1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCC(O)CCl
Reaction time: 8 h
Yield: 131.1 %

Procedure:
A suspension of epichlorhydrin (27.8 g) and sodium acetate (12.3 g) in acetic acid (36 g) is heated at 50°-55° C. for 8 hours. The reaction mixture is allowed to stand overnight and concentrated in vacuum. The residue is neutralized with aqueous sodium hydrogencarbonate and shaken with ether. The ethereal layer is dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is distilled in vacuum to give 1-acetoxy-3-chloro-2-propanol (30 g) as an oil boiling at 115°-116° C./13 mm Hg. The yield is 65.4%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[N:29][NH:30]2)=[CH:26][CH:25]=1>C(OCCO)C>[NH:30]1[C:31]2[C:27](=[CH:26][CH:25]=[C:24]([NH:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])[CH:32]=2)[CH:28]=[N:29]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1ccc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2c1
Yield: 97.2 %

Procedure:
Using an analogous procedure to that described in Example 141, 200.0 mg (0.914 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 105.6 mg (0.914 mmol) of pyridine hydrochloride was reacted with 147.8 mg (1.1 mmol) of 6-aminoindazole to give 280.0 mg (97.3%) of the product as a deep yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 315.9. HRCIMS: calcd 315.112 for C18H13N5O (M+), obsd 315.1124.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:16])=[CH:11][C:12]=2[O:14][CH3:15])[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[CH2:6][C:5]1([CH3:25])[CH3:24])(=[O:3])[CH3:2].[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1.N1C=CC=CC=1>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:16][C:32](=[O:33])[C:29]3[CH:30]=[CH:31][C:26]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:27][CH:28]=3)=[CH:11][C:12]=2[O:14][CH3:15])[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[CH2:6][C:5]1([CH3:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COc1cc(N)cc2c1N(C(C)=O)C(C)(C)CC2(C)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2)cc2c1N(C(C)=O)C(C)(C)CC2(C)c1ccccc1

Procedure:
Acylation of 1-acetyl-6-amino-8-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) with 4-biphenylcarbonyl chloride (100 mg) and pyridine (100 l) in tetrahydrofuran (5 ml) was performed according to the method described in example 6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([O:16][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Reactant: O=C(CBr)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)OCC(=O)c1ccc(F)cc1
Yield: 99.5 %

Procedure:
The title compound (3.2 g) was prepared from (S)-2-carboxymethyl-pyrrolidine-1-carboxylic acid tert butyl ester (2.02 g) and 2-bromo-4′-fluoroacetophenone (1.91 g) according to the method of description 36.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][CH2:12][C:13](Cl)=[O:14]>C1COCC1>[Cl:11][CH2:12][C:13]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:14]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.71 h

Procedure:
To a solution of 4-nitroaniline 37b (6.9 g, 50 mmol) in THF (50 mL) was added dropwise a solution of chloroacetyl chloride (100 mmol) in dry THF (50 mL) at room temperature. The reaction mixture was stirred for additional 40-45 minutes and then evaporated in vacuo to dryness. The solid residue was triturated with saturated NaHCO3 solution (aqueous) and then collected by filtration. The solid product was washed with water, followed by hexane, and dried to give 2-chloro-N-(4-nitrophenyl)acetamide, 10.02 g (94%); mp 182-183° C. (Lit. 181-183° C.58). 1H NMR (DMSO-d6) δ: 4.34 (2H, s, CH2), 7.83-7.85 (2H, d, J=9.1 Hz, Ar—H), 8.23-8.26 (2H, d, J=9.1 Hz, Ar—H), 10.88 (1H, brs, NH).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH:7]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C1COCC1>[CH:7]1([NH:12][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)CBr
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CNC1CCCC1
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A solution of methyl bromoacetate (17.4 mL, 188 mmol) in THF (40 mL) was dropwise added to a solution of cyclopentylamine (18.6 mL, 188 mmol) and triethylamine (26.1 mL, 188 mmol) in THF (150 mL) at 0° C. Following addition, the reaction was allowed to reach room temperature and was stirred overnight. The triethylammonium salts were filtered and rinsed with scant THF. The combined filtrates were concentrated in vacuo. The desired product was distilled from the residuals under reduced pressure to yield 20.2 g of compound 225 (68% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.73 (s, 3 H) 3.41 (s, 2 H) 3.00-3.13 (m, J=12.90, 6.39, 6.39 Hz, 1 H) 1.77-1.87 (m, 2 H) 1.67-1.74 (m, 2 H) 1.48-1.59 (m, 2 H) 1.29-1.41 (m, 2 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[Br:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:39]([C:38]1[CH:42]=[CH:43][C:35]([Br:34])=[CH:36][CH:37]=1)=[O:40])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(Br)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 4-bromobenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-bromophenyl 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl ketone as a colorless powder. APCI-Mass m/Z 664/666 (M+H). 1H-NMR (DMSO-d6) δ 1.69 (s, 3H), 1.97 (s, 3H), 1.98 (s, 3H), 2.04 (s, 3H), 4.11 (d, J=4.2 Hz, 2H), 4.30 (ddd, J=10.0, 4.3 and 4.2 Hz, 1H), 5.28 (t, J=9.8 Hz, 1H), 5.58 (t, J=9.6 Hz, 1H), 5.93 (t, J=9.4 Hz, 1H), 6.33 (d, J=9.0 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.73-7.77 (m, 4H), 7.80 (d, J=8.2 Hz, 1H), 8.17 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]([OH:17])([CH2:14][C:15]#[CH:16])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:20][C:19]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:17])([CH2:14][C:15]#[C:16][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:18]=1
Reactant: C#CCC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OC(CC#Cc1ccccc1)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reaction time: 8 h

Procedure:
2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-yn-2-ol (0.27 g; 0.83 mmol), iodobenzene (0.14 mL; 1.3 mmol), dichlorobis(triphenylphosphine)palladium (31.7 mg; 0.045 mmol), copper iodide (17.8 mg; 0.093 mmol) and triethylamine (0.25 mL; 1.8 mmol) were suspended in THF (5 mL) and the resulting mixture stirred vigorously overnight. The reaction mixture was then concentrated in vacuo and the resulting crude brown oil was purified by column chromatography (SiO2; 50% ether/CH2Cl2) to yield the title compound as an orange-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([N:11]([CH2:19][C@H:20]([OH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:4]=2[CH:3]=1.[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:32][N:33]([CH3:38])[S:34]([NH:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([N:11]([CH2:19][C@H:20]([OH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:4]=2[CH:3]=1)(=[O:36])=[O:35]
Reactant: Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2

Procedure:
Under nitrogen, a solution of (2S)-1-[N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (150 mg), dimethylaminosulfonyl chloride (43 μl) and pyridine (31 μl)in toluent (5 ml) was stirred at 80° C. for 24 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give (2S)-1-[N-(3-dimethylaminosulfonylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (156 mg).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:23]1[CH2:28][CH:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CS(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:23]3[CH2:28][CH2:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:25][CH2:24]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: C1=C(c2ccccn2)CCNC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CC=C(c4ccccn4)CC3)nc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (450 mg, 1.42 mmol) in DMSO (5.0 ml) was added 2-(1,2,3,6-tetrahydropyridin-4-yl)pyridine (300 mg, 1.87 mmol) and DIEA (361 mg, 2.79 mmol), and the reaction mixture was stirred overnight at 90° C. The reaction mixture was extracted with ethyl acetate (3×50 ml), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the residue, which was purified by preparative silica gel plate chromatography (dichloromethane:ethyl acetate:petroleum ether (40:1:12)) to afford methyl 2-(4-fluorophenyl)-3-(4-(pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)quinoxaline-6-carboxylate as a yellow solid (410 mg).
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH:24]1[CH2:30][C:29](=[O:31])[O:28][C:26](=[O:27])[CH2:25]1.Cl>[OH-].[Na+]>[C:14]([C:12]1[CH:13]=[C:8]([N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:29]([CH2:30][CH:24]([CH3:23])[CH2:25][C:26]([OH:28])=[O:27])=[O:31])[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1cc(Nc2ccccc2)cc(C(C)(C)C)c1O
Reactant: CC1CC(=O)OC(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CC(=O)O)CC(=O)N(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 140 °C
Yield: 54 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2.97 g (0.01 mole) of 4-anilino-2,6-di-t-butylphenol and 6.40 g (0.05 mole) of 3-methylglutaric anhydride was heated at 140° C. for 2 hours. After cooling, the reaction mixture was suspended in 10% sodium hydroxide, and acidified with 10% hydrochloric acid. The resulting precipitate was collected, rinsed with water, air dried, and recrystallized twice from a mixture of ethyl acetate and hexane to give a beige solid. This material was purified by silica gel chromatography, eluting with ethyl acetate, followed by trituration with a mixture of ethyl acetate and hexane. The resulting solid was recrystallized from a mixture of ethyl acetate and hexane to give 2.3 g of white solid 4-[N-(3,5-di-t-butyl-4-hydroxyphenyl)-N-phenylcarbamoyl]-3-methylbutyric acid, m.p. 153°-155° C. Analysis: Calculated for C26H35NO4 :% C, 73.4; % H, 8.3; % N, 3.3 Found: % C, 73.4; % H, 8.6; % N, 3.1.