Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][N:5]([O:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH3:3].[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18].CN1C=CN=C1>>[C:17]([OH:20])(=[O:19])[CH3:18].[C:17]([OH:20])(=[O:19])[CH3:18].[CH2:14]([O:13][N:5]([O:4][CH2:1][CH2:2][CH3:3])[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:15][CH3:16]
Reactant: CC(=O)OC(C)=O
Agent: CCCON(OCCC)c1cccc(O)c1
Agent: Cn1ccnc1
Product: CC(=O)O
Temperature: 135 °C
Reaction time: 3 h

Procedure:
22.5 parts of N,N-dipropoxy-m-aminophenol were charged to a reactor vessel followed by 22.0 parts of-acetic anhydride and 0.5 parts of 1-methylimidazole. The mixture was then heated to about 130 to 140° C. and held for 3 hours. The acetic acid and excess anhydride were then distilled out at a temperature from 130 to 140° C. leaving the N,N-dipropoxy-m-aminophenol diacetate product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[Br:10]Br>C(Cl)Cl>[BrH:10].[Br:10][C:7]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([CH3:9])[C:5]=1[NH2:6]
Reactant: Cc1cc(F)ccc1N
Reactant: BrBr
Solvent: ClCCl
Product: Br
Product: Cc1cc(F)cc(Br)c1N

Procedure:
To a solution of 4-fluoro-2-methylaniline (5.0 g, 40.0 mmol) in DCM (100 mL) at RT was added bromine (2.06 mL, 40.0 mmol). The reagent appeared to react instantly and a solid precipitate was formed. The reaction was filtered and washed with DCM to give 2-bromo-4-fluoro-6-methylaniline hydrobromide as a light tan solid.
Reaction SMILES: I(O)(=O)(=O)=O.[F:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH:13]([F:15])[F:14])[C:8]=1[CH:16]=[O:17].[Cr](Cl)([O-])(=O)=[O:19].[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[F:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH:13]([F:14])[F:15])[C:8]=1[C:16]([OH:19])=[O:17]
Reactant: Cn1nc(C(F)F)c(C=O)c1F
Reactant: O=[Cr](=O)([O-])Cl
Agent: [O-][I+3]([O-])([O-])O
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1nc(C(F)F)c(C(=O)O)c1F
Reaction time: 0.5 h

Procedure:
A suspension of 79.7 g (350 mmol) of periodic acid in 640 ml absolute acetonitrile was stirred for 30 min. To this was added 56.6 g (318 mmol) of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde at 0° C. and a solution of 1.4 g (6 mmol) of pyridinium chlorochromate in 130 ml dry acetonitrile. The reaction mixture was stirred for 2.5 hours at room temperature. 1600 ml of ethyl acetate was added to the reaction mixture and the separated organic phase was washed consecutively with brine/water(1:1), saturated sodium metabisulfite and brine. Then the organic phase was dried with sodium sulphate, and evaporated under vacuum to give the expected product as a pale yellow solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([OH:14])(=[O:13])[CH3:12].C([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O)C>>[F:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:18]1[CH:19]([CH2:12][C:11]([OH:14])=[O:13])[CH2:20][CH2:21][CH2:22][C:17]2=1
Reactant: CCC1CCCCC1=O
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)CC1CCCc2c1[nH]c1ccc(F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-fluorophenyl)hydrazine hydrochloride and ethyl-2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: CI.[CH3:3][N:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:20][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([N:4]([CH3:3])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CN(c1ccccc1)c1ccc(C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Methyl iodide (227 mg, 0.1 mL, 1.68 mmol) was added drop wise to a suspension of 4-(Methyl-phenyl-amino)-benzoic acid (120 mg, 0.56 mmol) and K2CO3 in DMF (5 mL). The resulting mixture was heated at 80° C. with stirring overnight. The mixture was filtered, cold water was then added, and the product was extracted with EtOAc. The organic layer was washed with saturated brine solution and dried over Na2SO4. The organic layer was then concentrated under reduced pressure to get the residue The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 5% EtOAc in Hexane as eluent) to afford 85 mg (75% yield) of 4-(Methyl-phenyl-amino)-benzoic acid methyl ester. 1H-NMR (CDCl3): δ 7.8 (d, 2H), 7.4 (T, 2H), 7.2 (m, 2H), 6.8 (d, 2H), 3.8 (s, 3H), 3.2 (s, 3H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:29])[CH2:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([OH:27])=[CH:13][CH:14]=2)[C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][CH2:39]Cl.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.Cl>C(#N)C>[C:1]([NH:5][C:6](=[O:29])[CH2:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:27][CH2:37][CH2:38][CH2:39][N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:13][CH:14]=2)[C:9]1=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCBr
Reactant: COc1cc(-c2cc3ccc(O)cc3c(=O)n2CC(=O)NC(C)(C)C)ccc1F
Reactant: C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(-c2cc3ccc(OCCCN4CCCC4)cc3c(=O)n2CC(=O)NC(C)(C)C)ccc1F

Procedure:
To a solution of N-tert-butyl-2-[3-(4-fluoro-3-methoxyphenyl)-7-hydroxy-1-oxo-1H-isoquinolin-2-yl]acetamide (INTERMEDIATE III.1) (25 mg, 0.063 mmol) in anhydrous acetonitrile (5 mL) were added K2CO3 (26 mg, 0.189 mmol) and 1-bromo-3-chloropropane (6.2 uL, 0.63 mmol). The reaction mixture was heated at reflux temperature for 16 h. Pyrrolidine (53 uL, 0.63 mmol) and additional K2CO3 (26 mg, 0.189 mmol) were added and the reaction mixture was heated at reflux temperature for 48 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude residue was purified by preparative HPLC to afford N-tert-butyl-2-[3-(4-fluoro-3-methoxyphenyl)-1-oxo-7-(3-pyrrolidin-1-ylpropoxy)-1H-isoquinolin-2-yl]acetamide (EXAMPLE 15) hydrochloride salt (4.4 mg, 0.008 mmol, 13%) as an HCl salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1.CCOC(C)=O>[CH3:21][S:22]([O:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a stirred solution of 174 (1.327 g, 4.144 mmol) in THF (30 mL) at 0° C. was added TEA (0.6931 mL, 4.973 mmol) and MsCl (0.3528 mL, 4.559 mmol) and the solution stirred for 1 h at 0° C. The mixture was diluted with EtOAc, washed with dilute HCl solution, aq. satd. NaHCO3, and brine, dried (MgSO4) and concentrated to afford 1.51 grams (91%) of (R)-3-(tert-butoxycarbonylamino)-3-(3,4-dichlorophenyl)propyl methanesulfonate (364). The product may contain some of the corresponding chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]3[N:19]=[C:18]([C@@H:20]4[CH2:25][C@@H:24]5[C@@H:22]([CH2:23]5)[N:21]4[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:17][C:16]=3[CH:33]=1)[CH:6]=[N:5]2.CC([O-])=O.[K+].[B:39]1(B2OC(C)(C)C(C)(C)O2)[O:43]C(C)(C)C(C)(C)[O:40]1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([O:28][C:26]([N:21]1[C@H:20]([C:18]2[NH:17][C:16]3[CH:33]=[C:12]([C:7]4[CH:6]=[N:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([B:39]([OH:43])[OH:40])[CH:3]=5)[N:8]=4)[CH:13]=[CH:14][C:15]=3[N:19]=2)[CH2:25][C@@H:24]2[C@H:22]1[CH2:23]2)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3cnc4cc(Br)ccc4n3)cc2[nH]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3cnc4cc(B(O)O)ccc4n3)cc2[nH]1
Temperature: 83 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
Pd(Ph3P)4 (23.28 mg, 0.020 mmol) was added to a degassed solution of (1R,3S,5R)-tert-butyl 3-(6-(6-bromoquinoxalin-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (102 mg, 0.201 mmol), KOAc (49.4 mg, 0.504 mmol) and bis(pinacolato)diboron (113 mg, 0.443 mmol) in dioxane (2 mL) and the reaction was stirred at 83° C. for 16 h. The reaction mixture was partitioned between EtOAc (20 mL) and sat. NH4Cl(aq.) (5 mL). The organic layer was dried (MgSO4), filtered and concentrated to an orange oil, which was purified by prep HPLC (H2O-MeOH with 0.1% TFA buffer) to yield 2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-ylboronic acid (57 mg, 0.121 mmol, 60.0% yield) as orange solid. LC-MS retention time 1.94 min; m/z 472 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [CH2:1]([C:3]1[S:24][C:6]2=[N:7][C:8]([CH3:23])=[C:9]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[C:5]2[C:4]=1[CH3:25])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36]1[CH2:40]OC[CH2:37]1.ICCC>CN(C=O)C>[CH2:1]([C:3]1[S:24][C:6]2=[N:7][C:8]([CH3:23])=[C:9]([CH:18]([CH2:37][CH2:36][CH3:40])[C:19]([O:21][CH3:22])=[O:20])[C:10]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[C:5]2[C:4]=1[CH3:25])[CH3:2]
Reactant: CCc1sc2nc(C)c(CC(=O)OC)c(-c3ccc(C)cc3)c2c1C
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc(CC)c(C)c2c1-c1ccc(C)cc1
Yield: 54.3 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.196 g; 0.554 mmol), LHMDS 1N in THF (0.635 mL; 0.635 mmol), 1-iodopropane (0.090 mL; 0.923 mmol) in DMF (8 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.119 g (54%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([NH2:9])[O:6][N:5]=2)[CH2:3][CH2:2]1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:1]1([C:4]2[N:8]=[C:7]([NH:9][C:17](=[O:18])[CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Nc1nc(C2CC2)no1
Product: O=C(Nc1nc(C2CC2)no1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 163° C. and MS: m/e=219 (M+) was prepared in accordance with the general method of example 44a from 3-cyclopropyl-[1,2,4]oxadiazol-5-ylamine (Helv. Chim. Acta, 49(1966), 1430-1432) and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[NH:13][CH:14]=[CH:15]4)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2[nH]ccc2c1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and indole-5-carboxylic acid (Aldrich) according to methods A and C; yield 77 mg, 0.23 mmol (65%): 1H NMR (300 MHz, methanol-d4) δ 2.00-2.31 (m, 5H), 2.48 (s, 2H), 3.49 (d, J=12 Hz, 2H), 3.56 (s, 2H), 3.85 (d, J=13 Hz, 2H), 4.31 (d, 1H), 6.57 (d, J=3 Hz, 1H), 7.33 (d, J=3 Hz, 1H), 7.44 (d, J=9 Hz, 1H), 7.66 (dd, J=9, 2 Hz, 1H), 8.18 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 296 (M+H)+; Anal. C18H21N3O.HCl.0.1H2O: C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:11][N:12]1[C:16](=[O:17])[CH2:15][NH:14][C:13]1=[O:18].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:15]1[NH:14][C:13](=[O:18])[N:12]([CH3:11])[C:16]1=[O:17]
Reactant: CN1C(=O)CNC1=O
Reactant: COc1ccccc1C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccccc1C=C1NC(=O)N(C)C1=O
Yield: 63.6 %

Procedure:
A mixture of 2-methoxybenzaldehyde (3.4 g,25 mmoles), 3-methyl hydantoin (3.0 g, 21 mmoles ), sodium acetate (6.0 g, 73 mmoles), acetic anhydride (3 ml), and acetic acid (20 ml) is stirred under an inert atmosphere and heated to reflux. After 15 hours the mixture is poured into water (200 ml), stirred, and the precipitate filtered off, rinsed three times with water and dried. Recrystallization from acetonitrile gave the pure product (3.1 g), mp 189°-190° C.
Reaction SMILES: Br.Cl[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]3[CH:22]=2)=[CH:9][C:8]=1[O:23][CH3:24].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]4[CH:22]=3)=[CH:9][C:8]=2[O:23][CH3:24])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc(-c2cn3ccc(C)cc3n2)ccc1OCCCCl
Reactant: C1CCNCC1
Agent: Br
Product: COc1cc(-c2cn3ccc(C)cc3n2)ccc1OCCCN1CCCCC1
Temperature: 25 °C

Procedure:
The product of Step C (184 mg) and piperidine (1.5 mL) were heated at 100° C. for 4 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted twice with additional ethyl acetate (10 mL) and once with dichloromethane (10 mL). The organic portions were combined, washed with brine, and evaporated. The residue was purified via silica gel chromatography (dichloromethane/2M ammonia in methanol) to give the title compound (150 mg). 1H-NMR (CD3OD) δ 8.17 (d, J=7.0 Hz, 1H), 7.93 (s, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.38 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 7.26 (s, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.68 (dd, J=7.0 Hz, J=1.5 Hz, 1H), 4.00 (t, J=6.0 Hz, 2H), 3.91 (s, 3H), 2.56 (m, 3H), 2.48 (br. s, 3H), 2.38 (s, 3H), 1.98 (m, 2H), 1.60 (m, 4H), 1.47 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Reactant: CCCCCCBr
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: CCCCCCN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CC=CC[C@@H]2C1=O

Procedure:
Prepared from compound 3 and 1-bromohexane as described for compound 8. Purified by chromatography; crystallized from petroleum ether (60-80° C.) at -20° C. M.p. 74-75° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[Cl:17][C:18]1[CH:23]=[C:22]([N:24]=C=O)[CH:21]=[C:20]([Cl:27])[CH:19]=1.[N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([NH:24][C:6]([N:8]2[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]2[C:10]([NH:38][C:34]2[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=2)[N:28]=[CH:29][CH:30]=[CH:31]3)=[O:12])=[O:7])[CH:21]=[C:20]([Cl:27])[CH:19]=1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Nc1ccc2ncccc2c1
Product: C=C1C[C@@H](C(=O)Nc2ccc3ncccc3c2)N(C(=O)Nc2cc(Cl)cc(Cl)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxy-carbonyl)-4-methyleneproline, 1,3-dichloro-5-isocyanatobenzene, and 6-quinolinamine the title compound was obtained in 65% purity by LC/MS. MS(ESI+): m/z=441.0.
Reaction SMILES: [NH2-:1].[Na+].Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C1C=CC=CC=1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[N:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:23]1
Reactant: Brc1ccccc1
Reactant: [NH2-]
Reactant: Cc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(N2CCCCCCC2)cc1
Temperature: 100 °C

Procedure:
4.3 g of sodium amide at a concentration of 50% in toluene, suspended in 18.9 cm3 (equivalent to 16.9 g) of heptamethylenamine, are heated to 100° C. for 20 minutes, and 7.85 g (equivalent to 5.03 cm3) of bromobenzene are then added dropwise. The reaction medium is heated to reflux for 18 hours and cooled to room temperature, and 50 cm3 of water are added. 100 cm3 of benzene are added, the organic phase is separated, extracted using 5% strength aqueous hydrochloric acid solution and alkalinized using 20% strength aqueous sodium hydroxide solution, the oil phase is separated, extracted with ethyl ether and dried and the solvent is evaporated off. After distillation of the residue (b.p. 118°-120° C. at 0.5 mm Hg), 9.4 g of expected product are obtained.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][OH:4].[C:5]([NH:13][C:14]1[CH:23]=[C:22](COC2C=CC=CC=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=O)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][CH:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]1([CH2:16][O:18][C:19]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1)[C:3]([OH:4])=[O:1])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(COc2ccccc2)cc1NC(=O)c1ccccc1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NC1C=CC=CC1(COc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.51 mL of 2.0 mol/b aqueous sodium hydroxide was added dropwise to a mixed solution of 3 mL of methanol and 3 mL of tetrahydrofuran containing 0.31 g of methyl 2-(benzamido)-4-(phenoxymethyl)benzoate while ice-cooled and stirred an room temperature for 5 hours and 30 minutes, the solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 0.21 g of 2-(benzamido)-1-(phenoxymethyl)benzoic acid as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[Br:44][C:45]1[CH:46]=[C:47]([C@H:51]([NH2:53])[CH3:52])[CH:48]=[CH:49][CH:50]=1>C(Cl)(Cl)Cl>[Br:44][C:45]1[CH:46]=[C:47]([C@H:51]([NH:53][C:36]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[O:23][CH3:24])=[O:42])[CH3:52])[CH:48]=[CH:49][CH:50]=1
Reactant: C[C@@H](N)c1cccc(Br)c1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)N[C@H](C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (91 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(3-bromophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (23 mg, yield 15%).
Reaction SMILES: S1C=CC=C1[C@]1(O[C@H](CO)[C@@H:11]([O:12][C@@H:13]2[O:30][C@H](CO[CH2:33][C:34]3[CH:39]=C[CH:37]=[CH:36][CH:35]=3)[C@H](OC(=O)C)[C@H](OC(=O)C)[C@H:14]2OC(=O)C)[C@H:9](O)[C@H]1NC(=O)C)O.N(CCCCCCO)=[N+]=[N-].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C>[C:13]([O:12][CH2:11][CH3:9])(=[O:30])[CH3:14].[CH3:37][CH2:36][CH2:35][CH:34]([CH3:39])[CH3:33]
Reactant: CC(=O)N[C@@H]1[C@@H](O)[C@H](O[C@@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@@H](CO)O[C@]1(O)c1cccs1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [N-]=[N+]=NCCCCCCO
Solvent: CC#N
Product: CCCC(C)C
Product: CCOC(C)=O
Yield: 65 %

Procedure:
Compound [13] (0.21-2.66 g, 0.54-7.05 mmol) and 6-azidohexanol (0.27-3.54 g, 1.08-14.1 mmol) are dissolved in dry acetonitrile and, at 0° C., molecular sieves (0.2-5 g) and trimethylsilyl trifluoromethanesulfonate (0.02-1.56 g, 1-70 mmol) are added. After the reaction is complete, the mixture is filtered and washed with saturated sodium bicarbonate solution. Concentration results in the crude product which is purified by chromatography on silica gel with an ethyl acetate/isohexane gradient (0.17-2.23 g, 0.35-4.58 mmol, about 65% yield). The product is subsequently taken up in methanol/hydrazine hydrate (1:1) (1-30 ml) and heated at 80° C. until reaction is complete. After evaporation of the solvent, the crude product is taken up in dichloromethane/methanol (1:1) and stirred at 0° C. with acetic anhydride (3.5-45.8 mmol) until reaction is complete. Evaporation is followed by reduction of the azide with hydrogen in the presence of catalytic amounts of palladium on carbon (10%) (0.01-1.5 g) in methanol (0.5-40 ml). The crude product compound [14] obtained after evaporation is purified by gel chromatography on Biogel P2 (0.12-1.54 g, 0.25-3.2 mmol, about 70% yield). FAB-MS: M+H+ =483. 1H-NMR [300 MHz, D2O]: 4.98 (Fuc-H -1), 4.28 (Gal-H-1), 4.33, 3.99-3.38 (m), 2.99, 2.09 (GlcNCOCH3), 1.72-1.32 (O--(CH2)5 --CH2 --N), 1.11 (Fuc-CH3) ppm.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:12]2[C:16]3[C:17]([CH3:31])=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.C(OCC)(=O)C>[CH:2]([C:6]1[CH:7]=[C:8]([CH:12]2[C:16]3[C:17]([CH3:31])=[C:18]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1cccc(C3OCCO3)c1)CO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1cccc(C=O)c1)CO2
Yield: 96.1 %

Procedure:
A mixed solution of N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (910 mg, 2.15 mmol) obtained in Example 73 and pyridinium p-toluenesulfonic acid (25 mg) in acetone (20 mL)-water (1.5 mL) was refluxed with heating for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 784 mg (yield: 96%) of the title compound. Melting point: 178-179° C. (ethyl acetate-hexane).