Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)=[N:11][C:10](=[O:20])[N:9]([CH2:21][CH3:22])[C:8]=2[N:23]=1)(=[O:3])[CH3:2].[CH:24]([O-])([O-])[O:25]C.[CH3:29]O>>[Cl:19][C:15]1[CH:14]=[C:13]([C:12]2[C:7]3[CH:6]=[CH:5][C:4]([C:1]([O:25][CH3:24])([O:3][CH3:29])[CH3:2])=[N:23][C:8]=3[N:9]([CH2:21][CH3:22])[C:10](=[O:20])[N:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC([O-])[O-]
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)=O)nc21
Reactant: CO
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)(OC)OC)nc21
Temperature: 25 °C
Yield: 69 %

Procedure:
7-Acetyl-4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one (1.62 g, 495 mmol) and 30 ml of methyl orthoformate were dissolved in 30 ml of methanol, a catalytically effective amount of Dowex-50W-X4 was added thereto, followed by heating overnight under reflux. After cooling to room temperature, insoluble matter was removed by filtration and the solvent was evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene-ethyl acetate) and recrystallized from diisopropyl ether to give 1.27 g (69%) of 4-(3-chlorophenyl)-1-ethyl-7-(1,1-dimethoxyethyl)pyrido[2,3-d]pyrimidin-2(1H)-one.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.O.Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1
Reactant: O=C1CCNCC1
Reactant: Fc1ccccc1CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CCN(Cc2ccccc2F)CC1
Yield: 81.9 %

Procedure:
64.00 g (0.443 mol) of o-fluorobenzylchloride was weighed, to which 250 mL of dichloromethane was added. 62.40 g (0.406 mol) of 4-piperidone hydrochloride monohydrate was added under stirring, and then 91.00 g (0.899 mol) of triethylamine was added dropwise under cold water cooling and stirring. The reaction was stirred at room temperature for 4.5 h, and then stirred under reflux and reacted overnight. On the next day, the reaction was cooled, filtered to remove solid, washed in sequence with dichloromethane and ethyl ether, combined, washed with water and dried, and the solvent was recovered to obtain 68.95 g crude product (82.00%), which was used directly in the next reaction.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@@H:6]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:4].[CH3:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>>[CH3:29][C:30]1[CH:31]=[C:32]([NH:36][C:37](=[O:38])[NH:1][CH2:2][C:3]([N:5]2[C@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@@H:6]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:4])[CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2-c2ccccc2)N1C(=O)CN
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3-c3ccccc3)SC[C@H]2C(=O)OC(C)(C)C)c1
Yield: 12.5 %

Procedure:
The procedure is similar to that described in Example 1A, but starting with 1.32 g of tert-butyl (2R,4R)-3-(2-aminoacetyl)-2-(2-phenylphenyl)-4-thiazolidinecarboxylate and 0.47 g of 3-methylphenyl isocyanate. The crude product is purified by chromatography on silica [eluent: methylene chloride/ethyl acetate (90:10 by volume)]. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in pentane, 0.22 g of tert-butyl (2R,4R)-3-{2-[3-(3-methylphenyl)-ureido]acetyl}-2-(2-phenylphenyl)-4-thiazolidinecarboxylate is thereby obtained in the form of an amorphous product; [α]D25 =-9.8±0.9° (C %=0.49; CHCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1B(O)O.Cl[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(-c2c(C)cccc2C)ncc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
A mixture of 2,6-dimethylphenylboronic acid (6.5 g, 43.5 mmol), 2-chloro-4-methyl-5-nitro-pyridine (5 g, 28.9 mmol), Pd(PPh3)4, (1.5 g, 1.5 mmol), Na2CO3 (4.6 g, 43.5 mm water (20 mL), and EtOH (5 mL) is heated in a sealed tube under nitrogen at 110° C. for 18 hours. The mixture is cooled to room temperature, diluted with EtOAc (150 mL), washed with saturated solution of Na2CO3 (50 mL 3×), water (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 6:1) to afford 2-(2,6-dimethyl-phenyl)-4-methyl-5-nitro-pyridine as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([N:30]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:6]=1)[CH:26]1[CH2:29][CH2:28][CH2:27]1)(=[O:33])[CH3:32]
Reactant: NC1CCC1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(C(C)=O)C1CCC1

Procedure:
{2′-[(Acetyl-cyclobutyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-30) was prepared according to the procedures outlined in Example 1 by using the following materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester, cyclobutylamine and acetyl chloride.
Reaction SMILES: OO.[CH3:3][C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:23]=[CH:22][C:14]3S[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:13]=3[CH:12]=2)=[CH:6][CH:5]=1.[S:24](=[O:28])(=O)(O)[OH:25]>C(O)(=O)C.C(Cl)Cl.CO>[O:25]=[S:24]1(=[O:28])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:16][C:17]=2[C:13]2[CH:12]=[C:11]([NH:10][C:7]3[N:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=3)[CH:23]=[CH:22][C:14]1=2
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(Nc2ccc3sc4ccccc4c3c2)nn1
Agent: OO
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(Nc2ccc3c(c2)-c2ccccc2S3(=O)=O)nn1
Temperature: 60 °C

Procedure:
Hydrogen peroxide (100 vols, 1 ml) was added to 2-(6-methylpyridazin-3-ylamino)dibenzothiophene (Example 74; 300 mgs, 1.03 mmol) in acetic acid (3 ml) and conc. sulphuric acid (0.1 ml) and the mixture was heated to 60° C. for 40 minutes. On cooling to room temperature the mixture was diluted with DCM:MeOH (1:19) washed with aqueous potassium carbonate, dried over sodium sulphate and concentrated. Chromatography (eluent gradient of DCM to DCM:MeOH(1:1)) gave the product as an off white solid (0.131 g). NMR: 9.87 (brs, 1H), 8.48 (brs, 1H), 8.00-7.70 (m, 5H), 7.65 (t, 1H), 7.45 (d, 1H), 7.20 (d, 1H), 2.52 (s, 3H); m/z 324.28.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.CCOC(C)=O>[CH2:1]([N:3]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:21](=[O:22])[CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1)[CH3:2]
Reactant: CCNCCc1ccccn1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CCc1ccccn1)C(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
N-Ethyl-N-(2-pyridin-2-ylethyl)amine (0.5 g, 3.32 mmol) and 3-(4-hydroxyphenyl)-propanoic acid (0.50 g, 3.00 mmol) was dissolved in dimethylformamide (5 ml) and cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (1.18 g, 3.66 mmol) and diisopropylethylamine (0.90 g, 7.0 mmol) were added and the solution was warmed to room temperature and stirred overnight. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). The organic phase was dried MgSO4) and EtOAc was removed by evaporation to give 0.913 gram of N-ethyl-3-(4 hydroxyphenyl)-N-(2-pyridin-2-ylethyl)propanamide (yield 91.9%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@H:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@H:13]([O:21][C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[O:32][C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CC[C@H](O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: CN(C)CC(=O)O
Agent: Cl
Product: CN(C)CC(=O)O[C@@H](CCc1ccc(C(C)(C)C)c(NC(=O)CC2c3ccccc3Oc3ccccc32)c1)CC1CCCCC1

Procedure:
Following a procedure similar to that described in Preparation 25, but using (S)-N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 102) and N,N-dimethylglycine hydrochloride as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained as a foam-like material.
Reaction SMILES: [CH:1]1([C:4]([NH2:6])=[O:5])[CH2:3][CH2:2]1.Cl[CH2:8][C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1.O1CCOCC1.O>[CH:1]1([C:4]2[O:5][CH:8]=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=O)C1CC1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1coc(C2CC2)n1
Temperature: 100 °C
Yield: 43.2 %

Procedure:
To a solution of cyclopropanecarboxamide (3.5 g, 41.46 mmol) in toluene and 1,4-dioxane (50 mL, 1:1) was added ethyl 4-chloro-3-oxobutanoate (20.0 g, 121.95 mmol). The mixture was heated to 100° C. for 18 h, then was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The crude material was purified via column chromatography on 100-200 mesh silica (20% ethyl acetate in petroleum ether) to afford ethyl 2-(2-cyclopropyloxazol-4-yl)acetate (3.5 g). MS (ES+APCI) 196.1; LCMS retention time: 4.029 min (Method Q1).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:6]
Reactant: COc1ccc2c(-n3cc(C(=O)O)c4ccccc43)ccnc2c1
Reactant: O=S(Cl)Cl
Product: COc1ccc2c(-n3cc(C(=O)Cl)c4ccccc43)ccnc2c1
Product: Cl

Procedure:
6 cm3 of thionyl chloride are added to 0.9 g (2.83 mmol) of 3-carboxy-1-(7-methoxyquinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 30 cm3 of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1.05 g of 3-chlorocarbonyl-1-(7-methoxyquinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[CH:6][CH:5]=1.C(I)[I:19].[N+]([O-])([O-])=O>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([I:19])[CH:5]=1
Reactant: ICI
Reactant: COC(=O)c1cccc(-c2ccc(C)cn2)c1
Agent: O=[N+]([O-])[O-]
Product: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1

Procedure:
5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester was treated with methylene iodide and isoamy nitrate using the procedure of step 5 of preparation 6, to afford 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=353.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1.Cl>C(O)CCC>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:1][C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][CH:3]=2)=[N:17][CH:18]=1
Reactant: Fc1ccc(Br)cn1
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: CCCCO
Product: FC(F)(F)c1ccc(Nc2ccc(Br)cn2)cn1
Temperature: 150 °C

Procedure:
A mixture of 5-amino-2-(trifluoromethyl)pyridine (0.5 g, 3.0 mmol, 1.0 equiv) and 5-bromo-2-fluoropyridine (0.47 mL, 4.6 mmol, 1.5 equiv) in 2 mL 1-butanol was charged with 0.15 mL of 4.0 M HCl (in dioxane) and heated to 150° C. via microwave heating. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and saturated bicarbonate, and the organic extracts were washed with brine and dried over sodium sulphate. Purification of the crude product by flash chromatography afforded the title compound: 1H NMR (400 MHz, CDCl3) δ 6.63 (br. s., 1H) 6.67 (d, J=9.35 Hz, 1H) 7.56 (d, J=8.59 Hz, 1H) 7.62 (dd, J=8.84, 2.53 Hz, 1H) 8.22-8.66 (m, 2H) 8.57 (d, J=2.78 Hz, 1H); (M+H)+320.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][CH3:20])=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:6]([N:8]([CH2:11]C)[CH2:9]C)=[O:7].[S:21](=[O:23])=[O:22].[NH2:24]OS(O)(=O)=O>>[NH2:24][S:21]([C:13]1[CH:14]=[C:15]([O:16][CH3:17])[C:3]([O:2][CH3:1])=[C:4]([CH2:18][CH2:19][CH3:20])[C:5]=1[C:6]([N:8]([CH3:11])[CH3:9])=[O:7])(=[O:23])=[O:22]
Reactant: O=S=O
Reactant: CCCc1c(C(=O)N(CC)CC)ccc(OC)c1OC
Reactant: NOS(=O)(=O)O
Product: CCCc1c(OC)c(OC)cc(S(N)(=O)=O)c1C(=O)N(C)C
Yield: 63 %

Procedure:
By a procedure analogous to that described for Preparation 6A, 9.2 g (32.9 mmol) of 3,4-dimethoxy-2-propyl-N,N-diethylbenzamide was reacted with sulfur dioxide and 5.6 g (49.4 mmol) of hydroxylamine-O-sulfonic acid to provide 7.4 g (63%) of 2-aminosulfonyl-4,5-dimethoxy-6-propyl-N,N-dimethylbenzamide which was cyclized in quantitative yield in acetic acid and phenylthiomethylated with 1.42 mL (15 mmol) of chloromethyl phenyl sulfide to provide 4.07 g of 5,6-dimethoxy-2-phenylthiomethyl-4-propylsaccharin. Reaction of 3.59 g (8.8 mmol) of the phenylthioether with 2.12 mL (26.4 mmol) sulfuryl chloride provided 2.84 g (97%) of 2-chloromethyl-5,6-dimethoxy-4-propylsaccharin.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:40])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35]Br)[C:24]=1[CH2:37][CH2:38][CH3:39])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:40])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:37][CH2:38][CH3:39])[CH3:16]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 76.6 %

Procedure:
A mixture of 3.00 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.65 g of 4-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]butanoic acid ethyl ester and 4.30 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 19 hours. The solvent was removed in vacuo to give a red oil which was purified by high pressure liquid chromatography to yield 6.42 g (76%) of 4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH:13]=O.[NH:15]([CH2:22][CH2:23][C:24]#[N:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH:15]([CH:22]=[C:23]([CH2:13][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH3:12])[CH:7]=1)[C:24]#[N:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CCCNc1ccccc1
Reactant: COc1ccc2c(c1)c(C=O)cn2C
Product: COc1ccc2c(c1)c(CC(C#N)=CNc1ccccc1)cn2C

Procedure:
The title compound was prepared from 5-methoxy-1-methylindole-3-carboxaldehyde (S. Misztal, Dessert. Pharm. Pharmacol., 1972, 24, 509) and 3-anilinopropionitrile by the procedure of Example 4A (71%); the structure was confirmed by 1H-NMR.
Reaction SMILES: [C:1]1([C:14]([O:16][CH3:17])=[O:15])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][CH3:22]>CN(C=O)C>[CH2:21]([N:12]1[C:13]2[C:1]([C:14]([O:16][CH3:17])=[O:15])=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:22]
Reactant: COC(=O)c1cccc2c1[nH]c1ccccc12
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cccc(C(=O)OC)c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.7 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of methyl 9H-carbazole-1-carboxylate (2 g, 8.89 mmol, 1.00 equiv) in DMF (20 mL). To this was added NaH (1.78 g, 74.17 mmol, 5.00 equiv) in several batches followed by addition of bromoethane (1.92 g, 17.94 mmol, 2.00 equiv). The resulting solution was stirred at room temperature for 6 hours. Upon completion, the reaction was then quenched with water (20 mL). The mixture was then extracted with ethyl acetate (3×20 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (50:1) affording methyl 9-ethyl-9H-carbazole-1-carboxylate as light yellow solid (1.3 g, 58%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27](C)([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClC(OC1C=[CH:40][C:39]([Cl:42])=[CH:38]C=1)=O.ClC(OC(C)C(F)(F)F)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:23]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]4[CH:28]=[CH:40][C:39]([Cl:42])=[CH:38][CH:29]=4)=[O:25])[CH2:22]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: CC(OC(=O)Cl)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2ccc(OCC3CCN(C(=O)Oc4ccc(Cl)cc4)C3)cc2=O)cc1

Procedure:
Example 18 was prepared according to procedures described in Example 2, Step A and Step C, substituting tert-butyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)methyl)pyrrolidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step A and 4-chlorophenyl chloroformate for 1,1,1-trifluoropropan-2-yl chloroformate in Step C. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J=8.25 Hz, 2 H), 7.61 (d, J=8.25 Hz, 2 H), 7.32 (d, J=8.80 Hz, 2 H), 7.25 (dd, J=7.70, 3.30 Hz, 1 H), 7.09 (d, J=8.80 Hz, 2 H), 6.06-6.12 (m, 1 H), 5.98-6.03 (m, 1 H), 3.92-4.09 (m, 2 H), 3.49-3.92 (m, 3 H), 3.34-3.48 (m, 1 H), 3.09 (s, 3 H), 2.73-2.89 (m, 1 H), 2.12-2.29 (m, 1 H), 1.79-1.97 (m, 1 H). MS (ESI) 503 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH:31]=[CH:30][C:28](=[O:29])[NH:27][C:25]1=[O:26].C(N(CC)CC)C.ClCCl>C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:27]2[C:28](=[O:29])[CH:30]=[CH:31][N:24]([CH3:23])[C:25]2=[O:26])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ccc(=O)n(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c1=O
Reaction time: 8 h

Procedure:
The mixture of 30 mg of (2S)-2-(t-butoxycarbonylamino)-3-[4-(dihydroxy boranyl)phenyl] propionic acid, 25 mg of 1-methyluracil, 27 mg of copper acetate(II), 40 mg of triethylamine and 4 ml of dichloromethane were stirred overnight. The reaction solvent was diluted by ethanol and filtered by Celite filtration. The residual material obtained by concentrating the filtrate was dilluted by 1N sodium hydroxide and washed with ethyl acetate. After making the water layer acidic by hydrochloric acid, the solution was extracted with ethyl acetate, washed with saturated NaCl aqueous solution, dried with magnesium sulfate and the solvent was removed to obtain a crude material of (2S)-2-(t-butoxycarbonylamino)-3-[4-(1-methyluracil-3-yl)phenyl] propionic acid. This crude material was diluted by 5 ml of ethanol and hexane solution including 2M trimethylsilyldiazomethane was added to give methyl ester. The reaction solvent was concentrated and purified by silica gel chromatography (ethyl acetate-ethanol) to obtain the title compound (7 mg).
Reaction SMILES: C(Cl)[Cl:2].FC(F)(F)S([O-])(=O)=O.[C:12]1([S+:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(Br)(Br)Br.C(Cl)Cl>CO>[Cl-:2].[C:12]1([S+:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCCl
Reactant: COc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: BrB(Br)Br
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Product: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C

Procedure:
To a methylene chloride solution of 20 g of the diphenyl-4-methoxyphenylsulfonium trifluoromethanesulfonate, 90 ml of a 1 M boron tribromide-methylene chloride solution was slowly dropwise added with stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture formed, methanol and distilled water were slowly added, followed by drying under reduced pressure to obtain a white crystal compound. The white crystal compound was dissolved in methanol, and ion exchange was effected using an anionic ion-exchange resin (Cl− type), followed by drying under reduced pressure to obtain 11.5 g of diphenyl-4-hydroxyphenylsulfonium chloride.