Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH2:24])[CH:7]=1)[CH3:2].N1C=CC=CC=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][NH:24][C:37](=[O:38])[C:36]2[CH:40]=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To [3-(2-aminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.084 g, 0.24 mmol) and pyridine (2.0 mL) in CH2Cl2 (2.5 mL) was added 4-chlorobenzoyl chloride (0.04 mL, 0.29 mmol), and the reaction was stirred for 30 minutes at room temperature. The mixture was partitioned between CH2Cl2 and 1N aqueous HCl, and the organic layer was separated and washed twice with 1N aqueous HCl. The organic layer was dried and concentrated, resulting in the formation of a white precipitate. The precipitate was filtered off, and the filtrate was concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2ccc3ccccc3n2)CC1
Yield: 7.5 %

Procedure:
Using the procedure from Example 1A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloroquinoline (124 mg, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (11 mg), a white solid, in 8% yield.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[N:29]=[C:30]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=[CH2:48])[C:42]=3[F:49])[S:31][C:32]=2[NH:33]C(=O)OC(C)(C)C)=[O:27])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.[H][H].B(Br)(Br)Br.C(Cl)Cl>CO>[NH2:33][C:32]1[S:31][C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH3:48])[C:42]=2[F:49])=[N:29][C:28]=1[C:26]([NH:25][C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[N:15]1[CH2:16][CH2:17][CH2:18][C@@H:12]([NH2:11])[CH2:13][CH2:14]1)=[O:27]
Reactant: [H][H]
Reactant: C=Cc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](NC(=O)OCc4ccccc4)CC3)c(NC(=O)OC(C)(C)C)s2)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](N)CC3)c(N)s2)c1F
Reaction time: 2 h

Procedure:
tert-butyl N-[4-[[5-[(4R)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(2-fluoro-3-vinyl-phenyl)thiazol-5-yl]carbamate (51 mg, 0.086 mmol) was dissolved in methanol (50 mL) and hydrogenated on H-Cube at 60° C. and 50 bar hydrogen pressure to reduce the double bond. The solution was concentrated and the residue was dissolved in DCM (5 mL). 1.0M solution of boron tribromide in methylene chloride (0.35 ml, 0.35 mmol) was added and the mixture was stirred for 2 h. The solvent was distilled off and the residue was purified via reverse phase HPLC to afford 383. MS (ESI) m/z: 458.3 [M+H+].
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:10]([CH3:12])=O)=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3].[C:13](OCC)(=[O:16])[NH:14][NH2:15]>C(O)(=O)C.C(O)CCC>[CH3:12][C:10]1[C:6]2[N:5]([C:4]([CH2:1][CH2:2][CH3:3])=[N:8][C:7]=2[CH3:9])[C:13](=[O:16])[NH:14][N:15]=1
Reactant: CCCc1nc(C)c(C(C)=O)[nH]1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Solvent: CC(=O)O
Product: CCCc1nc(C)c2c(C)n[nH]c(=O)n12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 59.7 g. of methyl 2-n-propyl-4--methyl-5-imidazolyl ketone, 41.14 g. of ethyl carbazate, 200 ml. of n-butanol and 4 drops of glacial acetic acid is warmed until solution is complete and then heated under reflux for 5 hours. The solution is concentrated in vacuo to an oily residue, 250 ml. of diphenyl ether are added and the resulting solution is heated with stirring in an oil bath for 30 minutes after the start of gas evolution. The temperature is maintained as closely as possible to the point at which gas evolution starts (150°-250° C.). The reaction is removed from the oil bath, cooled to 50° C. and diluted with 1-2 volumes hexane. The product is collected, washed with petroleum ether and then dissolved in 200 ml. of chloroform. This solution is filtered through 250 ml. of Magnesol® followed by an 800 ml. chloroform wash. The filtrate is concentrated in vacuo and the residue is recrystallized from 250 ml. of ethyl acetate, giving 48.2 g. of the desired product as off-white crystals, m.p. 154°-155° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:24])[C:10]2=[O:32])=[CH:5][CH:4]=1.[C:33](O)(=[O:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(N(CC)CC)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:23]([OH:24])[CH2:22][CH2:21][CH:11]2[C:10](=[O:32])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:47])=[CH:4][CH:5]=3)[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CNC(=O)CCCCCCCCCCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one (5), and 23 μl of triethylamine in 1 ml of dimethylformamide was added to a solution of 371 mg of dodecanedioic acid, 63 μl of diisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC(Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gave the product of molecular weight 646.81 (C38H47F1N2O6); MS (ESI) 647.35 (M+H+)
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][OH:30])=[C:27]([CH3:33])[CH:26]=1>>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:30][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:27]([CH3:33])[CH:26]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Product: Cc1cc(Br)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
Tert-butylchlorodiphenylsilane (13.06 g) and imidazole (9.7 g) were added to a solution of 4-bromo-2-methylbenzyl alcohol (9.55 g) in N,N-dimethylfocmamide (80 ml) at 5° C. and the mixture was allowed to warm to room temperature, and stirred for 18 hours. The mixture was extracted with ethyl acetate and the extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 1-bromo-4-(tert-butyldiphenylsilyloxymethyl)-3-methylbenzene (20.5 g) as a colorless oil.
Reaction SMILES: FC1C=C(C2CC(=O)C3C(=CC=C(O)C=3)O2)C=CC=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[C:28](=[O:30])[CH3:29].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH:34]=O>>[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH:34]1[CH2:29][C:28](=[O:30])[C:22]2[C:21](=[CH:26][CH:25]=[C:24]([OH:27])[CH:23]=2)[O:20]1
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(=O)c1cc(O)ccc1O
Agent: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Product: O=C1CC(c2ccc(F)cc2F)Oc2ccc(O)cc21

Procedure:
2-(2,4-Difluorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 1,6 ml of 2,4-difluorobenzaldehyde. 1H NMR (400 MHz, d6-DMSO) δ: 9.46 (s, 1H), 7.73 (m, 1H), 7.34 (m, 1H), 7.19 (m, 1H), 7.13 (d, 1H, J 2.9 Hz), 7.04 (dd, 1H, J 8.8, 2.9 Hz), 6.95 (d, 1H, J 8.8 Hz), 5.74 (dd, 1H, J 13.5, 2.8 Hz), 3.28 (dd, 1H, J −16.9, 13.5 Hz), 2.74 (dd, 1H, J −16.9, 2.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=1>CS(C)=O.CCOC(C)=O>[CH3:22][C:21]1[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccnc1F
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cccnc1Oc1ccc(N)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-aminophenol (0.87 g, 8.0 mmol) in DMSO (12 mL) was added cesium carbonate (3.1 g, 9.6 mmol) and 2-fluoro-3-picoline (0.89 g, 8.0 mmol). The resulting mixture was heated to 80° C. for 16 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and brine several times to remove DMSO. The aqueous layer was back extracted with EtOAc and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide 4-(3-methylpyridin-2-yloxy)benzenamine as tan solid. MS (ESI, pos. ion) m/z: 201.2 (M+1).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([CH2:17][CH2:18][OH:19])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C(O)=O)CC=CCC1.C(Cl)(Cl)Cl.[N+:33]([O-:38])([N+]([O-])=O)=[O:34]>O>[OH:19][CH2:18][CH2:17][C:16]1[C:4]2[O:3][C:2]([N+:33]([O-:38])=[O:34])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=[CH:14][CH:15]=1
Reactant: OCCc1cccc2c(-c3ccccc3)c(Br)oc12
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C(O)C1CC=CCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1oc2c(CCO)cccc2c1-c1ccccc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 28.6 g. (0.0904 mole) of 2-bromo-7-(2-hydroxyethyl)-3-phenylbenzofuran (the product of step A, Example 5) and 15.1 g. of 4-cyclohexenecarboxylic acid in 250 ml. of chloroform is added dropwise 10.8 g. (0.118 mole) of dinitrogen tetraoxide in 30 ml. of chloroform. After 16 hours, 7 g. of dinitrogen tetraoxide and 5 g. of 4-cyclohexenecarboxylic acid in 30 ml. of chloroform are added, and the mixture is heated at 45° C. for four hours. Water is added to the mixture, the chloroform layer is separated and washed with water, then thrice with sodium bicarbonate solution, thrice with water, once with saturated sodium chloride solution and dried. Evaporation provides a yellow residue. Thin layer chromatographic analysis shows two main products. This residue is recrystallized from 50/50 ethanol/water, then again from carbon tetrachloride to yield 7-(2-hydroxyethyl)-2-nitro-3-phenylbenzofuran as a yellow solid, m.p. 133.5°-136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH:21]1([CH2:24][O:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=2)[CH2:23][CH2:22]1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([O:25][CH2:24][CH:21]4[CH2:22][CH2:23]4)=[N:27][CH:28]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(OCC2CC2)nc1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(OCC4CC4)nc3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 6-cyclopropylmethoxy-nicotinic acid (CAS1019546-29-2, WO2008130320) following procedure I yielded the title compound as a light yellow solid. MS (ISP): m/z=463.2 [M+H]+.
Reaction SMILES: ClC[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCCN2CCOCC2)cc1
Temperature: 62.5 °C
Reaction time: 17.5 h
Yield: 2180.8 %

Procedure:
A 50 L jacketed reactor equipped with a reflux condenser and temperature probe was charged with 4-(3-chloropropyl)morpholine (2.44 kg, 0.54 mol), 4-bromophenol (2.27 kg, 0.54 mol, 1.0 equiv.), powdered potassium carbonate (6.331 kg, 1.88 mol, 3.50 equiv.), and DMF (12.2 L) and stirred. The reaction mixture was then heated to 60-65° C. and stirred overnight. After 17.5 h, the reaction mixture was cooled to 20-25° C. The reaction mixture was charged to a different reactor equipped with bottom valve for the work-up. While maintaining a temperature between 20-30° C., DI water (48.7 L) was charged to the reactor. The phases were separated. The aqueous layer was extracted with MTBE (3×24.4 L). To the combined organics, DI water (18.3 L) and then 6M sodium hydroxide (18.2 L) were added. The mixture was stirred for 2-5 minutes and the phases were separated. The organic phase was washed with water (24.4 L) and brine (24.4 L), dried over magnesium sulfate, filtered, and concentrated to give 3370 g of a yellow oil (89% crude yield, 99.4% AUC by HPLC).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:5])[CH3:4].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:23]([N:6]([C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[C:3](=[O:5])[CH3:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)Nc1cc(Oc2ccccc2)ccc1C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1ccccc1)c1cc(Oc2ccccc2)ccc1C(=O)O
Reaction time: 0.5 h

Procedure:
60% Sodium hydride 30 mg was added to N,N-dimethylformamide 2.0 mL solution of 2-(acetamido)-4-phenoxybenzoic acid 0.10 g at room temperature, and it was stirred at same temperature for 30 minutes. Benzyl bromide 0.092 mL was added to the reaction mixture at room temperature, and it was stirred at same temperature for 2 hours and 30 minutes. 60% Sodium hydride 15 mg was added to the reaction mixture at room temperature, and it was stirred at same temperature for 30 minutes. Benzyl bromide 0.022 mL was added to the reaction mixture at room temperature, and it was stirred at same temperature for 1 hour and 30 minutes. 1.0 mol/L Hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate:acetic acid=40:10:1] to give 2-(N-benzylacetamido)-4-phenoxybenzoic acid 0.10 g of colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+].O>CC(=O)CC>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:19]=[CH:18][C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:14][CH:15]=4)[CH2:10][C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1-2
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1-2

Procedure:
A mixture of 18.8 g (0.05 mole) of 2,7-bis(4-chlorobutyryl)fluorene, prepared in Example 10, 34.0 g (0.4 mole) of piperidine, 16.6 g (0.1 mole) of potassium iodide in 200 ml of butanone is stirred and refluxed for three days. The reaction mixture is poured into 1000 ml of water, and the solid which is precipitated is filtered and recrystallized twice from chloroform-acetone to give 2,7-bis(4-piperidinobutyryl)fluorene, M.P. 157°-159° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].O1CCOCC1.[Br:18]N1C(=O)CCC1=O>COCCO>[Br:18][C:7]1[NH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][C:8]=1[CH2:10][OH:11]
Reactant: CCCCc1nc(CO)c[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: COCCO
Solvent: C1COCCO1
Product: CCCCc1nc(CO)c(Br)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
10 g of 2-butyl-1H-imidazole-4-methanol (obtained by EP 0,253,310) were introduced into 150 ml of dioxane and 150 ml of 2-methoxyethanol with stirring and 12.7 g of N-bromo succinimide were added. The mixture was stirred at 40° C. for 2 hours and the reaction medium was allowed to cool down to ambient temperature for 90 minutes. After evaporation, the crystals were taken up in 250 ml of ethyl acetate and 150 ml of water and extraction was carried out with ethyl acetate. The extracts were washed with water, dried and filtered. Activated charcoal was added to the solution which was stirred for 10 minutes, followed by filtration and evaporation. The crystals were solubilized in 64 ml of hot ethyl acetate and then the solution stood for 90 minutes at 0° C. After separation, the crystals were washed with ethyl acetate, then with methylene chloride and separated and dried to obtain 4.39 g of the expected product melting at 160 ° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:19])[CH3:18].[H][H]>C(OCC)(=O)C>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:19])[CH3:18]
Reactant: [H][H]
Reactant: COc1cc(OC)c(C(C)=O)c(O)c1CC=C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(C(C)=O)c(O)c1CCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
An ethyl acetate solution of 22.2 g of 2'-hydroxy4',6'-dimethoxy-3'-(3-methyl-2-butenyl)acetophenone was added into a sufficiently hydrogen gas-absorbed suspension of 1.5 g of 5% palladium-carbon in 20 ml of ethyl acetate, and the mixture was stirred at room temperature for 2 hours in a hydrogen gas atmosphere. After the reaction, the reaction mixture was filtered and the solvent was removed by distillation. The residue was recrystallized from n-hexane to obtain 20.4 g (yield=91.2%) of 2'-hydroxy-3'-isopentyl-4',6'-dimethoxyacetophenone in the form of a colorless needle.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:26])=[C:8](C(OC(C)(C)C)=O)[N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:26][C:30]([NH:29][CH2:27][CH3:28])=[O:31])=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)c(F)c2)c(C(=O)OC(C)(C)C)c1N
Product: CCNC(=O)Nc1cn(-c2ccc(Cl)c(F)c2)cc1C(=O)OCC
Yield: 76 %

Procedure:
Following general method 4, employing 3-amino-1-(4-chloro-3-fluoro-phenyl)-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester and ethyl isocyanate, afforded the title compound as a yellow solid (0.65 g, 76%); LCMS (method B): RT=3.87 min, M+H+=354; 1H NMR (DMSO-D6, 400 MHz): 8.27 (s, 1H), 7.91 (d, J=2.7 Hz, 1H), 7.86 (dd, J=10.9, 2.6 Hz, 1H), 7.68-7.63 (m, 2H), 7.54-7.50 (m, 1H), 7.23 (t, J=5.3 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 3.13-3.05 (m, 2H), 1.31 (t, J=7.1 Hz, 3H), 1.05 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:12]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:10]([CH3:20])=[C:11]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[N:12]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1[nH]c(-c2ccccc2Cl)nc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OC(C)(C)C)nc(-c2ccccc2Cl)n1-c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Yield: 72.5 %

Procedure:
t-Butyl 2-(2-chlorophenyl)-5-methylimidazole-4-carboxylate (70 mg, 0.24 mmol) was mixed with 4-fluoro-1-nitrobenzene (27 μL, 0.25 mmol) and potassium carbonate (66 mg, 0.48 mmol) in dry DMF and heated at 120° C. for 4 h. The mixture was diluted with water and filtered to give a yellow solid which was chromatographed over silica gel (40% EtOAc in hexane) to afford a yellow solid (72 mg, 73%): 1H NMR (300 MHz, CDCl3) δ 8.20 (m, 2H), 7.51 (m, 1H), 7.25 (m, 5H), 2.45 (s, 3H), 1.66 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4].CCN(C(C)C)C(C)C.[S:18](Cl)([C:21]1[C:33]([CH3:34])=[C:32]2[C:26]([O:27][C:28]([CH2:31]2)([CH3:30])[CH3:29])=[C:24]([CH3:25])[C:22]=1[CH3:23])(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[NH:1]([S:18]([C:21]1[C:33]([CH3:34])=[C:32]2[C:26]([O:27][C:28]([CH2:31]2)([CH3:30])[CH3:29])=[C:24]([CH3:25])[C:22]=1[CH3:23])(=[O:19])=[O:20])[C@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4]
Reactant: Cc1c(C)c(S(=O)(=O)Cl)c(C)c2c1OC(C)(C)C2
Reactant: COC(=O)[C@@H](N)CO
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2
Reaction time: 8 h
Yield: 82.7 %

Procedure:
H-Ser-OMe, 3.5 g (22.6 mmol), was suspended in (40 mL) of chloroform. Under ice cooling, DIEA (8.7 mL, 49.7 mmol) and Pbf-Cl (5.86 g, 20.3 mmol) were sequentially added and stirred overnight while gradually elevating to room temperature. After the reaction was stopped by adding satd. citric acid aqueous solution, chloroform was distilled off under reduced pressure and the whole was extracted with AcOEt. The organic layer was washed sequentially with satd. citric acid aqueous solution, satd. sodium bicarbonate aqueous solution and satd. sodium chloride aqueous solution, and then dried over anhydrous MgSO4. After concentration under reduced pressure, flash chromatography was performed using AcOEt:n-hexane=1:1 to give Pbf-Ser-OMe (6.94 g, 82.7%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([F:22])[CH:21]=1)[NH:18][CH:17]=[C:16]2[C:23]#[N:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.OCCC(N1C2C(=CC=CC=2)C(C#N)=C1)C1C=CC=CC=1>>[F:22][C:20]1[CH:21]=[C:13]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][OH:3])[CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[C:16]2[C:23]#[N:24]
Reactant: CCOC(=O)CC(c1ccccc1)c1cc(F)c2[nH]cc(C#N)c2c1
Agent: N#Cc1cn(C(CCO)c2ccccc2)c2ccccc12
Product: N#Cc1c[nH]c2c(F)cc(C(CCO)c3ccccc3)cc12

Procedure:
7-Fluoro-5-(3-hydroxy-1-phenyl-propyl)-1H-indole-3-carbonitrile LXXXVIII (328 mg) was prepared from 3-(3-cyano-7-fluoro-1H-indol-5-yl)-3-phenyl-propionic acid ethyl ester using the procedure described above for preparation of -(3-Hydroxy-1-pheny-propyl)-1H-indole-3-carbonitrile LX (Example 14).