Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[Cl:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:17]1[CH:18]=[C:14]([Cl:13])[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16]1
Reactant: FC(F)(F)c1n[nH]cc1Cl
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(Cl)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 83 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.82 g), 4-chloro-3-trifluoromethyl-1H-pyrazole (0.63 g) and potassium carbonate (0.61 g) were stirred in DMF (10 ml) at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-chloro-3-trifluoromethyl-1H-pyrazole (0.98 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1.Br[C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23]>C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)(Br)C(=O)O
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(O)ccc2n1C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C

Procedure:
A mixture of 5.4 g (0.02 mole) of 3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-ol, and 5.1 g (0.03 mole) of 2-bromo-2-methyl-propanoic acid was heated for two hours to 90°-130° C. Subsequently the mixture was taken up in chloroform/methanol (8:2) and chromatographed on silicagel. The evaporation residue of the eluate was stirred with cyclohexane and suction filtered.
Reaction SMILES: F[B-](F)(F)F.C[O+:7]([CH3:9])[CH3:8].[N+:10]([C:13]1[CH:29]=[CH:28][C:16]([CH2:17][O:18][C:19]([N:21]2C[CH2:25][NH:24][C:23](=O)[CH2:22]2)=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(=O)([O-])O.[Na+]>ClCCl>[CH3:8][O:7][CH:9]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:19]([O:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:29][CH:28]=1)=[O:20]
Reactant: O=C1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 17 h

Procedure:
Trimethyloxonium tetrafluoroborate (97%, 3.7 g) was added to the dry dichloromethane (120 mL) solution of 4-p-nitrobenzyloxycarbonyl-piperazin-2one (6.7 g) at room temperature and stirred for 17 hours. The reaction mixture was treated with saturated sodium hydrogen carbonate aqueous solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×100 mL), then the combined organic layer was washed with saturated sodium hydrogen carbonate aqueous solution and brine. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduce pressure and the title compound was obtained as a pale brown solid. Yield; 5.7 g, 80.6.
Reaction SMILES: [CH:1]([NH:4][C:5](=[NH:7])[CH3:6])([CH3:3])[CH3:2].Br[C:9](=[CH:13]OC)[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH3:6])=[N:7][CH:13]=1)(=[O:12])[CH3:11]
Reactant: CC(=N)NC(C)C
Reactant: COC=C(Br)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)c1cnc(C)n1C(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 16.2 g (0.162 mol) of N-isopropylacetamidine (which was prepared in the above-mentioned Reference Example 1), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours, for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was distilled under reduced pressure (0.4 kPa, 85° C.) to give 10.9 g (yield: 61%) of 5-acetyl-1-iso-propyl-2-methylimidazole as pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([O:9][C:3]2[CH:4]=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=2[F:1])[CH:14]=[CH:13][N:12]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: Clc1ccnc(Cl)c1
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Yield: 55.9 %

Procedure:
Using a procedure analogous to Example A2, 2-fluoro-4-aminophenol (2.6 g, 24 mmol) and 2,4-dichloropyridine (2.88 g, 20 mol) were combined to provide 4-(2-chloropyridin-4-yloxy)-3-fluoro-phenylamine (3.2 g, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=5.6 Hz, 1H), 6.99 (m, 1H), 6.90 (m, 2H), 6.50 (d, J=1.6 Hz, 1H), 6.41 (d, J=10.4 Hz, 1H), 5.51 (s, 2H); MS (ESI) m/z: 239.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.O[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Reactant: OCCc1ccncc1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCc1ccncc1
Yield: 56.2 %

Procedure:
Using an analogous procedure to that described in Example 20, 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), was reacted with 4-(2-hydroxyethyl)pyridine (0.11 g, 0.9 mmol), (Zhur. Obshchei. Khim. 1958, 28, 103-110), to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(4-pyridyl)ethoxy)cinnoline (0.15 g, 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:14][OH:15])[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CCCC2=NO
Temperature: 25 °C
Yield: 83 %

Procedure:
6-Aminotetralone (1.98 g, 12.3 mmol), hydroxylamine hydrochloride (0.85 g, 12.3 mmol), sodium acetate (2.52 g, 30.7 mmol), and water (3.3 ml) were dissolved in ethanol (10 ml), and the mixture was heated to reflux 4 hours. After cooling to room temperature, the mixture was diluted with water (20 ml), and the resulting precipitate was filtered to obtain 6-Amino-3,4-dihydro-2H-naphthalen-1-one oxime as a light brown solid, 1.80 g. (83% yield) 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.48-7.53 (m, 1H), 6.36-6.40 (m, 1H), 6.27 (s, 1H), 5.20 (s, 2H), 2.44-2.53 (m, 4H), 1.60-1.69 (m, 2H); MS (m/e) 177 (M+1).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+].[BH4-].[Na+]>CN(C)C=O>[CH3:8][CH:9]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCCCCCO
Reactant: C=CCCCCCCC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCC(C)OCCCCCO
Temperature: 25 °C

Procedure:
To a mixture of 12.6 grams of mercuric acetate and 8.3 grams of 1,5-pentanediol in 100 ml of dimethylformamide is added 5.0 grams of 1-nonene. The mixture is stirred at room temperature for ten minutes and 40 ml of an aqueous NaOH solution (3 Molar) is added followed by 40 ml of an aqueous NaBH4 solution (0.5 Molar in 3 Molar NaOH). The solution is decanted from the mercuric salts and concentrated. The residue is partitioned between ethyl acetate and water and the organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to give a clear liquid. This liquid is flash chromatographed, initially with a 19 to 1 ratio of hexane to ethyl acetate and, subsequently, with a 9 to 1 ratio, to give 5-(2-nonyloxy)pentanol as a clear liquid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9][OH:10]>O.CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:6][CH:7]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][C:9]([OH:2])=[O:10]
Reactant: CC(C)CCCC(C)CCO
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)CCCC(C)CC(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of chromium trioxide (55.5 g, 0.555 mol) in water (68 ml) and 2M-sulphuric acid (12 ml) was added dropwise to a solution of 3,7-dimethyloctanol (43.7 g, 0.308 mol) in acetone (100 ml), the temperature was maintained at 40-60° C. and the reaction mixture was left stirring overnight. Acetone was carefully removed in vacuo, the reaction mixture was diluted in water and washed with diethyl ether (2×200 ml). The ethereal solution was washed with 10% sodium hydroxyde solution (200 ml); and the aqueous phase was acidified with 36% HCl (200 ml) and washed once more with diethyl ether (2×200 ml). The organic layer was dried (MgSO4) and the diethyl ether was removed in vacuo. The crude product was distilled to give a colourless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH:40](=O)[CH:41]([CH3:43])[CH3:42]>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][N:35]4[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)C=O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4CC(C)C)ncn3)cccc2s1

Procedure:
N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)piperidine-2-carboxamide, Example 49(a), (0.50 g, 0.90 mmol) was reacted with isobutyraldehyde (0.16 mL, 1.8 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 613 (M+1). Mp: 153.4-154.9° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(S(F)(F)[F:18])CC)C>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([F:18])([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(O)c1cccnc1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(F)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2-chloro-3-pyridinyl)propan-2-ol (1 g; 5.83 mmol) in dichloromethane (10 mL) cooled to −70° C. was added diethylaminosulphur trifluoride (1.1272 g; 0.857 mL; 6.993 mmol) dropwise. On completion of the addition the reaction mixture was allowed to warm to room temperature and stir for 30 min. TLC showed starting material consumed. The reaction mixture was poured onto sodium carbonate solution and extracted with dichloromethane. The dichloromethane extracts were combined, washed with water, dried over magnesium sulphate filtered and evaporated under reduced pressure to give an oil. Yield=0.9 g. 1H NMR (360 MHz) DMSO-d6 δ: 1.83 (3H, s), 1.89 (3H, s), 7.30 (1H, dd, J 4.6 and 7.7 Hz), 8.00 (1H, dd, J 1.9 and 7.9 Hz), 8.34 (1 H, dd, J 1.9 and 4.7 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[NH2:15][CH2:16][CH:17]1[CH2:19][CH2:18]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: NCC1CC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1

Procedure:
In analogy to the procedure described in example 38b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with aminomethyl-cyclopropane in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-chloro-6-(cyclo-propylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=268.
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]([F:16])([F:15])[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10]>CCOCC>[F:4][C:5]([F:15])([F:16])[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:3])=[O:10]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 97.8 %

Procedure:
An excess solution of diazomethane in ether was added to an ice-cooled and stirred solution of m-trifluoromethylbenzoic acid (8.0 g, 42.1 mmol) in 50 ml of ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl m-trifluoromethylbenzoate (8.4 g, 41.2 mmol, yield 97.8%, b.p. 76°-78° C./12 mmHg), which was assigned the structure by the following data:
Reaction SMILES: Br[CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[I:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[I:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCCCCCCCC(C)Br
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCCCC(C)Oc1cccc(I)c1
Temperature: 75 °C
Reaction time: 14 h
Yield: 33.3 %

Procedure:
To a stirred solution of ethyl 10-bromoundecanoate (9.7 g, 33.0 mmol) in dry DMF (66 ml) was added 3-iodophenol (7.99 g, 36.3 mmol) and potassium carbonate (5.02 g, 37.6 mmol). The reaction was immersed in an oil bath which was warmed to 75° C. over 0.5 hr. After stirring for 14 hrs under an N2 atmosphere, the oil bath temperature was increased to 85° C. After stirring for an additional 4 hrs at 85° C., the reaction was allowed to cool, diluted with DMF (200 ml), filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up in ether (500 ml). The organic phase was washed with water (100 ml), 1M aqueous sodium hydroxide (100 ml), water (2×100 ml) and brine (100 ml), dried (Na2SO4), filtered and evaporated in vacuo to provide crude ethyl 10-(3-iodophenoxy)undecanoate which was contaminated with olefinic esters. Flash column chromatography (silica, 1-2%; EtOAc in hexanes) provide ethyl 10-(3-iodophenoxy)-undecanoate as a clear oil (4.75 g, 33.3%).
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([CH:7]([C:10]#[N:11])[C:8]#[N:9])([CH3:6])[CH3:5]>CCO>[CH:4]([C:7]1[C:10]([NH2:11])=[N:2][NH:3][C:8]=1[NH2:9])([CH3:6])[CH3:5]
Reactant: CC(C)C(C#N)C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)c1c(N)n[nH]c1N
Temperature: 80 °C

Procedure:
Hydrazine monohydrate (2.05 mL, 42 mmol) was added to a solution of the product from Example 112A (1.16 g, 10.7 mmol) in EtOH (15 mL). The reaction flask was evacuated and purged with nitrogen (3 cycles), then heated at 80° C. for 22 hours. The yellow solution was cooled to room temperature and concentrated under vacuum. Toluene (8 mL) was added to the residue, and the mixture was concentrated under vacuum to remove excess hydrazine (repeated twice more) to provide the title compound. MS (ESI) m/z 141 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:26](=[O:27])[CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(4R,5S)-4-Methyl-5-phenyl-oxazolidin-2-one (25.21 g, 142.269 mmol) is dissolved in anhydrous THF (100 mL) and cooled to −78° C. n-Butyl lithium (2.5 M in hexanes, 62.60 mL, 156.5 mmol) is added dropwise over 10 min. The reaction is stirred at −78° C. for 10 min. Phenylacetyl chloride (20.73 mL, 156.5 mmol) is dissolved in anhydrous THF (50 mL) and added dropwise over 10 min. The reaction is stirred at −78° C. for 2 h. The reaction is poured onto brine (300 mL) and extracted with ethyl acetate (2×250 mL). Extracts are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow oil which solidified upon standing. Therude product is purified by column chromatography over silica eluting with 5→45% ethyl acetate in hexanes to afford (4R,5S)-4-methyl-5-phenyl-3-phenylacetyl-oxazolidin-2-one as a white solid: 1H NMR (400 MHz, DMSO-D6) δ 0.8 (d, J=6.6 Hz, 3 H) 4.2 (m, 2 H) 4.8 (m, 1 H) 5.9 (d, J=7.3 Hz, 1 H) 7.2 (m, 3 H) 7.3 (m, 5 H) 7.4 (m, 2 H); LC/MS 296.2 (M+1), 294.1 (M−1).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:35])[CH:7]=[C:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22](=[O:34])[NH:23][C:24]2[CH:28]=[C:27]([C:29]([O:31]C)=[O:30])[N:26]([CH3:33])[CH:25]=2)=[CH:16]3)=[O:12])[CH:9]=1)=[O:4].[OH-].[Na+]>O.CO>[OH:31][C:29]([C:27]1[N:26]([CH3:33])[CH:25]=[C:24]([NH:23][C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([C:11]([NH:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:35])[CH:7]=2)=[O:12])=[CH:21][CH:20]=3)=[O:34])[CH:28]=1)=[O:30]
Reactant: COC(=O)c1cc(NC(=O)c2ccc3[nH]c(C(=O)Nc4cc(C(=O)OC)n(C)c4)cc3c2)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(NC(=O)c2ccc3[nH]c(C(=O)Nc4cc(C(=O)O)n(C)c4)cc3c2)cc1C(=O)O
Yield: 86.8 %

Procedure:
A solution of 4-({1-[2-(5-methoxycarbonyl-1 methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl}-amino)-1-methyl-1H-pyrrole-2carboxylic acid methyl ester 8 (1.04 g, 2.18 mmole) and NaOH (10 mmole) in a mixture of water/MeOH (1/4) (25 ml) was stirred at 50C for 6 h and then overnight at ambient temperature. The reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in water (50 ml) and acidified with 1M HCl up to pH=3. The precipitate was collected on the filter and washed with water (3×50 ml) and dried over phosphorus pentoxide in dessicator to give 0.85 g (87%) of 4-({1-[2-(5-hydroxycarbonyl-1-methyl-1H-pyrrol-3-ylcarbamoyl)-1H-indol-5-yl]-methanoyl}-amino)-1-methyl-1H-pyrrole-2-carboxylic acid 9 as white crystalline material. MS: 448.08 (M−H). 1H-NMR (DMSO-d6): 11.96 (s, 1H, H-1, indole); 10.45&10.25 (s&s, 1H&1H, —C(═O)NH); 8.30 (m, 1H, H-6, indole); 7.48 (m, 3H with *, H-7, indole); 7.49&7.46 (d&d, *, H-3 or H-5, Py1&Py2); 7.39 (s, 1H, H-3, indole); 6.91 (m, 2H, H-3 or H-5, Py1&Py2); 3.84&3.83 (s&s, 6H, NCH3, Py1&Py2).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1.[OH-].[Na+]>CN(C=O)C.O>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:10][C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH:17]=1
Reactant: Brc1cncc(Br)c1
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2cncc(Br)c2)cc1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
Sodium hydride (1.53 g of 80% in mineral oil, 51 mmol) was slowly added to a solution of 4-fluorophenol (5.6 g, 50 mmol) in DMF (100 mL) as it was stirred and cooled (ice water bath) under a nitrogen atmosphere. The resulting mixture was warmed to ambient temperature and stirred for 1 h. 3,5-Dibromopyridine (5.9 g, 25 mmol) was added and the mixture was then heated at 90° C. (bath temperature) for 62 h. The mixture was cooled, diluted with water (150 mL), poured into 5N sodium hydroxide (150 mL), and extracted with diethyl ether (2×150 mL). The combined ether extracts were washed with water, dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography on silica gel, using 5% ethyl acetate: hexane as eluent, to yield 1.4 g (21%) of a colorless oil.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:17]=1[O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O-:23])=[O:22].[F:36][C:37]([F:53])([F:52])[C:38]1[CH:39]=[C:40]([S:48](Cl)(=[O:50])=[O:49])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1>N1C=CC=CC=1>[CH:1]([OH:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:47][C:44]([F:45])([F:46])[C:42]1[CH:41]=[C:40]([S:48]([NH:15][C:16]2[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:17]=2[O:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([O-:23])=[O:22])(=[O:49])=[O:50])[CH:39]=[C:38]([C:37]([F:53])([F:52])[F:36])[CH:43]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)[O-]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=C([O-])c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Benzhydrol 2-(2-amino-4-trifluoromethylphenoxy)benzoate (4 g, 8.6 mmol) was dissolved in pyridine (25 mL) and stirred under argon at room temperature. 3,5-bis(trifluoromethyl)benzenesulfonyl chloride (4.05 g, 12.9 mmol) was added in portions, and the mixture stirred for 16 h. The solvent was evaporated, and the residue was purified by flash chromatography (silica gel, ethyl acetate/hexane) to give the title compound as a white solid. 1H NMR (250 MHz, CDCl3) δ8.25 (br s, 1H), 8.15 (s, 2H), 7.99 (dd, 1H), 7.85-7.92 (m, 2H), 7.1-7.5 (m, 13H), 7.01 (s, 1H), 6.72 (d, 1H), 6.45 (dd, 1H).
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]3[C:22]([N:23]=[C:24]4[CH2:30][CH2:29]CC[CH2:26][C:25]=24)=[CH:21][CH:20]=[N:19]3)=[CH:13][CH:12]=1.ClCCC[O:35]C1C=CC(C2N3C(=CC=N3)N=C3C=2CCC3)=CC=1.O[C@@H]1CCNC1>>[N:19]1[N:18]2[C:22]([N:23]=[C:24]3[C:25](=[C:17]2[C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][C@@H:6]([OH:35])[CH2:2]4)=[CH:12][CH:13]=2)[CH2:26][CH2:29][CH2:30]3)=[CH:21][CH:20]=1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1
Reactant: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Agent: O[C@@H]1CCNC1
Product: O[C@@H]1CCN(CCCOc2ccc(-c3c4c(nc5ccnn35)CCC4)cc2)C1

Procedure:
Using the method described for the preparation of 10-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 8-[4-(3-chloro-propoxy)-phenyl]-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and 3-(R)-hydroxy-pyrrolidine provided the title compound.