Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[CH:23]1(CN)[CH2:28][CH2:27]C[CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH:4]2[CH2:27][CH2:28][CH2:23][CH2:24][CH2:25]2)=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: NCC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(COC(=O)NCC2CCCCC2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 52 %

Procedure:
To a stirred yellow solution of VII (293.8 mg, 0.861 mmol) in anhydrous THF (10 mL) was added cyclohexylmethanamine (165 mg, 123 μL, 1.1×0.861 mmol) and then, dropwise, triethylamine (96 mg, 133 μL, 1.1×0.861 mmol). The solution was stirred for 45 minutes at room temperature. The colorless solution was then diluted with CH2Cl2 and washed with 1N HCl, distilled water, and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate (1:1, v/v) to yield 150.2 mg (52%) of 13 as a clear colorless oil: Rf=0.55 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 6.98 (d, 3J=8.0 Hz, 1H), 6.95 (d, 1H), 6.91 (dd, 3J=8.0 Hz, 1H), 5.04 (s, 2H, CH2O), 4.75 (bs, 1H, NH), 3.81 (s, 3H, OCH3), 3.01 (t, 3J=6.4 Hz, 211, NCH2), 2.29 (s, 3H), 1.70-1.62 (m, 5H), 1.42 (bs, 1H), 1.23-1.11 (m, 3H) and 0.92 (q, 3J=11.5 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1B(O)O>>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[C:8]1[C:7]2[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: Cc1cccc(C)c1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Yield: 62 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2,6-dimethylbenzeneboronic acid according to the procedure described in example 8 gave 4-(2,6-dimethylphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (17) (I, Ar=2,6-dimethylphenyl) in a 62% yield; mp 230–238° C. (dec). 1H NMR δ [(CD3)2SO] 11.72 (s, 1H), 10.95 (s, 1H), 9.25 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.35 (s, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 2H), 7.06 ((dd, J=8.7, 2.3 Hz, 1H), 1.93 (s, 6H). EIMS found M+: 356,1159, C22H16N2O3 requires 356,1161.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:30]=3)[CH2:32][CH2:33]2)=[O:19])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(NC(=O)OCC(Cl)(Cl)Cl)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1

Procedure:
A solution of 2,2,2-trichloroethyl [3-(acetylamino)phenyl]carbamate (200 mg, 0.614 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (151 mg, 0.614 mmol), diisopropylethylamine (0.107 ml, 0.614 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (107 mg, 41.3%) as a solid.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:4][CH2:5][C:6]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7]
Reactant: COc1ccccc1CN(C(=O)COC(C)=O)c1ccccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccccc1CN(C(=O)CO)c1ccccc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 7 h
Yield: 95.6 %

Procedure:
In 6 ml of methanol was dissolved 525 mg of N-acetoxyacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline, and then 537 mg of potassium carbonate was added, followed by stirring at 50° C. for 7 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:3) and allowed to stand at room temperature to give 450 mg of N-hydroxyacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline as crystals.
Reaction SMILES: C([Li])CCC.C(NC1CCCCC1)(C)C.C(=NC1CCCCC1)C.[CH:25]1([C:28](=[C:31]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)C=O)[CH2:27][CH2:26]1.[O:46]1C[CH2:49][CH2:48][CH2:47]1>>[CH:25]1([C:28](=[C:31]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[CH:49]=[CH:48][CH:47]=[O:46])[CH2:26][CH2:27]1
Reactant: C1CCOC1
Reactant: O=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Agent: CC(C)NC1CCCCC1
Agent: CC=NC1CCCCC1
Agent: [Li]CCCC
Product: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (2.9 mL of 1M solution, 6 mmol) was added to a solution of N-isopropylcyclohexylamine (0.85 g, 6 mmol) in 10 mL of tetrahydrofuran at -20° C. After stirring for 30 minutes and further cooling to -50° C., N-ethylidenecyclohexanamine (3 mL of 2M solution, 6 mmol) was added. After stirring for an additional 30 minutes and continued cooling to -70° C., 2-cyclopropyl-3,3-bis(4-fluorophenyl)-2-propenal (0.85 g, 2 mmol) was added. The mixture was stirred for 4 hours at -70° C. and quenched with saturated ammonium chloride. The mixture was extracted with diethyl ether. The diethyl ether was dried with magnesium sulfate and concentrated in vacuo. The residue was stirred for 16 hours with a mixture of 50 mL of benzene, 15 mL of acetic acid and 35 mL of water. The mixture was diluted to 250 mL with water and extracted with diethyl ether. The extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 0.38 g of the title compound; m.p. =139°-140° C.
Reaction SMILES: [C:1]1(=[O:14])[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12]O)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:12][CH2:11][CH2:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[C:1](=[O:14])[CH2:2][CH2:3]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2cc(CCCO)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CCc2cc(CCCBr)ccc21
Reaction time: 15 h
Yield: 28.1 %

Procedure:
Compound 56-2 (1.15 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (1.74 g) and N-bromosuccinimide (1.18 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (430 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH3:18])[CH2:4][NH:5][C:6]1[N:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11]C)=[O:9])[CH3:2].[O:19]=C(Cl)OC(Cl)(Cl)Cl>ClCCCl.O1CCOCC1>[CH2:1]([CH:3]([CH2:17][CH3:18])[CH2:4][N:5]1[C:6]2[N:16]=[CH:15][CH:14]=[CH:13][C:7]=2[C:8](=[O:9])[O:10][C:11]1=[O:19])[CH3:2]
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CCC(CC)Cn1c(=O)oc(=O)c2cccnc21
Yield: 35.7 %

Procedure:
The product of Example 3A (0.664 g, 2.65 mmol) and diphosgene (1.57 g, 7.96 mmol) in 13 mL of 1,2-dichloroethane and 1.3 mL of 1,4 dioxane were reacted at 80° C. for 16 hours. The reaction was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (9:1) to provide the title compound (0.235 g, 36%). 1H NMR (300 MHz, CDCl3) δ 0.95 (m, 6H), 1.40 (m, 4H), 1.52 (m, 2H), 4.21 (m, 1H), 7.25 (m, 1H), 8.41 (dd, J=7.72, 1.84 Hz, 1H), 8.70 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: CON(C)[C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[CH3:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][Mg]Cl>C1COCC1>[CH3:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)=[O:5]
Reactant: COCCCC[Mg]Cl
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Solvent: C1CCOC1
Product: COCCCCC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
A stirred solution of (±)-tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.73 g, 6.4 mmol) in dry THF (40 mL) was cooled in an ice-salt bath and 1.34 M 4-methoxybutylmagnesium chloride in THF (10 mL, 1.34 mmol) was added dropwise over 3 min. The cooling bath was allowed to expire and the mixture was stirred at rt for 6 h, poured into ice cold 3% aq HCl (100 mL) and extracted with ether (2×100 mL). The combined ether extracts were washed with satd aq NaHCO3 (35 mL), dried over MgSO4 and concentrated to afford (±)-tert-butyl 2-(5-methoxypentanoyl)morpholine-4-carboxylate (1.78 g, 93%) as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[O:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](Cl)=[O:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>O1CCCC1>[O:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]([N:9]3[CH2:8][CH2:7][N:6]([C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[CH2:11][CH2:10]3)=[O:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: c1csc(N2CCNCC2)n1
Reactant: O=C(Cl)c1ccc2c(c1)CCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc2c(c1)CCO2)N1CCN(c2nccs2)CC1
Temperature: 60 °C
Yield: 76.3 %

Procedure:
To a solution of 9 g of 1-(2-thiazolyl) piperazine and 5 g of anhydrous triethylamine in 200 ml of anhydrous tetrahydroduran, there were added dropwise, a solution of 9.1 g of 5-coumaranyl carboxylic acid chloride in 20 ml of tetrahydrofuran. After the completion of the addition, the reaction mixture was heated at 60° C for two hours, then, the so-formed precipitate was suction-filtered off. The filtrate was evaporated under reduced pressure and the crystalline residue was washed with water then recrystallized in 70 ml of ethanol. There were obtained 12 g of 1-(5-coumaranyl carbonyl)-4-(2-thiazolyl) piperazine, melting (K) at 150°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37])/[C:28](=[N:30]/O)/[NH2:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]1[O:6][N:29]=[C:28]([C:27]2[CH:32]=[CH:33][C:34]([O:35][CH:36]([CH3:37])[CH3:38])=[C:25]([Cl:24])[CH:26]=2)[N:30]=1)[C:11]#[N:12]
Reactant: N#Cc1ccc(C(=O)O)c(Cl)c1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C#N)cc3Cl)n2)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.4 %

Procedure:
To a 250 mL RBF equipped with a stir bar was charged with 2-chloro-4-cyanobenzoic acid (3.0 g, 16.52 mmol), anhydrous DCM (80 mL), and DMF (0.064 mL, 0.826 mmol). Oxalyl chloride (8.26 mL, 16.52 mmol) (2M solution in DCM) was then added slowly and the mixture was stirred under nitrogen at ambient temperature. Upon addition of the oxalyl chloride, gas evolution began and the suspended solid began to dissolve. After about 2-3 hours, the reaction became translucent. The mixture was concentrated in vacuo. The resulting crude material was dissolved in pyridine (50 mL). To this was added (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (1.258 g, 5.50 mmol). The mixture was heated to about 100° C. under an atmosphere of nitrogen for about 16 hrs. The resulting mixture was cooled to ambient temperature. Pyridine was removed under reduced pressure and the resulting material was triturated in DCM and MeOH mixture (about 1:1). The resulting precipitate was left standing for a few minutes at ambient temperature then was collected via filtration, washed with a mixture of 1:1 DCM/MeOH, and then with straight MeOH and dried in a vacuum oven for about 48 hrs to yield 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile (1.529 g, 4.09 mmol) as a beige solid. 1H NMR (400 MHz, DMSO) δ ppm 8.39 (d, J=1.53 Hz, 1H), 8.35 (d, J=8.15 Hz, 1H), 8.09 (dd, J=8.14, 1.53 Hz, 1H), 8.05 (d, J=2.11 Hz, 1H), 8.00 (dd, J=8.63, 2.12 Hz, 1H), 7.39 (d, J=8.82 Hz, 1H), 4.82 (sept, J=6.04 Hz, 1H), 1.35 (d, J=6.01 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[Br:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(Br)cc1N
Yield: 93.6 %

Procedure:
To 2-nitro-4-bromoaniline (340 mg, 1.57 mmol) in absolute ethanol (20 mL) was added SnCl2 (1.50g, 7.91 mmol) and refluxed overnight. The reaction mixture was then basified to pH 11 with 2N NaOH and extracted with ether to give 275 mg (94%) of product. This product was used without further purification for the synthesis of JSK IV-37.
Reaction SMILES: [CH2:1]([S:9][CH2:10][CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>C1C=CC=CC=1>[C:19]([O:12][CH2:11][CH2:10][S:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: CCCCCCCCSCCO
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C=C(C)C(=O)OCCSCCCCCCCC
Temperature: 5 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
2(n-Octylthio)ethanol (13.10 grams, 0.0688 mole) and anhydrous pyridine (65.5 grams) were charged to a three-necked flask fitted with a condenser protected with a drying tube, dropping funnel, thermometer and magnetic stirrer. The solution was cooled to 5° C., and methacrylyl chloride (7.20 grams, 0.0688 mole) was then added dropwise over a 26-minute period. The reaction solution was maintained at 9°-11° C. throughout the addition period, and then at 25° C. for another three hours with stirring. The reaction mixture was then diluted with 150 ml of benzene, and the pyridine hydrochloride present was removed by filtration. The filtrate was washed twice with dilute hydrochloric acid, then with water until neutral and finally dried over anhydrous sodium sulfate. The benzene solvent was stripped off leaving 13.1 grams of crude product which was purified by vacuum distillation to yield 11.8 grams of the desired ester with a boiling point of 111°-124° C./0.07 mm in a yield of 66%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH2:14])[C:6]([NH2:13])=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].C([O:21][C:22](=O)[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][O:38]C3CCCCO3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[OH:38][CH2:37][C:33]1[CH:32]=[C:31]([C:27]2[CH:26]=[C:25]([C:24]3[CH2:23][C:22](=[O:21])[NH:13][C:6]4[CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:3]([C:2]([F:15])([F:16])[F:1])=[CH:4][C:5]=4[N:14]=3)[CH:30]=[CH:29][CH:28]=2)[CH:36]=[CH:35][N:34]=1
Reactant: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(C(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 4,5-bis-trifluoromethyl-benzene-1,2-diamine [CAS-No. 30454-92-3] (244 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) in toluene (10 ml) under reflux conditions for 2 h according to the general procedure M and subsequent treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (291 mg, 61%).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=O)=O.[C-:14]#[N:15].[K+].C(=O)(O)[O-].[Na+]>CCO.O>[Cl:13][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([CH2:6][N+:15]#[C-:14])[CH:12]=1
Reactant: CS(=O)(=O)OCc1cncc(Cl)c1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [C-]#[N+]Cc1cncc(Cl)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
To a mixture of (5-chloropyridin-3-yl)methyl methanesulfonate (2.09 g, crude) in EtOH (45 mL) and water (5 mL) was added potassium cyanide (926 mg, 14.3 mmol), and the resulting mixture was stirred at 85° C. for 2 h. Sodium bicarbonate was added and the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (50% ethyl acetate in petroleum ether) to afford the title compound as a yellow solid (820 mg, 5.43 mmol, 48% yield, 2 steps). MS (ESI) m/z 153.1 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=O)#[N:2].[C:15]1(C)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22].[CH2:24](N(CC)CC)C.CCOC(C)=O>C(O)C>[C:19]1([CH3:24])[CH:20]=[CH:15][C:16]([N:21]2[C:1]([NH2:2])=[CH:3][C:4]([C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=3)=[N:22]2)=[CH:17][CH:18]=1
Reactant: Cc1ccccc1NN
Reactant: CCN(CC)CC
Reactant: N#CCC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(-c3ccc([N+](=O)[O-])cc3)cc2N)cc1

Procedure:
To a solution of 2-cyano-4′nitroacetophenone in ethanol (100 mL) at room temperature was added tolylhydrazine (6.44 g, 0.04 mol) and triethylamine (15.4 mL, 0.11 mol). The resulting solution was heated to reflux and maintained at reflux for 1 h. The solution was cooled to room temperature at which time EtOAc (500 mL) was added. The organic solution was washed with brine (2×500 mL), dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel eluting with 1:1 hexane/EtOAc to yield 1-(4-tolyl)-3-(4-nitrophenyl)-5-aminopyrazole as a solid.
Reaction SMILES: [C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[H][H]>CO.[Rh].[Pd]>[NH2:2][CH2:1][C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: N#CC1(CC(=O)O)CCCCC1
Agent: [Pd]
Agent: [Rh]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
One gram of 10% rhodium on carbon, containing 1% palladium, (Pearlman, W. M., Tetrahedron Letters, pages 1663-1664 (1967)) is slurried in 30 ml methanol and reduced under hydrogen in a Parr shaker. 1-Cyanocyclohexaneacetic acid (16.7 g, 0.1 mol) is dissolved in 40 ml methanol and combined with the reduced catalyst. The mixture is placed under 50 pounds per square inch gauge (psig) hydrogen and shaken for two hours at room temperature. The catalyst is removed by filtration, and the filtrate is condensed to a volume of 25 ml by vacuum distillation. Isopropanol, 100 ml, is added and an additional 25 to 50 ml of solvent is removed by vacuum distillation. The resultant slurry is cooled at 0° to 5° C. for 24 hours and filtered and dried to give 13.65 g (79% of theory) of 1-(aminomethyl)-cyclohexaneacetic acid; mp 162°-163° C.
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1)([CH3:22])[CH2:5][CH2:6][C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9]>CC(O)(CC)CC>[NH3:9].[CH3:22][C:4]([N:23]1[CH2:24][CH2:25][CH:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27][CH2:28]1)([CH3:3])[CH2:5][CH2:6][C:7]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]([NH2:9])=[O:1]
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CCC(Oc2ccccc2)CC1
Reactant: [OH-]
Agent: CCC(C)(O)CC
Agent: [K+]
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CCC(Oc2ccccc2)CC1
Product: N
Temperature: 25 °C

Procedure:
Potassium hydroxide (512 mg, 9.12 mmol) was added to a solution of the product of example 86(200 mg, 0.46 mmol) in 3-methyl-3-pentanol (4 mL) and the mixture was heated under reflux for 20 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo and the residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0 to 90:10:1, afforded the title compound as a colourless glass in 93% yield, 193 mg.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=2)[C:11]([CH3:20])=[C:10]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:3])=[O:2]>Br>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([CH3:20])=[C:10]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:3])=[O:2]
Reactant: COc1ccc2c(c1)c(C)c(-c1cccnc1)n2CCCCCC(=O)O
Agent: Br
Product: Cc1c(-c2cccnc2)n(CCCCCC(=O)O)c2ccc(O)cc12

Procedure:
A solution of 1.70 g of 1-(5-carboxypentyl)-5-methoxy-3-methyl-2-(3-pyridyl)indole in 85 ml of 48% hydrobromic acid is heated under reflux for 0.5 hour. Purification of the resulting product yields 1-(5-carboxypentyl)-5-hydroxy-3-methyl-2-(3-pyridyl)indole.