Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][C:9]([C:11]1[CH:12]=[CH:13][C:14](O)=[CH:15][C:16]=1[OH:17])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)Cl>[OH:17][C:16]1[CH:15]=[C:14]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:13]=[CH:12][C:11]=1[C:9](=[O:10])[CH3:8]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: OC1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1ccc(OC2CCOCC2)cc1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 31.3 %

Procedure:
A mixture of tetrahydro-4H-pyran-4-ol (1.53 g, 15 mmol), 2,4-dihydroxyacetophenone (1.52 g, 10 mmol), and triphenyiphosphine, polymer-bound (5 g, 3 mmol P/g resin, 15 mmol) in CH2Cl2 (150 mL) was treated with diethyilazodicarboxylate (2.61 g, 15 mmol) and stirred at 20° C. for 20 h. The reaction mixture was treated with ether (200 mL) and the resin was filtered off and discarded. The filtrate was concentrated irn vacuo and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 25% ether in hexanes) to yield the white solid product (0.74 g, 31%).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)=O)CCCC1.S(Cl)(Cl)=O.[S:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH:1]1([C:6]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCC1
Reactant: c1ccsc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(O)C1CCCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cccs1)C1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Cyclopentanecarboxylic acid chloride, prepared from 100 mmol cyclopentanecarboxylic acid and 120 mmol of thionyl chloride, was dissolved in 100 mL of methylene chloride, and the solution was cooled in an ice bath. Thiophene (13.4 mL, 100 mmol) and SnCl4 (25 mL of a 1M solution in methylene chloride) were added. The reaction was warmed to room temperature and stirred for 72 hours. The reaction was quenched with 1 N HCl, and the mixture was extracted with three portions of methylene chloride. The organic extract was washed with satd aqueous NaHCO3, was dried over MgSO4, and filtered through a pad of silica gel. The solvent was removed by rotary evaporation to give 12.28 g of crude product, which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:13][NH:14][CH2:15][C:16]1(C)[CH2:18][CH2:17]1.[C:20](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([N:14]([CH3:13])[CH2:15][CH:16]2[CH2:18][CH:17]2[CH3:20])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CNCC1(C)CC1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1CC1CN(C)c1cc(C(=O)O)cc(Cl)n1
Yield: 90.6 %

Procedure:
A solution of 2,6-dichloroisonicotinic acid (0.25 g, 1.3 mmol), methyl-[(methylcyclopropyl)methyl]amine hydrochloride (0.53 g, 3.9 mmol) and cesium carbonate (1.25 g, 6.5 mmol) in 5 mL DMF was heated to 120° C. in a sealed tube for 72 hr. The reaction was partitioned between 1M HCl and ethyl acetate. The organics were washed with water (4×), brine, dried over sodium sulfate, filtered and evaporated in vacuo to give 0.3 g (90%) of crude 2-chloro-6-{methyl[(2-methylcyclopropyl)methyl]amino}isonicotinic acid as a brown oil: LCMS (M+H)=255.0.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])=[C:15]([O:26][CH3:27])[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39]Br.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C)C=O.O>[CH3:27][O:26][C:15]1[CH:14]=[C:13]([O:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:37][CH2:38][CH2:39][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[C:3]([O:28][CH3:29])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH:18]=[CH:17][C:16]=1[NH:19][C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1OC
Reactant: C1COCCN1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCCN4CCOCC4)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A starting compound (N-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 1,3-dibromopropane(0.10 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate. The intermediate, potassium carbonate (138 mg), and morpholine (0.040 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 74 mg (yield 71%) of the title compound.
Reaction SMILES: N[C:2]1[N:7]([CH2:8][C:9]2C=CC(Cl)=CC=2)[C:6](=[O:16])[NH:5][C:4](=O)[C:3]=1NC(=O)C(C)C.CC(C)([O-:27])C.[K+].C(Br)C.Cl>CN(C=O)C>[CH2:8]([N:7]1[C:2](=[O:27])[CH:3]=[CH:4][NH:5][C:6]1=[O:16])[CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C(=O)Nc1c(N)n(Cc2ccc(Cl)cc2)c(=O)[nH]c1=O
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCBr
Product: CCn1c(=O)cc[nH]c1=O
Reaction time: 1.5 h

Procedure:
13.47 g (40 mM) of 6amino-1-(4-chlorobenzyl)-5-isobutyrylaminouracil were dissolved in 130 ml of DMF, treated at 5° C. with 4.57 g (40.8 mM) potassium t-butoxide and after dissolution, 3.28 ml (44 mM) of ethylbromide added. After 3 hr another 1.14 g of t-BuOK and 1.64 ml of ethylbromide were added. After a further 1.5 hr, 1.64 ml of ethylbromide were supplemented. After a total of 22 hr the solution was neutralized with 1N HCl to pH 7 and the solvents evaporated in vacuo. The residue was taken up in dichloromethane-water and the organic phase collected giving 17.66 of crude 3-ethyl uracil, which was dissolved in 17.6 ml of 1N NaOH and heated under reflux for 1 hr. The solution was treated twice with 1 g of charcoal, filtered and neutralized with 5N HCl to pH 7. The solid was diluted with water, collected, and dried. The crude material was recrystallized from methanol to give 7.42 g (49.2%) of 3-(4-chlorobenzyl)-1-ethyl-8-isopropyl-xanthine, mp 221-2° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11].Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH2:19]=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([CH2:19][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]#[N:11]
Reactant: C=O
Reactant: N#CCc1c(F)cccc1F
Reactant: C1COCCN1
Agent: Cl
Product: N#CC(CN1CCOCC1)c1c(F)cccc1F

Procedure:
In a manner similar to Preparation 11 react 2,6-difluorobenzeneacetonitrile with morpholine hydrochloride and paraformaldehyde to obtain the title compound.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[O:14]=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.[Cl-].[NH4+]>O1CCCC1>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:15]1([OH:14])[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18]1
Reactant: Fc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2F)C1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
3.1 ml (6.1 mmol) of a 2M solution of isopropylmagnesium chloride in tetrahydrofuran are added to a solution of 1.1 g (6.2 mmol) of 1-bromo-2-fluorobenzene in 4 ml of tetrahydrofuran, cooled beforehand to −25° C. After stirring for 30 minutes at −25° C., a solution of 0.65 g (3.7 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 7.5 ml of tetrahydrofuran is added. The reaction medium is stirred for 30 min and then a saturated aqueous solution of ammonium chloride is added. The organic compounds are extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is dried over magnesium sulphate and then filtered and evaporated. The crude product is purified by silica gel chromatography, elution being carried out with a 5/5 heptane/ethyl acetate mixture. 135 mg of 3-(2-fluorophenyl)-3-hydroxy-1-(tert-butoxycarbonyl)-azetidine are obtained in the form of a white solid with a yield of 14%.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[O:13][C:14]([CH3:17])(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:22])C>[Ir](Cl)(Cl)Cl.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:1]1([CH2:7][C:20]([O:13][CH2:14][CH3:17])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCO
Agent: Cl[Ir](Cl)Cl
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 52.5 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg), iridium trichloride (1 mg, 1 mol %), and Xantphos (2.9 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 24 h. After the reaction was completed, carbon monoxide was discharged, and 43 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 53%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 34 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 96%.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]1[CH2:21][CH:20]2[N:22](C(OCC)=O)[CH:17]([CH2:18][CH2:19]2)[CH2:16]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].[I:28][Si](C)(C)C>C(Cl)Cl>[I-:28].[C:1]([NH:4][CH:5]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]1[CH2:21][CH:20]2[NH2+:22][CH:17]([CH2:18][CH2:19]2)[CH2:16]1)[CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1CC(c1ccc(Cl)cc1C(CC)NC(C)=O)C2
Reactant: C[Si](C)(C)I
Solvent: ClCCl
Product: CCC(NC(C)=O)c1cc(Cl)ccc1C1CC2CCC(C1)[NH2+]2
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-{2-[1-(acetylamino)propyl]-4-chlorophenyl}-8-azabicyclo[3.2.1]octane-8-carboxylate (2-9) (0.200 g, 0.51 mmol) in DCM (5.0 mL) was added iodotrimethylsilane (0.360 mL, 2.55 mmol) slowly. The mixture was stirred at room temperature overnight. After the reaction was completed, the solvents were removed under vacuum and solid was washed with ether (2×5 mL) to give (2-10) as yellow solid.
Reaction SMILES: [Br:1][CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[OH:13][CH2:14][C:15]([NH:18][C:19]([NH2:21])=[S:20])([CH3:17])[CH3:16]>C(O)C>[BrH:1].[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:21]=[C:19]([NH:18][C:15]([CH3:17])([CH3:16])[CH2:14][OH:13])[S:20][C:2]=2[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(Br)C(=O)c1ccc(Br)cc1
Reactant: CC(C)(CO)NC(N)=S
Solvent: CCO
Product: Br
Product: Cc1sc(NC(C)(C)CO)nc1-c1ccc(Br)cc1
Yield: 100.3 %

Procedure:
A mixture of 2,4′-dibromopropiophenone (3.940 g, 13.5 mmol) and N-(2-hydroxy-1,1-dimethylethyl)thiourea (2.000 g, 13.5 mmol), prepared in step 2 of Example 52, in 80 mL of absolute ethanol was refluxed under nitrogen for 3 h. The solvent was removed under reduced pressure to give 2-{[4-(4-bromophenyl)-5-methyl-1,3-thiazol-2-yl]amino}-2-methylpropan-1-ol hydrobromide (5.717 g, 100%) as a tan oil, MS (ESI) m/z 341.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.Cl.Cl.[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C@H:25]2[CH2:29][CH2:28][CH2:27][NH:26]2)[CH:24]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:18][C:19]1[CH:24]=[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Fc1cncc([C@H]2CCCN2)c1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3CCCC3c3cncc(F)c3)nc12
Temperature: 95 °C
Yield: 68.4 %

Procedure:
Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B; 0.50 g, 2.22 mmol), (R)-3-fluoro-5-(pyrrolidin-2-yl)pyridine dihydrochloride (0.53 g, 2.22 mmol) and diisopropylethylamine (1.46 mL, 8.86 mmol) were combined in isopropanol (2 mL) and heated at 95° C. for 70 hours. The crude product was purified by reverse phase chromatography, eluting with 0-50% acetonitrile/water to yield the title compound (540 mg, 68.6% yield). MS (apci) m/z=356.0 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:33])[C@H:5]([CH3:32])[CH2:6][C@H:7]([NH:21][C:22]([C:24]1O[CH:26]=[C:27]([OH:31])[C:28](=[O:30])[CH:29]=1)=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[CH3:34][NH2:35]>O>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:21][C:22]([C:24]2[N:35]([CH3:34])[CH:26]=[C:27]([OH:31])[C:28](=[O:30])[CH:29]=2)=[O:23])[CH2:6][C@@H:5]([CH3:32])[C:4]([OH:3])=[O:33])=[CH:10][CH:11]=1
Reactant: CN
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)c(O)co1
Solvent: O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)c(O)cn1C)C(=O)O

Procedure:
To a suspension of (2R,4S)-5-biphenyl-4-yl-4-[(5-hydroxy-4-oxo-4H-pyran-2-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester (Example 23-1) (50 mg) in water (1 mL) is added methylamine (1 mL of a 40% solution in water) and the resulting mixture is heated to reflux for 6 hours. The mixture is under reduced pressure and is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) to elute the title compound; HPLC Retention time 1.21 minutes (condition C): MS 435.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (d, J=7.07 Hz, 3 H) 1.45-1.65 (m, 1 H) 1.82-1.98 (m, 1 H) 2.25-2.38 (m, 1 H) 2.63-2.78 (m, 1 H) 2.79-2.97 (m, 1 H) 4.14-4.32 (m, 1 H) 6.45 (br. s., 1 H) 7.26-7.39 (m, 2 H) 7.45 (t, J=7.58 Hz, 2 H) 7.55-7.68 (m, 4 H) 8.79 (d, J=9.09 Hz, 1 H).
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[C:27](=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[CH2:20]([O:19][C:17](=[O:18])[CH2:27][NH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C12CC3CC(C1)C(N)C(C3)C2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C12CC3CC(C1)C(NCC(=O)OCc1ccccc1)C(C3)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 4-aminoadamantane-1-carboxylate obtained in Reference Example 11 (1.87 g) in tetrahydrofuran (20 ml), water (10 ml), benzyl chloroformate (1.53 g) and sodium carbonate (1.13 g) were added and stirred at room temperature for 5 hours. Benzyl chloroformate (0.76 g) was further added and stirred at room temperature for 2 hours. After insoluble materials were filtered off, the solvent was concentrated and the residue was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=200:1 to 100:1) to give methyl 4-{[2-(benzyloxy)-2-oxoethyl]amino}-adamantane-1-carboxylate (3.30 g) as a colorless powder.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([C:19]1[CH:31]=[C:30]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([C:32](Cl)=[O:33])=[CH:27][C:28]=3[CH2:29]2)=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1>O1CCOCC1>[C:1]([NH:9][NH:10][C:32]([C:26]1[CH:25]=[CH:24][C:23]2[C:22]3[C:30](=[CH:31][C:19]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=3)[CH2:29][C:28]=2[CH:27]=1)=[O:33])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)NN
Reactant: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)Cl)ccc1-2
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)NNC(=O)CCCCCC)ccc1-2
Temperature: 0 °C
Yield: 69.8 %

Procedure:
Then, in a 50 ml-three-necked flask, 0.32 g (2.22 mM) of heptanohydrazide and 15 ml of dioxane were placed. To the mixture, a solution of the above-prepared 7-octyl-2-fluorenecarbonyl chloride in 5 ml of dioxane was added, followed by addition of 0.84 ml of pyridine at about 85° C. under stirring and further stirring for 30 minutes at 85°-88° C. After the reaction, the reaction mixture was cooled and poured into 200 ml of ice water to precipitate a crystal. The crystal was recrystallized from a mixture solvent of toluene-acetone to obtain 0.68 g of N-heptanoyl-N'-(7-octyl-2-fluorenecarbonyl) hydrazine (Yield: 69.8%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][CH3:20])[C:3]=1[CH3:21].[OH2:22].C[N+]1([O-])CC[O:27]CC1>CC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH3:20])(=[O:27])=[O:22])[C:3]=1[CH3:21]
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: CSc1ccccc1-c1nc2cc(F)ccc2c(Cl)c1C
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1Cl
Temperature: 25 °C
Reaction time: 35 h

Procedure:
To a solution of 4-chloro-7-fluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline (95 mg, 0.30 mmol) (described herein) in acetone (3.5 mL) and water (0.88 mL) was sequentially added NMO (105 mg, 0.90 mmol) and osmium tetroxide (4.7 μL, 0.015 mmol). The reaction mixture was stirred at rt for 35 h, then quenched with 15 mL 10% aqueous sodium thiosulfate solution, concentrated to remove the acetone, and partitioned between EtOAc and 10% aqueous sodium thiosulfate solution. The organic layer was washed with brine, dried (MgSO4), and concentrated, affording 4-chloro-7-fluoro-3-methyl-2-(2-(methylsulfonyl)-phenyl)quinoline. Mass Spectrum (ESI) m/e=350 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH2:37][CH2:38][O:39][CH3:40])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:40][O:39][CH2:38][CH2:37][NH:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1)(=[O:34])=[O:35]
Reactant: COCCNS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: COCCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-(2-methoxy-ethyl)-benzenesulfonamide (example B.28) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (400 mg, 70%). MS (ISP) 569.1 [(M+H)+]; mp 185–187° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]1=[O:17].[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[OH:1][CH2:2][CH2:3][N:4]1[C:5](=[O:17])[CH:6]=[CH:7][C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:12][CH2:11]2)=[CH:9]1
Reactant: O=C1CCC(c2ccc(=O)n(CCO)c2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(=O)n(CCO)c3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-(2-hydroxy-ethyl)-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=2)[C:8]1=[O:21].Cl>O1CCCC1.O>[O:21]=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=2)[CH:15]=[CH:16][N:7]1[CH2:6][CH:2]=[O:1]
Reactant: COC(=O)c1ccc2ccn(CC3OCCO3)c(=O)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2ccn(CC=O)c(=O)c2c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of methyl 2-(1,3-dioxolan-2-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.23 g, 0.8 mmol) in tetrahydrofuran (5 mL) was added 1.0 M hydrochloric acid in water (9.0 mL). The reaction mixture was heated to 65° C. and stirred overnight. The mixture was cooled to rt, water was added and the mixture was extracted with DCM (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (30% to 100% EtOAc/hexanes) to afford methyl 1-oxo-2-(2-oxoethyl)-1,2-dihydroisoquinoline-7-carboxylate (0.11 g, 56%). LC-MS: (FA) ES+ 246.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[CH:13]2)(=O)=O.[CH2:17]([CH2:19][NH2:20])[OH:18]>C(O)C.C(OCC)(=O)C>[OH:18][CH2:17][CH2:19][NH:20][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[CH:13]2
Reactant: NCCO
Reactant: CS(=O)(=O)OCCc1cccc2cc[nH]c12
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCNCCc1cccc2cc[nH]c12
Yield: 84.6 %

Procedure:
To a solution of 7-(2-(methanesulfonyloxy)eth-1-yl)indole (0.79 g, 3.3 mmol) in ethanol (50 mL) was added ethanolamine (5 mL, 82 mmol) and the reaction stirred at reflux overnight. The reaction was diluted with ethyl acetate (150 mL) and washed with water (3×50 mL), saturated aqueous sodium chloride (2×50 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 0.57 g (85%) 7-(2-(N-[2-hydroxyeth-1-yl]amino)eth-1-yl)indole as a light-brown solid.