Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][S:10]([CH2:13][C:14]#[N:15])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[F:18][C:19]([S:22][CH2:23][CH2:24]OS(C(F)(F)F)(=O)=O)([F:21])[F:20]>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][S:10]([CH:13]([CH2:24][CH2:23][S:22][C:19]([F:21])([F:20])[F:18])[C:14]#[N:15])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCS(=O)(=O)Cc1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
Compound II-5 was prepared from (3-trifluoromethyl-phenylmethanesulfonyl)-acetonitrile and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]#[N:20])[CH:10]=1)=O)(=[O:3])[CH3:2].C[Si]([N:25]=[N+:26]=[N-:27])(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCOC(C)=O>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]#[N:20])[CH:10]=2)[N:27]=[N:26][N:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Nc1cc(C#N)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1cc(C#N)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.7 %

Procedure:
To a solution of 2-{[3-cyano-5-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 29, 3.38 g, 11.8 mmol) in tetrahydrofuran (100 mL) was added trimethylsilylazide (3.14 mL, 23.6 mmol), triphenylphosphine (6.20 g, 23.6 mmol) then di-isopropylazodicarboxylate (4.60 mL, 23.6 mmol). The reaction was warmed to 50° C. and stirred for 6 hours. The reaction was cooled and diluted with EtOAc (150 mL). The solution was washed with water (100 mL), passed through a hydrophobic frit and the solvent removed under vacuum. The residue was purified by silica chromatography (Biotage SP4, eluting 10% EtOAc in iso-hexane (4 column volumes) then a gradient from 10-35% EtOAc in iso-hexane (over 8 column volumes)) to yield the title compound as a yellow solid (3.33 g)
Reaction SMILES: CS([O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:7])(=O)=O.[CH:21]1[C:22]([I:30])=[CH:23][C:24]([I:29])=[C:25](O)[C:26]=1[I:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:27][C:26]1[CH:25]=[C:24]([I:29])[CH:23]=[C:22]([I:30])[C:21]=1[O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:7]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CCCCCCCCCCCCCC(C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCC(C)Oc1c(I)cc(I)cc1I
Temperature: 85 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
To a solution of 2-methanesulfonyloxypentadecane (15.5 g, 48.1 mmol) in dry DMF (200 ml) was added triiodophenol (22.6 g, 47.9 mmol) and potassium carbonate (6.6 g, 47.8 mmol). The reaction flask was immersed in an oil bath which was heated to 85° C. over a period of 0.5 hr. The reaction was stirred under N2 atmosphere for 16 hrs. At the end of this period the reaction was processed as for Example 1 except at 4 times the volumes to provide a brown residue. Flash column chromatography (silica, hexanes) provided 2-(2,4,6-triiodophenoxy)pentadecane (19.2 g, 58.8%) as a white solid. Mp: 56°-58° C.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[O:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][NH2:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][NH:36][CH2:16][CH:15]([OH:17])[CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][CH2:10]2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1
Reactant: COc1ccc(CCN)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCNCC(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1OC
Yield: 24.5 %

Procedure:
3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 2 g (0.01 mol) of 2-(3,4-dimethoxyphenyl)ethylamine were refluxed with heating together with 200 ml of DMF for 24 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate, and after washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5.1 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate--methanol and methylene chloride--methanol respectively to obtain 1.2 g of the subject compound in a viscous liquid state.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:17]1[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][C:18]=1[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH:23]=[CH:24][C:17]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)#[N:20]
Reactant: CCS(=O)(=O)c1ccc(Cl)c(C#N)c1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc(C(F)(F)F)c2)c(C#N)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from example 12 step (i).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N:9]([O-])=[O:10].[Na+]>>[CH3:1][C:2]1[C:3](=[O:8])[CH:4]=[CH:5][C:6](=[N:9][OH:10])[CH:7]=1
Reactant: Cc1ccccc1O
Reactant: O=N[O-]
Agent: [Na+]
Product: CC1=CC(=NO)C=CC1=O

Procedure:
2-Methyl-1,4-benzoquinone-4-oxime was prepared by reaction of 2-methylphenol with sodium nitrite under acidic conditions by the method described by T. Ishikawa et al. in J. Org. Chem. 1996, 61, page 2778.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.F[C:12]1[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[O:6]1[C:5]2[CH:9]=[CH:10][C:2]([O:1][C:15]3[CH:16]=[CH:17][CH:12]=[C:13]([F:18])[N:14]=3)=[CH:3][C:4]=2[O:8][CH2:7]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: Fc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1cccc(Oc2ccc3c(c2)OCO3)n1
Temperature: 50 °C

Procedure:
To DMSO (5 mL) was added 5-hydroxy-1,3-benzodioxolane (1.09 g, 7.9 mmol), difluoropyridine (0.72 mL, 7.9 mmol), and cesium carbonate (2.62 g, 8.0 mmol). After heating at 50° C. for 18 hours, the reaction was partitioned with water and ethyl acetate. The organic layer was washed with water, brine, and dried (Na2SO4). The solvent was removed to give 2-(1,3-benzodioxol-5-yloxy)-6-fluoropyridine.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([CH3:17])=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][NH:22][NH2:23]>>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][N:22]1[C:2]2[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]3[O:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]([C:15]=23)=[N:23]1
Reactant: CN(C)CCNN
Reactant: Cc1ccc(Cl)c2c(=O)c3ccccc3oc12
Product: Cc1ccc2c3c(nn2CCN(C)C)-c2ccccc2Oc13

Procedure:
By condensation of 1-chloro-4-methyl-9-xanthenone with 2-(dimethylamino)ethylhydrazine was obtained 2-(2-(dimethylamino)ethyl)-5-methyl-2H(1)benzopyrano[4,3,2-cd]indazole. To 0.11 g. of this base in ethanol (10 ml.) was added 30% aqueous hydrogen peroxide (0.2 ml.). After 22 hours at room temperature the solution was evaporated to dryness under reduced pressure and the residue crystallized from ethanol-ether to give 2-(2-(dimethylamino)ethyl)-5-methyl-2H(1)benzopyrano[4,3,2-cd]indazole N-oxide sesquihydrate, m.p. 139°-140° (decomp.).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[O:40][C:24]3=[CH:25][N:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:30]=4[F:39])[CH:28]=[C:23]3[CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl>[F:39][C:30]1[CH:31]=[C:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=[CH:34][C:29]=1[C:27]1[CH:28]=[C:23]2[CH:22]=[C:21]([CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[O:40][C:24]2=[CH:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (1.2 mL) is added to 4-[5-(2-fluoro-4-methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.78 g) in dichloromethane (14 mL). The mixture is stirred at room temperature overnight. Aqueous NaHCO3 solution is added, the resulting mixture is stirred for 5 min, and the phases are separated. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with water and dried (Na2SO4). The solvent is evaporated to give the title compound. LC (method 1): tR=0.59 min; Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:11])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:14](I)[CH3:15].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:11])=[N:8][N:9]([CH2:14][CH3:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cn(CC)nc1N
Reaction time: 0.5 h

Procedure:
To a solution of 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester (5.0 g, 32 mmol) in acetonitrile is added sodium hydride (1.28 g, 32 mmol) at RT. After 30 min of stirring, a solution of ethyl iodide (2.57 ml, 32 mmol) in acetonitriloe is added dropwise. The reaction mixture is stirred at RT for 16 h. Water is added followed by anhydrous sodium sulfate. The mixture is filtered and concentrated at reduced pressure. The crude product is chromatographed on silica gel using 30% ethyl acetate in hexanes to provide a regioisomeric mixture of N-ethylated 3-amino-1H-pyrazole-4-carboxylic acid ethyl esters. This mixture is used in the following reaction step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Br)cc1

Procedure:
The product (6.49 g) is obtained according to the method of stage 1 of Example 4, by using 3.73 mL of 2-fluoro-nitrobenzene and 7.31 g of 4-bromoaniline in the presence of 6.36 g of potassium tert-butanolate in 120 mL of DMSO.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3](=O)[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Cl.[CH:27]1([NH:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.N1CCCCC1>C(O)C>[CH:27]1([N:33]2[CH:5]([C:6]3[CH:7]=[C:8]([C:12]4[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:4][C:3]([C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])=[N:34]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NNC1CCCCC1
Reactant: CSc1ccc(-c2cccc(C=CC(=O)C(F)(F)C(F)(F)F)c2)cc1
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3C3CCCCC3)c2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
4,4,5,5,5-Pentafluoro-1-(4′-methylsulfanyl-biphenyl-3-yl)-pent-1-en-3-one (200.0 mg, 0.54 mmol) prepared in Step 3 of Preparation 4, cyclohexylhydrazine hydrochloride (98.0 mg, 0.59 mmol), and piperidine (107.0 uL, 1.08 mmol) were added to ethanol (5.0 mL). The reaction mixture was stirred at 100° C. for 18 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:18]([OH:28])=[CH:19][C:20]4[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=4[CH:27]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:18](=[CH:19][C:20]5[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=5[CH:27]=4)[O:28][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: Cn1c(=O)oc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Product: Cn1c(=O)oc2cc3c(cc21)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 5-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1H,1′H)-dione was obtained (65%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.47-7.28 (m, 11H), 7.18-7.11 (m, 2H), 7.06-6.99 (m, 1H), 6.89 (s, 1H), 6.64 (d, J=7.9 Hz, 1H), 6.45 (s, 1H), 4.92 (d, J=9.4 Hz, 1H), 4.81 (d, J=9.4 Hz, 1H), 3.18 (s, 3H); MS (ES+) m/z 475.0 (M+1).
Reaction SMILES: [I-].C[NH+:3]1[CH2:8][CH:7]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[N:10]=2)[CH2:6][N:5]([C:15](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4]1.[ClH:34]>C(O)(C(F)(F)F)=O>[ClH:34].[CH3:15][N:5]1[CH2:6][CH:7]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[N:10]=2)[CH2:8][N:3]=[CH:4]1
Reactant: Cc1noc(C2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[NH+](C)C2)n1
Agent: Cl
Agent: [I-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C2CN=CN(C)C2)n1
Temperature: 25 °C

Procedure:
1-Methyl-3 -triphenylmethyl-5(3-methyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidinium Iodide (330 mg, 0.6 mmol) was dissolved in TFA (1 mL) with stirring in a stoppered round bottom flask at room temperature. After 18 hours stirring the excess TFA was evaporated in vacuo, and the dark residue triturated with ether. The ether was decanted leaving an oily residue that was taken up in ice cold sat. Na2CO3 and then extracted with chloroform. After drying and evaporation the chloroform fraction gave the free base which was converted to its HCl salt and recrystallized (methanol/ether) to yellow crystals 15 mg (12%) identified by 300 MHz nmr and ms m/z=180.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.[CH:20]1([CH2:26]O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH2:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Reactant: OCC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)OCC2CCCCC2)C1
Reaction time: 16 h
Yield: 11.4 %

Procedure:
To a solution of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid (200 mg, 0.7 mmol) and cyclohexyl methanol (80 mg, 0.7 mmol) in dichloromethane (10 ml) were added N,N′-dicyclohexylcarbodiimide (177 mg, 0.86 mmol) and 4-dimethylaminopyridine (105 mg, 0.86 mmol) and the contents were stirred at 25 deg C. for 16 h. The reaction mixture was concentrated to dryness to obtain the crude compound which was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml) to give 30 mg (11.3%) of cyclohexylmethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate as TFA salt. 1H NMR (DMSO) TFA SALT 10.39 (bs, 1H), 7.60 (s, 1H), 7.50 (d, 1H), 7.2 (d, 1H), 5.3-5.1 (dd, 2H), 4.70 (d, 1H), 4.30 (bs, 1H), 4.0 (d, 2H), 3.85 (bs, 1H), 3.50 (bs, 1H), 3.10 (s, 2H), 2.85 (s, 3H), 1.60-0.90 (m, 11H).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1.Cl[C:18]([O:20][CH3:21])=[O:19].CN(C1C=CC=CN=1)C.CCN(CC)CC>CCOC(C)=O>[CH3:21][O:20][C:18]([C:3]1[C:4](=[O:16])[S:5][C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:2]=1[OH:1])=[O:19]
Reactant: COC(=O)Cl
Reactant: CCCCCCCCC1(C)SC(=O)C=C1O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCC1(C)SC(=O)C(C(=O)OC)=C1O
Yield: 59.4 %

Procedure:
To 32 (91 mg, 0.37 mmol), methyl chloroformate (63 μL, 0.81 mmol), dimethylaminopyridine (DMAP) (23 mg, 0.18 mmol) and NEt3 (108 μL, 0.77 mmol) following General Procedure L was obtained 70 (66 mg, 59%, 79% based on recovered starting material) after flash chromatography (30% EtOAc/2% AcOH/Hexanes-10% THF/2% AcOH/EtOAc). 1H NMR (300 MHz, MeOD) δ 0.86 (t, J=6.9 Hz, 3H), 1.20 (bs, 12H), 1.35 (s, 3H), 1.55 (m, 1H), 1.71-1.75 (m, 1H), 3.59 (s, 3H); 13C NMR (75 MHz, MeOD) δ 13.3, 21.8, 24.4, 27.0, 28.5, 28.6, 29.0, 30.2, 31.0, 50.4, 58.3, 124.6, 168.1, 187.7, 196.7. HRMS (EI) m/z calculated for C15H24O4S+) 300.1389 obsd. 300.1375.
Reaction SMILES: [H-].[Li+].[O:3]=[C:4]1[NH:9][CH:8]=[CH:7][N:6]=[C:5]1[C:10]([O:12][CH3:13])=[O:11].Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]1=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc[nH]c1=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1nccn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
LiH (7.8 mg, 0.980 mmol) was added to the solution of methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate (100 mg, 0.65 mmol) in DMF (3 mL) at 0° C. After 30 minutes stirring, (chloromethyl)benzene (0.15 mL, 1.30 mmol) was added to the reaction mixture at 0° C., and then the reaction was warmed to room temperature. After stirring for 4 hours, the reaction mixture was quenched with ice water, extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to give the crude material that was purified by silica gel flash column chromatography (2% MeOH in CH2Cl2) to afford 0.102 g (64%) of the desired product.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH:12]([NH:15][NH2:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23]([CH:24]=O)=[C:22](Cl)[N:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:17][C:18]1[N:19]=[CH:20][N:21]=[C:22]2[N:15]([CH:12]3[CH2:13][CH2:14][CH:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:10][CH2:11]3)[N:16]=[CH:24][C:23]=12
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: CC(C)c1noc(C2CCC(NN)CC2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)c1noc(C2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Temperature: 140 °C
Yield: 36 %

Procedure:
A mixture of [4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-hydrazine (Intermediate 12; 230 mg, 1.0 mmol), 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 182 mg, 1.0 mmol) and sodium carbonate (218 mg, 2.1 mmol) in acetonitrile was heated in the microwave at 140° C. for 10 min. Saturated aqueous sodium carbonate was added and the reaction mixture was filtered. The filtrate was extracted with ethyl acetate, and the combined organic layers were dried (sodium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 10% ethyl acetate/hexanes to give 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (125 mg, 35%) as a white solid. Mass spectrum M+=346.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:24]=[C:23]([C:25]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[C:22]([C:33]([F:36])([F:35])[F:34])=[CH:21][C:10]=2[C:11]([O:13]CC2C=CC=CC=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].O.Cl>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:24]=[C:23]([C:25]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:26])[C:22]([C:33]([F:36])([F:34])[F:35])=[CH:21][C:10]=2[C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(F)(F)F)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To a solution of phenylmethyl 2-[(phenylmethyl)oxy]-4-(1-piperidinylcarbonyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 57; 170 mg, 0.34 mmol) in tetrahydrofuran (4 ml) was added LiOH (24.55 mg, 1.03 mmol) and water (1 ml). The solution was heated at 45° C. for one hour then room temperature for 18 hours. 2M hydrochloric acid (0.51 ml, 1.03 mmol) was added and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (20 ml) and 2M HCl (10 ml). The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo to give the title compound. 139 mg.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].OS(O)(=O)=O.[CH2:13](O)[CH3:14]>C1C=CC=CC=1>[C:1]([O:7][CH2:13][CH3:14])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: CCO
Reactant: C=CCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: C=CCCC(=O)OCC
Reaction time: 15 h

Procedure:
To a solution containing 4-pentenoic acid (20.73 g, 207 mmol) in ethanol (100 mL) and benzene (200 mL) was added H2SO4 (250 μL). The solution was refluxed and monitored by GC (50° C., 1 min to 250° C. at 10° C./min; DB-5; tR of acid 4.4 min, ester 3.8 min). After 15 h, the reaction was complete; about 1/2 of the solvent was removed under reduced pressure and diluted with 150 mL ether. This was extracted with H2O (1×150 mL), saturated NaHCO3 (2×150 mL), H2O(1×150 mL), and brine (1×100 mL). The organic layer was dried over K2CO3, the solvent was removed under water aspirator vacuum, and the residue was distilled to yield ethyl 4-pentenoate, a compound having the following structure: ##STR11## (20.79 g, 162 mmol, 78%; bp760 144° C.): 1H--NMR (200 MHc, CDCl3) δ 1.25 (t, J=7.2 Hz, 3 H, CH3), 2.36 (m, 4 H, CH2CH2), 4.14 (q, J=7.2 Hz, 2 H, OCH2), 4.95-5.13 (m, 2 H, H2C=), 5.81 (m, 1 H, =CH); 13C--NMR (50 MHc, CDCl3) δ 14.2 (CH3), 28.6, 33.5 (C--H2CH2), 115.3 (H2C=), 136.5 (=CH), 172.8 (C=O).