Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:34])[CH2:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:20][CH:19]=1)[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:34])[CH2:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: NNC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(COc1ccc(C(=O)OCc2ccccc2)cc1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added benzyl 4-(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 215 mg of the title compound (77%) as a orange powder in 98.3% purity by HPLC (Rt: 5.16, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C(O[N:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][N:7]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[S:6]1(=[O:25])=[O:24])(=O)C.[C:26]([O:29]CC)(=[O:28])[CH3:27].Cl>C1COCC1.CO.O>[Cl:18][C:17]1[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=[C:13]([Cl:23])[C:12]=1[N:7]1[S:6](=[O:24])(=[O:25])[N:5]([CH2:27][C:26]([OH:29])=[O:28])[CH2:10][CH:9]([CH3:11])[CH2:8]1
Reactant: CCOC(C)=O
Reactant: CC(=O)ON1CC(C)CN(c2c(Cl)cc(C(F)(F)F)cc2Cl)S1(=O)=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1CN(CC(=O)O)S(=O)(=O)N(c2c(Cl)cc(C(F)(F)F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To ethyl 2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl acetate (220 mg, 0.45 mmol) in THF (10 mL) and MeOH (10 mL), was dropwisely added LiOH monohydrate (94 mg, 0.45 mmol) in water (3 mL) and agitated for 5 hr at room temperature. After addition of ethyl acetate (30 mL) and water (30 mL), pH of the resultant was adjusted to 3 with 1 N HCl and extracted to obtain the organic layer. The resultant was dried over MgSO4, concentrated under reduced pressure, and crystallized with ethyl acetate (1 mL) and hexane (10 mL), giving the compound of interest (163 mg, 86%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.67 (s, 1H), 7.64 (s, 1H), 4.53-4.47 (m, 1H), 4.12-3.91 (m, 3H), 3.46-3.42 (m, 1H), 3.26-3.19 (m, 1H), 2.59 (m, 1H), 0.96 (d, 3H, J=6.7 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12]2)=[CH:7][N:6]=1)=[O:4].[Li+].[OH-]>CO.C1COCC1.O>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:14]=[CH:15][N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=2)[N:12]=1
Reactant: COC(=O)c1ccc(-n2ccc(C(F)(F)F)n2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-n2ccc(C(F)(F)F)n2)cn1
Reaction time: 22 h
Yield: 99.2 %

Procedure:
To a solution of 5-(3-trifluoromethyl-pyrazol-1-yl)-pyridine-2-carboxylic acid methyl ester (67 mg) in MeOH (4 ml) and THF (0.5 ml) was added a solution of LiOH (23 mg) in water (1 ml) and stirring was continued at 22° C. for 22 h. The mixture was evaporated and the residue partitioned between 1 N aqueous HCl and ethyl acetate, the organic layer was washed with water, dried and evaporated to give 5-(3-trifluoromethyl-pyrazol-1-yl)-pyridine-2-carboxylic acid (63 mg) as a white solid. MS (ESI): m/z=255.9 [M−H]−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[N:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[Cl:20][C:21]1[C:22](B(O)O)=[CH:23][C:24]([F:27])=[N:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:20][C:21]1[C:22]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:5]=[N:4][C:3]=2[C:16]([F:19])([F:18])[F:17])=[CH:23][C:24]([F:27])=[N:25][CH:26]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: FC(F)(F)c1ncc(NCC2CCOCC2)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1cc(-c2nc(NCC3CCOCC3)cnc2C(F)(F)F)c(Cl)cn1
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 67 %

Procedure:
6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine (0.020 g, 0.068 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (0.036 g, 0.203 mmol), and sodium carbonate (0.088 ml, 0.176 mmol, 2 M in H2O) were dissolved in DME (0.70 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf) CH2Cl2 adduct (0.011 g, 0.014 mmol). The reaction mixture was then heated in a microwave at 110° C. for 25 min. Boronic acid (˜0.036 g, 0.203 mmol) and PdCl2(dppf) CH2Cl2 adduct (˜0.011 g, 0.014 mmol) were added. Heating in the microwave was continued at 110° C. for 25 min. The reaction mixture was then filtered through a pad of Celite. The filtrate was then concentrated in vacuo to give 0.0759 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 25 EtOAc/75 heptane to 100 EtOAc gave 0.0178 g (67%) of 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine. LCMS (m/z): 391.1 (MH+), retention time=0.96 min.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:11][CH2:12][CH3:13])C=CC=CC=1.[CH3:30][O:31][C:32]([CH3:40])([CH3:39])[CH2:33][CH2:34][CH2:35][C:36](=O)[CH3:37].O>CN(C)C=O>[CH2:16]1[CH2:15][O:14][C:10]([CH2:11][CH2:12][CH:13]=[C:36]([CH3:37])[CH2:35][CH2:34][CH2:33][C:32]([O:31][CH3:30])([CH3:40])[CH3:39])([CH3:9])[O:17]1
Reactant: COC(C)(C)CCCC(C)=O
Reactant: CCCC1(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)OCCO1
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)CCCC(C)=CCCC1(C)OCCO1
Temperature: 0 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
8.15 g of potassium tert.-butylate were added to a solution of 38 g of triphenyl 2,2-ethylenedioxy-pentyl phosphonium bromide in 400 ml of dimethylformamide cooled to 0° C. and then 12.75 g of 6-methoxy-6-methyl-2-heptanone were added. The mixture was stirred for 4 hours at 0° C. and was then poured into water. The mixture was extracted with petroleum ether (b.p.= 40°-75° C.) and the extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The yellow oil was chromatographed over silica and was eluted with a 8-2 benzene-ethyl acetate mixture to obtain 9.15 g of 2,2-ethylenedioxy-10-methoxy-6,10-dimethyl-5-undecene in the form of a colorless oil which was a mixture of the E and Z isomers with respect to the double bond in the 5-position. A supplementary chromatography under pressure and elution with a 9-1 benzene-ethyl acetate mixture gave a separation of the E and Z isomers.
Reaction SMILES: [Cu:1].[CH2:2]1[C@H](N[C@@H]2[C@H](O)[C@@H](O)[C@H](O)C(CO)=C2)[C@H](O)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1CO.[Cu].C1[C@H](N[C@@H]2[C@H](O)[C@@H](O)[C@H](O)C(CO)=C2)[C@H](O)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1CO.C1OC(=O)C2C(Cl)=C(Cl)C(Cl)=C(Cl)C1=2.[Cu+].[CH3:86][C:87]1([CH:102]=[CH2:103])O[C:91](=[O:92])[N:90]([C:94]2[CH:95]=[C:96]([Cl:101])[CH:97]=[C:98]([Cl:100])[CH:99]=2)[C:88]1=[O:89].[Cu].C1OC(=O)C2C(Cl)=C(Cl)C(Cl)=C(Cl)C1=2>>[Cu:1].[CH3:2][C:87]12[C:88](=[O:89])[N:90]([C:94]3[CH:95]=[C:96]([Cl:101])[CH:97]=[C:98]([Cl:100])[CH:99]=3)[C:91](=[O:92])[C:102]1([CH3:103])[CH2:86]2
Reactant: C=CC1(C)OC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: OCC1=C[C@H](N[C@H]2C[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Cu+]
Agent: [Cu]
Agent: O=C1OCc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Product: CC12CC1(C)C(=O)N(c1cc(Cl)cc(Cl)c1)C2=O

Procedure:
The fungicidal preparations containing the inorganic copper fungicide and chemicals (such as fungicides, etc.) other than ingredients (a) and (b) include a Bordeaux mixture containing basic copper calcium sulfate; copper-sulfur fungicides, such as Engei Bordeaux (trade name, produced by Sankei Chemical Co., Ltd.), etc.; copper-validamycin fungicides; copper-validamycin-fthalide fungicides; copper-pyrifencox fungicides; copper(I)-vinclozolin fungicides; copper-fThalide fungicides; copper-procymidone fungicides, such as Scletane Wettable Powder (trade name, produced by Hokko Chemical Industry Co., Ltd.); copper(I)-fosetyl vegtable powders; copper-metalaxyl fungicides, such as Ridomil Copper Wettable Powder (trade name, produced by Nihon Nohyaku Co., Ltd.); iprodione copper(I) fungicides, such as Daisedo Wettable Powder (trade name, produced by Yashima Chemical Industry Co., Ltd.); iminoctadine triacetate-copper fungicides; oxadixyl copper(I) fungicides; oxolinic acid-copper fungicides; kasugamycin-copper fungicides, such as Kasumin Bordeaux Dust 3DL (trade name, produced by Hokko Chemical Industry Co., Ltd.), Kasumin Bordeaux (trade name, produced by Dai-ichi Noyaku K.K. and Hokko Chemical Industry Co., Ltd.), etc.; dithianon copper(I) fungicides; streptomycin-copper fungicides, such as Do Stomy Wettable Powder (trade name, produced by Nihon Nohyaku Co., Ltd.), etc.; sodium hydrogencarbonate-copper fungicides, such as G-Fine Wettable Powder (trade name, produced by Yashima Chemical Industry Co., Ltd.); and copper-organocopper fungicides, such as Oxy Bordeaux (trade name, produced by Sankyo Co., Ltd.), Kinset Wettable Powder (trade name, produced by Agro-Kanesho Co., Ltd.), Kinset Wettable Powder 80 (trade name:, produced by Agro-Kanesho Co., Ltd.), etc.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]Br)[CH:6]=1.[CH3:22][C@@H:23]1[C@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:26][C:25](=[O:34])[NH:24]1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:24]2[C@H:23]([CH3:22])[C@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:26][C:25]2=[O:34])[CH:6]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid methyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1.N[CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CN(C)C=O>[Cl:8][CH:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([CH3:19])=[C:11]([CH3:20])[N:10]1[CH2:22][CH2:23][CH2:24][CH2:25][OH:26]
Reactant: NCCCCO
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C)N(CCCCO)C(Cl)C([N+](=O)[O-])=C1
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Under a nitrogen atmosphere, triethylamine (14.19 mL, 101.8 mmol, 1.5 eq) was added in a single portion to a mixture of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (15.0 g, 67.86 mmol, 1.0 eq) and N,N-dimethylformamide (DMF) (200 mL). The reaction mixture was stirred for 10 minutes, 4-amino-1-butanol (8.76 mL, 95 mmol, 1.4 eq) in DMF (20 mL) was added, and the reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to provide crude product as an oil. The oil was partitioned between ethyl acetate (300 mL) and water (50 mL). The aqueous layer was back-extracted with ethyl acetate (2×50 mL). The combined organic phases were separated, washed with water (3×30 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide an orange solid. This material was recrystallized from ethyl acetate/hexanes to provide 12.2 g of 4-(2-chloro-5,6-dimethyl-3-nitropyridin-1-yl)butan-1-ol.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([O:16][C:17]2[CH:28]=[CH:27][C:20]([O:21][CH:22]([CH3:26])[C:23](O)=[O:24])=[C:19]([F:29])[CH:18]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.C1C=CC=CC=1>CN(C)C=O>[Cl:5][C:6]1[C:7]([O:16][C:17]2[CH:28]=[CH:27][C:20]([O:21][CH:22]([CH3:26])[C:23]([Cl:3])=[O:24])=[C:19]([F:29])[CH:18]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1F)C(=O)O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1F)C(=O)Cl
Reaction time: 3 h

Procedure:
Thionyl chloride (7.24 g, 0.0608 mole) was added to a stirred solution of 2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-2-fluorophenoxy)propanoic acid (21.0 g, 0.0553 mole), benzene (150 ml), and dimethyl formamide (0.3 g). Refluxing was effected for three hours. The benzene and residual thionyl chloride were removed by distillation under vacuum. The resulting amber colored oil (21 g) was shown to be the desired acid chloride by NMR and IR spectroscopy. This material was used directly in subsequent reactions.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].F[C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:22][C:21]1[C:16]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:17][CH:18]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:20]=1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 2.011 g, 10.98 mmol) and DIPEA (1.744 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140° C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (0-15% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[O:11][CH2:12][C:13](=[O:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCCCC1>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2OC)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccc2OC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of ethyl 2-[(2-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.28 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.2 mmol) in ethanol (4.0 mL), piperidine (0.12 mL, 1.2 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.30 g, y. 74%).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11]C)=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:20][CH:19]=1>C(#N)C>[CH3:13][C:5]1[C:6](=[O:11])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3](=[O:2])[C:4]=1[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[C:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:30][CH:31]=1
Reactant: COc1c(C)c(C)c(OC)c(CCCOc2ccc(CC3SC(=O)NC3=O)cc2)c1C
Solvent: CC#N
Product: CC1=C(C)C(=O)C(CCCOc2ccc(C=C3SC(=O)NC3=O)cc2)=C(C)C1=O
Yield: 11.6 %

Procedure:
Following a procedure similar to that described in Example 1, but using 15.8 g of 5-{4-[3-(2,5-dimethoxy-3,4,6-trimethylphenyl)propoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Preparation 4), 78.1 g of ceric ammonium nitrate and 350 ml of acetonitrile, 1.7 g of the title compound, melting at 230°-232° C., were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].C1C(=O)N([Cl:18])C(=O)C1>CC(O)=O>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[Cl:18]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(N)c(Cl)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mL) was stirred at 70° C. for approximately 16 h. The mixture was concentrated. H2O was added to the residue and the solid product was filtered off and washed (sat. NaHCO3 and H2O). To eliminate H2O, THF was added and removed under reduced pressure to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][NH:34][CH2:35][CH2:36][CH2:37]OC)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:43][O:44][CH2:45]CCN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][N:34]5[CH2:2][CH2:37][CH2:36][C@H:35]5[CH2:43][O:44][CH3:45])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:12])=[O:11])[CH3:9]
Reactant: COCCCN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCCCOC)cs4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CN5CCC[C@H]5COC)cs4)cc23)CC1
Yield: 4.6 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (2S)-2-[(methyloxy)methyl]pyrrolidine (115.18 mg, 1 mmol) for 3-(methyloxy)-1-propanamine to afford 3 mg of the title compound (4.6%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C=C2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CC2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 59.2 %

Procedure:
To 15.0 g (0.045 moles) of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]} methylene-2, 4-thiazolidinedione, in 375 ml of ethyl acetate, 3.0 g of 10% palladium on carbon was added. The mixture was heated at 80° C. in the presence of 50 psi (345 KPa) of hydrogen for 4.5 hours. An additional 3.0 g of 10% palladium on carbon was added and the mixture was again heated at 80° C. in the presence of 50 psi (345 KPa) of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to afford a solid. The solid was recrystallized from toluene and dried at 60° C. to obtain 8.93 g (59% yield) of subtitled compound.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:33])[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([NH:5][C:6](=[O:33])[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C(=O)NCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CCCCNC(=O)C(=O)NCCCCCO
Yield: 93 %

Procedure:
A mixture of N1-n-butyl-N2-(5-(tert-butyldiphenylsilyloxy)pentyl)oxalamide (65 mg, 0.14 mmol) and n-tetrabutylammonium fluoride (0.41 mL, 1 M soln, 0.42 mmol) in dry THF solution was stirred at room temperature under an argon atmosphere for 12 h. All volatiles were evaporated in vacuo, the residue was dissolved in EtOAc (30 mL) and the organic layer was washed with water (10 mL), brine (15 mL), dried and evaporated. Purification of the residue via SiO2 column chromatography using EtOAc/hexanes (1:2) as eluent gave the title compound (30 mg, 92%) as a colorless solid, mp 136-137° C. TLC: 50% EtOAc/hexane, Rf˜0.28; 1H NMR (300 MHz) δ 7.65 (br s, NH, 1H), 7.60 (br s, —NH, 1H), 3.65 (t, J=6.0 Hz, 2H), 3.35-3.25 (m, 4H), 1.90 (br s —OH, 1H), 1.60-1.50 (m, 6H), 1.40-1.35 (m, 4H), 0.92 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz) δ 160.25, 160.10, 62.70, 39.80, 39.65, 32.40, 31.45, 29.20, 23.25, 20.20, 13.85. HRMS calcd for C11H23N2O3 [M+1]+ 231.1709, found 231.1701.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:44][CH:45]1[C@H:49]2[C@H:50](OC3CCCCO3)[N:51](C(OC(C)(C)C)=O)[C:52]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:53]=3[C:54](=[O:55])[N:48]2[CH2:47][CH2:46]1)[CH2:9][CH2:10][CH2:11][O:12][CH:13]1[C@H:17]2[C@H:18](OC3CCCCO3)[N:19](C(OC(C)(C)C)=O)[C:20]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=3[C:22](=[O:23])[N:16]2[CH2:15][CH2:14]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:44][CH:45]1[C@@H:49]2[CH:50]=[N:51][C:52]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:53]=3[C:54](=[O:55])[N:48]2[CH2:47][CH2:46]1)[CH2:9][CH2:10][CH2:11][O:12][CH:13]1[C@@H:17]2[CH:18]=[N:19][C:20]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=3[C:22](=[O:23])[N:16]2[CH2:15][CH2:14]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 58.8 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15b (170 mg, 0.17 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16b (58 mg, 0.1 mmol, 62%) as a solid: [α]20D=+517° (c=0.18, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 2.04-2.09 (m, 8H, 2-H, 2′-H, 13-H, 13′-H), 2.30-2.36 (m, 4H, 1-H, 1′-H), 3.57-3.62 (m, 2H, 3-H, 3′-H), 3.71-3.74 (m, 2H, 11a-H, 11a′-H), 3.79-3.85 (m, 2H, 3-H, 3′-H), 3.93 (s, 6H, 7-OMe, 7′-OMe), 4.11-4.21 (m, 4H, 12-H, 12′-H), 6.82 (s, 2H, 9-H, 9′-H), 7.52 (s, 2H, 6-H, 6′-H), 7.66 (d, 2H, J=4; 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.7, 29.4, 46.6, 53.7, 56.1, 68.5, 110.5, 111.5, 120.2, 140.6, 147.8, 150.7, 162.3, 164.6; IR (neat): 3316, 2972, 1601, 1505, 1433, 1381, 1262, 1217, 1091 cm−1; MS (FAB) m/z (relative intensity) 611 ([M+2×MeOH]+., 32), 579 ([M+MeOH]+., 11), 547 (M+., 100).