Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].C1(C)C=CC=CC=1.C([O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])C.[OH-].[Na+]>C(OCC)(=O)C.O>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[CH2:3][CH2:2][NH:1][C:20](=[O:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCC
Reactant: CN1CCCC1CCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NCCC1CCCN1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
Toluene (0.7 ml), dried using MS 4A, was mixed with 0.83 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 0.14 ml (0.98 mmol) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 2 minutes. After stirring for 20 minutes, the temperature was raised to room temperature, and 0.4 ml of a toluene solution of 0.2 g (0.65 mmol) of linoleic acid ethyl ester was added dropwise over 1 minute. After stirring for 2 hours at 70° C., the mixture was cooled with ice, and 10 ml of a 1N NaOH solution was added dropwise (inner temperature 12˜27° C.). The mixture was stirred for 10 minutes, and water and ethyl acetate were added. Then, the mixture was separated into respective layers, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride. After this layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure on a 30° C. water bath to obtain the captioned compound (yield 0.114 g). This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:1→9:1)) for purification. NMR and mass spectrum confirmed the purified compound to have the following structure:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH:8]([CH2:11]O)[CH2:9]O)[CH:5]=C[CH:7]=1.[C:15]1([CH:21]([NH2:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CCN(C(C)C)C(C)C>CC#N>[CH:21]([N:28]1[CH2:9][CH:8]([C:4](=[CH2:5])[C:3]([CH2:13][CH3:14])=[C:2]([Br:1])[CH3:7])[CH2:11]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1c(Br)cccc1C(CO)CO
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C(C(CC)=C(C)Br)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C
Reaction time: 12 h
Yield: 24.5 %

Procedure:
A mixture of 2-(3-bromo-2-ethyl-phenyl)-propane-1,3-diol (D128) (8 g, 30.87 mmol) in 150 mL of CH3CN was added diphenylmethylamine (5.66 g, 30.87 mmol), trifluoromethanesulfonic anhydride, DIPEA at 0° C., and the reaction mixture was stirred for 12 hr at 70° C., then the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to afford 1-benzhydryl-3-(3-bromo-2-ethyl-1-methylene-but-2-enyl)-azetidine (D129) (3 g,).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][CH:35]=1)[O:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[F:36][C:19]([F:18])([F:37])[C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][CH:35]=1)[O:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:27]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccnc1Oc1cccc(C(F)(F)F)c1

Procedure:
A solution of 1.5 grams (0.011 mole) 3-nitroaniline and 1.0 gram (0.011 mole) triethylamine in 100 milliliters toluene was placed in a flask. There was slowly added, with stirring, a solution of 3.2 grams (0.011 mole) 2-(3-trifluoromethylphenoxy)nicotinoyl chloride in 25 milliliters toluene. The rate of addition was controlled so as to maintain the temperature below 35° C. After the addition was complete the mixture was stirred at 45° C., for one hour, cooled, poured into 100 milliliters toluene, and washed with two 150-milliliter portions of water. The organic phase was separated, dried with magnesium sulfate, filtered and the solvent removed to produce 3.3 grams (73.3% of theoretical yield) of the desired product, m.p. 90°-95° C. The structure was confirmed by mass spectrometry.
Reaction SMILES: [F:1][C:2]([F:39])=[CH:3][C:4]1[N:5]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29]CC4C=CC(OC)=CC=4)=[CH:25][CH:24]=3)=[N:21][CH:22]=2)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1>C(O)C.O1CCCC1.[C].[Pd]>[F:39][CH:2]([F:1])[CH2:3][C:4]1[N:5]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:14])[CH3:15])[CH:8]=1
Reactant: COc1ccc(COc2ccc(-c3ccc(-c4nc(C=C(F)F)cn4COCC[Si](C)(C)C)cn3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(CC(F)F)nc1-c1ccc(-c2ccc(O)cc2)nc1
Reaction time: 24 h
Yield: 56.6 %

Procedure:
In ethanol (50 mL) and tetrahydrofuran (20 mL) was dissolved 5-[4-(2,2-difluoroethenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-2-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine (0.84 g), 10% palladium-carbon (50% water contained, 395 mg) was added to the solution, and the mixture was stirred under hydrogen atmosphere for 24 hours. The reaction mixture was filtered by using a membrane filter, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4-{5-[4-(2,2-difluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenol (373 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=C[CH:21]=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([C:8](=[O:9])[CH3:21])[CH:7]=1
Reactant: c1cc[nH+]cc1
Reactant: OCc1cc(Br)ccc1F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: ClCCl
Product: CC(=O)c1cc(Br)ccc1F
Temperature: 20 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
5-Bromo-2-fluoro-phenyl-methanol (50.0 g, 228 mmol) along with 300 mL DCM was charged into 2 liter round bottom flask. Crushed pyridinium dichromate (171.0 g, 456 mmol) and powdered molecular sieves (10 g) were both added into the flask. The heterogeneous reaction mixture was stirred for 16 hours at 20° C. The resulting reaction mixture was filtered through Celite and washed with ether (500 mL×3). The combined filtrate was concentrated under reduced pressure. The crude product was eluted through a short silica gel pad (3 inch in length) with 10% EtOAc in hexane. The resulting product (42.0 g, yield=84%) was used in the following step.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([C@H:26]3[CH2:31][CH2:30][C@H:29]([CH:32]=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][CH:29]([CH:32]=[CH2:1])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC1CCC(C=Cc2ccc([C@H]3CC[C@H](C=O)CC3)cc2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(c2ccc(C=CC3CCC(CCCCC)CC3)cc2)CC1

Procedure:
Potassium tert-butoxide (1.0 eq, 0.44 g, 3.62 mmol) was added slowly with stirring for 3 minutes to 32 ml of solution including methyltriphenylphosphonium bromide (1.2 eq, 1.55 g, 4.33 mmol) dissolved in THF. Then, the solution was stirred for 30 minutes at a room temperature and THF solution (35 ml) of trans-4-{4-[2-(4-pentyl-cyclohexyl)ethenyl]phenyl}cyclohexane carbaldehyde (1.32 g, 3.62 mmol) obtained in Example 4-2 was added slowly dropwise for 10 minutes to reaction mixture, and then was stirred at a room temperature for 24 hours. The white precipitate was filtered under reduced pressure and the filtrate was washed by water (100 ml) and extracted with ether (20 ml×1 time) The aqueous layer was extracted by chloroform (20 ml×3 times). The organic layer was collected, washed by water (30 ml×2 times) and salt water (brine, 20 ml×1 time), dried by anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane, Rf=0.36). The remnant was dissolved in chloroform (3 ml), and cold ethanol (8 ml) was added dropwise by pipette and stirred with glass rod to recrystallize 1.02 g (77%) of 1-[2-(4-pentyl-cyclohexyl)ethenyl]-4-(4-vinyl-cyclohexyl)benzene.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:16](=[O:19])[CH2:17][CH3:18])[CH2:6]1)C.O.[NH2:21]N.C(O)(=O)C>CO>[C:16]([N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[NH:21][N:2]=[CH:4][C:5]=2[CH2:6]1)(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)N1CC(=CN(C)C)C(=O)c2ccccc21
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCC(=O)N1Cc2cn[nH]c2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
A mixture of 3-dimethylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.838 g), hydrazine hydrate (0.66 g), and acetic acid (0.792 g) in methanol (30 ml) was stirred at room temperature for 3 hours. To the mixture was added acetic acid (1 ml) and evaporated in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 4,5-dihydro-5-propionyl-1H-pyrazolo[4,3-c]quinoline (1.77 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 26.3 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.16 g, 0.006 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (3.65 g, 0.028 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (2.00 g, 0.006 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (650 mg, 25%) as a yellow oil.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Azidobenzoic acid (846 mg, 5.08 mmol), HOBt (416 mg, 3.05 mmol, 0.6 eq.) and N-(2-aminoethyl)morpholine (0.716 ml, 5.34 mmol, 1.05 eq.) were dissolved in acetonitrile (9 ml) and DMF (3 ml), WSC (1.19 g, 6.10 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (40 ml), and washed with 5% aqueous sodium carbonate solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(C)C>[OH:8][C:6]1[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:23]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=c1[nH]c(Cl)cc2nccn12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cc4nccn4c(O)n3)cc2)CC1
Reaction time: 6 h
Yield: 43.1 %

Procedure:
A flask charged with 7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one (Preparation H, 1.75 g, 10.3 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (4.00 g, 10.3 mmol), potassium phosphate (4.38 g, 20.6 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.738 g, 1.55 mmol), and tris(dibenzylideneacetone)dipalladium (0.473 g, 0.516 mmol) was evacuated and backfilled with argon. Isopropanol (50 mL) and water (0.744 mL, 41.3 mmol) were added. The reaction was fitted with a septum and argon was bubbled through the reaction for 20 minutes before it was sealed and allowed to proceed at 90° C. for 6 hours. The reaction was recharged with catalyst, argon was bubbled through for 10 minutes, and the reaction was sealed and allowed to react at 90° C. for two days. The solvent was concentrated under reduced pressure, 200 mL of 2:1 2.5M potassium hydroxide/methanol was added and the reaction was stirred for 1 hour. A large amount of solids were observed so another 200 mL of the above mentioned mixture was added and much of the solid was dissolved. The solid was collected by means of vacuum filtration through a pad of celite and was then washed with 200 mL of the above mentioned mixture. The rinse was isolated and the pH was adjusted with 1 M hydrochloric until pH=9. The resulting solids were collected by means of vacuum filtration. This solid was taken up in 300 mL of water and allowed to stir for 30 minutes before the solid was collected by means of vacuum filtration and washed with water. The solid was dried on high vacuum and triturated with methanol. The mixture was filtered and the solid was dried under high vacuum to afford tert-butyl 4-(4-(5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)phenyl)piperidine-1-carboxylate (1.75 g, 4.44 mmol, 43.0% yield). MS (apci) m/z=395.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:37])[CH:11]=2)=[N:6][CH:7]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:50].Cl>>[ClH:1].[ClH:50].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][NH:28][CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:37])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CNCC2
Yield: 97 %

Procedure:
tert-Butyl 7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (108 mg, 0.207 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (99 mg, 97%) as a white solid: mp 290-320° C. dec; 1H NMR (300 MHz, CD3OD) δ 8.61 (d, J=2.1 Hz, 1H), 7.95 (dd, J=8.4, 2.4 Hz, 1H), 7.62 (d, J=7.6 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.05 (dd, J=8.3, 1.8 Hz, 1H), 6.36 (dd, J=7.6, 2.2 Hz, 1H), 6.13 (d, J=2.6 Hz, 1H), 5.28 (s, 2H), 4.48 (s, 2H), 3.73 (s, 3H), 3.67 (t, J=6.2 Hz, 2H), 3.02 (t, J=6.2 Hz, 2H); ESI MS m/z 421 [M+H]+; HPLC (Method B) 98.2% (AUC), tR=12.0 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[S:5].Cl[CH2:13][S:14][C:15]#[N:16]>>[S:14]([CH2:13][O:6][C:4](=[S:5])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1])[C:15]#[N:16]
Reactant: N#CSCCl
Reactant: OC(=S)c1ccc(Cl)cc1Cl
Product: N#CSCOC(=S)c1ccc(Cl)cc1Cl
Yield: 81 %

Procedure:
15.8 g (0.064 mol) of the K salt of 2,4-dichloro-thiobenzoic acid and 6.3 g (0.06 mol) of chloromethyl thiocyanate were reacted and processed as in Example 1 B. 13.5 g of a yellowish oil having a density of 1.45 (this corresponds to a yield of 81% of the theoretical conversion). Use Examples
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[S:11])[CH:5]2[CH3:12].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:13][C:5]1([CH3:12])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]1=[S:11]
Reactant: CC1C(=S)Nc2ccc(Cl)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(Cl)C(=S)Nc2ccc(Cl)cc21

Procedure:
A solution of 5-chloro-3-methylthiooxindole (1.35 g, 6.3 mmol) and N-chlorosuccinimide (950 mg, 7 mmol) in carbon tetrachloride (100 ml) was refluxed for 1 hour, cooled, and the precipitate was removed by filtration. The filtrate was concentrated to dryness, yielding crude 3,5-dichloro-3-methylthiooxindole. The residue was dissolved in 25 ml of tetrahydrofuran and added rapidly to a vigorously stirred slurry of red mercuric oxide (1.37 g, 6.3 mmol) and boron trifluoride etherate (900 mg, 6.3 mmol) in 100 ml of 20 percent aqueous tetrahydrofuran. After stirring for 3 hours, the solution was filtered through a pad of Celite and the filtrate was extracted with chloroform. The chloroform extracts were dried over anhydrous magnesium sulfate, filtered and the filtrates were concentrated to give a red solid which was chromatographed on silica gel with chloroform as the eluent. There was obtained 5-chloroisatin (850 mg, 75%), mp 248°-251° (recrystallized from ethanol).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][C:21](=[CH:23][C:24]#[N:25])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1.N12CCCN=C1CCCCC2>C(#N)C>[Si:1]([O:18][CH:19]1[CH2:22][C:21]([CH2:23][C:24]#[N:25])([N:26]2[CH:30]=[C:29]([C:31]3[C:32]4[CH:39]=[CH:38][N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:33]=4[N:34]=[CH:35][N:36]=3)[CH:28]=[N:27]2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)[Si](OC1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of (3-{[tert-butyl(diphenyl)silyl]oxy}cyclobutylidene)acetonitrile (1.859 g, 4.065 mmol) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.28 g, 4.06 mmol) in acetonitrile (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.61 mL, 4.1 mmol). The reaction was stirred overnight. The solvent was remove in vacuo. The crude was purified with silica gel column to give of the product (2.7 g, 79%) as an oil. LCMS (M+H)+: 663.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])=[CH:2]1.[B]=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.B(OC(C)C)(OC(C)C)OC(C)C.N1CCCCC1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12](=[O:17])[CH2:13][C:14](=[O:16])/[CH:15]=[CH:32]/[C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[CH:35][CH:34]=2)=[CH:2]1
Reactant: CC(=O)CC(=O)C=Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(OCc2ccccn2)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(/C=C/c1ccc(OCc2ccccn2)cc1)CC(=O)/C=C/c1c[nH]c2ccccc12
Temperature: 70 °C
Yield: 44.7 %

Procedure:
In a 20 mL reaction vessel were placed 31.0 mg (136 μmol) of 6-(1H-indol-3-yl)hex-5-ene-2,4-dione and 13.2 mg (0.190 mmol) of boron oxide and they were dissolved in 0.88 mL of ethyl acetate. To the mixture under stirring at 70° C., 29 mg (0.14 mmol) of 4-(2-pyridylmethoxy)benzaldehyde and 62 μL (0.27 mmol) of triisopropyl borate were sequentially added. After the mixture was stirred at the same temperature for 1 hour, a solution of 2.7 μL (27 μmol) of piperidine in ethyl acetate (0.135 mL) was added and the mixture was further stirred for 1 hour. To the reaction mixture was added a 1:1 solution (0.4 mL) of 1 N hydrochloric acid and saturated brine at room temperature and the mixture was stirred for 5 minutes to 1 hour (further, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution as needed). The resulting organic phase was directly subjected to purification by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol) to give 25.7 mg (45% yield) of the title compound as an orange powder.
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([N:12]2[C:21]3[CH:16]([CH2:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[N:12]1([S:9]([C:6]2[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=2)(=[O:11])=[O:10])[C:21]2[CH:16]([CH2:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc(S(=O)(=O)N2CCCC3CC=CC=C32)nn1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(S(=O)(=O)N2CCCC3CC=CC=C32)n[nH]1
Temperature: 100 °C
Yield: 3.3 %

Procedure:
A mixture of 3-methoxy-6-(tetrahydroquinoline-1-sulfonyl)-pyridazine (1.14 mmol, 112 mg), conc. HCl (2 mL), and dioxane (5 mL) was heated at 100° C. for two hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue and extracted with EtOAc. The EtOAc extract was washed with water, collected, dried, filtered and the filtrate was evaporated to a residue, which was crystallized from ether to yield 6-(tetrahydroquinoline-1-sulfonyl)-2H-pyridazin-3-one (33%, 11 mg); mp 200° C.