Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1([C:38]2[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[S:40][N:39]=2)[CH2:37][CH2:36]1.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:41]3[S:40][N:39]=[C:38]([CH:35]4[CH2:37][CH2:36]4)[CH:42]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C2CC2)ns1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc(C3CC3)ns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (50 mg, 0.100 mmol), 3-cyclopropyl-5-(tributylstannyl)isothiazole (62.0 mg, 0.150 mmol) and tetrakis(triphenylphosphine)palladium(0) (34.6 mg, 0.030 mmol) in toluene (10 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid, which was used without further purification (58.9 mg, 100%). ESI-MS m/z [M+H]+ calc'd for C28H36FN5O6S, 590. found, 590.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][O:13]C(C)(C)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.[OH-].[Na+].C([O-])([O-])=O.[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Al+3]>O.C(O)C>[CH2:1]([O:8][CH2:9][CH:10]([OH:11])[CH2:14][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(COCc2ccccc2)O1
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Al+3]
Solvent: CCO
Solvent: O
Product: OCC(O)COCc1ccccc1
Temperature: 70 °C

Procedure:
Into a 1 L beaker were weighed 222 g (1.0 mol) of 4-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolane prepared in 1-2, 250 ml of ethanol, and 400 ml of distilled water, and the whole was adjusted to pH 2 with phosphoric acid. With introducing nitrogen thereinto, the solution was heated to 70° C. After 1.5 hours of the reaction, the solution was adjusted to pH 7.0 with sodium hydroxide. The resulting salt was subjected to adsorption treatment with an adsorbent “KYOWAAD 1000” (manufactured by Kyowa Hakko Kogyo Co., Ltd.) and then subjected to solvent removal to obtain 3-benzyloxy-1,2-propanediol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]=[N+]=[N-].[Cl:12][CH2:13][C:14](=[O:38])[C@:15]1([OH:37])[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([C@@H:30]([OH:34])[CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:35])[CH:25]=[CH:26]2)[CH2:21][CH2:20]3)[CH2:17][C@H:16]1[OH:36]>CCOCC.CO>[Cl:12][CH2:13][C:14](=[O:38])[C@:15]1([OH:37])[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([C@@H:30]([OH:34])[CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:35])[CH:25]=[CH:26]2)[CH2:21][CH2:20]3)[CH2:17][C@H:16]1[O:36][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CCl
Reactant: [N-]=[N+]=CCOC1CCCCO1
Solvent: CO
Solvent: CCOCC
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCOC1CCCCO1)[C@]2(O)C(=O)CCl

Procedure:
A solution of 2-(tetrahydropyran-2-yloxy)-1-diazoethane (prepared from 0.21 mole of N-[2-(tetrahydropyran-2-yloxy)ethyl]urea as described in Example 1) in 400 ml of 3:1 ether-pentane is diluted with 100 ml each of ether and methanol at 0°C and stirred vigorously while 21-chloro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate (12 mmoles) is added. After nitrogen evolution ceases the solvents are removed in vacuo to yield the title compound.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)=[NH:4].N[C:19]1[CH:20]=[CH:21][C:22]([F:27])=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:20]=[CH:21][C:22]=1[F:27])#[N:25]
Reactant: N#Cc1cc(N)ccc1F
Reactant: CS(=O)(=O)NCCNc1nonc1C(=N)NO
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(C#N)c1

Procedure:
The title compound was prepared according to the procedure of Example 17, step E, using N-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-cyano-4-fluoroaniline [Aldrich, product #639877] as the starting materials. LCMS for C13H14FN7NaO4S (M+Na)+: m/z=406.0. 1H NMR (400 MHz, DMSO-d6): δ 11.65 (s, 1H), 9.08 (s, 1H), 7.35 (m, 1H), 7.18 (m, 3H), 6.56 (m, 1H), 6.23 (m, 1H), 6.24 (s, 2H), 3.32 (m, 2H), 3.14 (m, 2H), 2.89 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)#[CH:2].Br[C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.CN(C=O)C.CCN(C(C)C)C(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]5)=[N:22][CH:23]=4)=[C:3]([C:1]#[C:2][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(C#Cc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 26a (131 mg, 0.268 mmol) and 2-bromoquinoline (558 mg, 2.68 mmol) were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry DMF (4 mL) and DIEA (0.468 mL, 2.68 mmol) were added via syringe and then the mixture was deoxygenated by bubbling argon through the stirred solution for 5 min. CuI (2.56 mg, 0.0134 mmol) and (Ph3P)2PdCl2 (18.9 mg, 0.0268 mmol) were added and then the reaction was stirred at rt for 1 h. The reaction was poured into water (50 mL) and then the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (20 mL) and brine (2×20 mL) and then dried over MgSO4 and filtered. The solution was concentrated under reduced pressure. The crude product was chromatographed on a 40 g SiO2 pre-packed column eluting with 0-60% ACN/DCM to afford compound 26b. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.97 (d, J=2.2 Hz, 1H), 8.27 (dd, J=8.9, 2.3 Hz, 1H), 8.12 (t, J=8.6 Hz, 2H), 8.04 (d, J=5.6 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.67-7.77 (m, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.49-7.59 (m, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.09 (d, J=5.6 Hz, 1H), 3.98-4.07 (m, 4H), 3.88-3.98 (m, 4H), 3.61-3.70 (m, 4H), 3.51-3.61 (m, 4H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H36N8O3: 617.3 (M+H). Found: 617.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>ClCCl>[CH2:18]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: C1CNCCN1
Reactant: CCCCCCCCCCCBr
Solvent: ClCCl
Product: CCCCCCCCCCCN1CCNCC1

Procedure:
Excess piperazine (5 eq) and 1-bromoundecane (1.0 eq) are dissolved in dichloromethane and allowed to react overnight. The mixture is extracted with aqueous sodium bicarbonate and the organic layer dried with sodium sulfate. The mixture is filtered, the solvent removed in vacuo and the residue purified by column chromatography.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:17][CH:16]=1>C1COCC1>[NH:26]1[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][OH:13])=[CH:16][CH:17]=2)=[N:23][N:24]=[N:25]1
Reactant: COC(=O)c1ccc(Cc2nnn[nH]2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccc(Cc2nnn[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminium hydride (0.142 g, 3.75 mmol) was taken in a dry, three-necked flask, fitted with a reflux condenser. Anhydrous ether (10 mL) was added. A solution of methyl-4-(1H-tetrazol-5-ylmethyl)benzoate (0.654 g, 3.0 mmol) in anhydrous THF (5 mL) was added dropwise. After the addition was complete, the mixture was heated to reflux for 2 hours. Then, the reaction mixture was cooled to 0° C. and quenched by cautious addition of water (10 mL) and 15% sodium hydroxide solution (10 mL). The reaction mixture was stirred for 30 minutes and then allowed to warm to room temperature. The aqueous phase was acidified to pH 4 and left for 2 days. A white precipitate was formed and filtered off, washed with water, and dried under vacuum, to give [4-(1H-tetrazol-5-ylmethyl)-phenyl]-methanol as a white solid. Yield: 0.290 g (51%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][C:11]=2[C:12](OC)=[O:13])=[CH:4][CH:3]=1.[OH-].[Li+].Cl.C(N(C(C)C)CC)(C)C.[F:40][C:41]1[C:46]([NH2:47])=[CH:45][CH:44]=[CH:43][N:42]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:21])=[CH:16][C:11]=2[C:12]([NH:47][C:46]2[C:41]([F:40])=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1
Reactant: Nc1cccnc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cccnc1F)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-(4-morpholinylcarbonyl)benzoate (may be prepared as described in Description 109, 93 mg, 0.25 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (19 mg, 0.79 mmol) and water (1 ml). The mixture was stirred at 50° C. for one hour, cooled and 2M hydrochloric acid (0.40 ml, 0.80 mmol) was added and the solvent removed in vacuo The residue was redissolved in N,N-dimethylformamide (4 ml) and diisopropylethylamine (0.11 ml, 0.62 mmol), 2-fluoro-3-pyridinamine (36.3 mg, 0.32 mmol) and HATU (284 mg, 0.75 mmol) were added. The solvent was removed in vacuo and the residue purified by MDAP to yield the title compound as an off-white solid. 5 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[C:25](B(O)O)=[C:26]2[CH2:31][CH2:30][CH2:29][N:27]2[N:28]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([C:25]3[C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[N:28][N:27]4[CH2:29][CH2:30][CH2:31][C:26]=34)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)cccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)cccc21

Procedure:
The titled intermediate was made via Preparation 33 (General Suzuki Coupling Method D) from 4-bromo-indole-1-carboxylic acid tert-butyl ester and 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5). MS (ESI) m/e 401 (M+1). TLC (SiO2): Rf0.5 (1:1 methylene chloride/[80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]).
Reaction SMILES: [O:1]([CH:8]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[C:9]([Cl:12])([Cl:11])[Cl:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:31])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.O>CC(C)=O>[O:1]([CH:8]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:23]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:31])[C:9]([Cl:10])([Cl:11])[Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(NC(Oc1ccccc1)C(Cl)(Cl)Cl)c1ccccc1O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: O=C(Oc1ccccc1)Oc1ccccc1C(=O)NC(Oc1ccccc1)C(Cl)(Cl)Cl
Reaction time: 3 h
Yield: 39 %

Procedure:
10 g of N-(1'-phenoxy-2',2',2'-trichloroethyl)-2-hydroxybenzamide and 5.2 g of phenyl chlorocarbonate were dissolved in 200 ml of acetone and the solution was kept at a temperature below 10° C. with an ice-water bath. 3.3 g of triethylamine were added dropwise thereto under stirring and the reaction was continued at room temperature for a further period of three hours. The reaction mixture was poured into water and the resulting crystals were recrystallized from methanol to obtain 5.2 g of N-(1'-phenoxy-2',2',2'-trichloroethyl)-2-phenoxycarbonyloxybenzamide as which crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([OH:9])[CH2:6]1)=[O:4].N1C=CC=CC=1.[O:16](S(C1C=CC(C)=CC=1)(=O)=O)[S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=O)=[O:18].[O-][Mn](=O)(=O)=O.[K+]>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([O:9][S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:18])=[O:16])[CH2:6]1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)[C@H]1C[C@@H](O)C1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)C1
Reaction time: 0.75 h

Procedure:
An ice bath cooled methylene chloride (80.0 mL) solution of cis-3-hydroxy-cyclobutanecarboxylic acid methyl ester (4.00 g, 31.0 mmol; predominantly cis) was charged with pyridine (3.00 mL, 37.0 mmol) and Ts2O (11.1 g, 34.0 mmol). After 45 min, TLC analysis (EtOAc) revealed no starting material (KMnO4 stain for alcohol sm). The reaction mixture was concentrated in vacuo, resuspended in ether (50.0 mL) and washed with 0.5 N HCl (2×25 mL), saturated bicarbonate (2×25 mL), water (2×25 mL), brine (1×25 mL), and then dried over Na2SO4, filtered and concentrated to yield the title compound as colorless oil, predominantly cis. 1H NMR (400 MHz, CDCl3): δ=2.44-2.55 (m, 7H), 2.56-2.65 (m, 1H), 3.65 (s, 3H), 4.59-4.77 (m, 1H), 7.33 (d, 2H, J=8.0 Hz), 7.77 (d, 2H, J=8.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23].C1C(=O)N(Br)C(=O)C1.[N:33]1([C:39](=[S:41])[NH2:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[C:7]([C:8]2[N:40]=[C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[S:41][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23]
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1Cl
Reactant: NC(=S)N1CCOCC1
Agent: O=C1CCC(=O)N1Br
Product: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using 2-propen-1-yl {2-chloro-3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate (3.00 g, 8.19 mmol), NBS (1.531 g, 8.60 mmol) and 4-morpholinecarbothioamide (1.677 g, 11.47 mmol) the title compound of Step C was obtained as an orange solid (4.03 g, 7.86 mmol, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 7.67-7.84 (m, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.29 (dd, J=7.7, 1.5 Hz, 1H), 6.41 (d, J=5.5 Hz, 1H), 5.83-6.08 (m, 1H), 5.36 (dd, J=17.2, 1.5 Hz, 1H), 5.23 (dd, J=10.4, 1.5 Hz, 1H), 4.62 (d, J=5.3 Hz, 2H), 3.73 (t, J=4.8 Hz, 4H), 3.57 (t, J=4.8 Hz, 4H). MS (ESI): 491.98 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][CH:11]2[S:15][C:14](=N)[NH:13][C:12]2=[O:17])=[CH:8][CH:7]=1.C([OH:29])C>Cl>[OH:1][CH2:2][CH:3]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:29])[NH:13][C:12]2=[O:17])=[CH:8][CH:7]=1
Reactant: Cc1cccnc1C(CO)COc1ccc(CC2SC(=N)NC2=O)cc1
Reactant: CCO
Agent: Cl
Product: Cc1cccnc1C(CO)COc1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
5-{4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]benzyl}-2-imino-4-thiazolidinone (2.3 g) was dissolved in a mixture of 2N-hydrochloric acid and ethanol (20 ml), and the solution was heated under reflux for 4 hours. After neutralization with aqueous sodium hydrogencarbonate solution, the solution was extracted with chloroform, and the chloroform layer was washed with water and dried (MgSO4). The solvent was distilled off to give 5-{4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]-benzyl}-2,4-thiazolidinedione in the form of crystals. Yield of 1.9 g. Recrystallization from ethanol produced colorless prisms. m.p. 182°-183° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:20][CH:19]2[C:18](=[O:21])[NH:17][C:16]3=[O:22])=[CH:11][CH:10]=1.CN(CCC)C.C(O)C>O1CCCC1>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]23[CH2:20][CH:19]2[C:18](=[O:21])[NH:17][C:16]3=[O:22])=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(C23CC2C(=O)NC3=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CCCN(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1ccc(C23CC2C(=O)NC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.4 ml of acetic anhydride in 10 ml of tetrahydrofuran is added dropwise to a solution of 4 g of 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione and 120 mg of dimethylaminopropane in 150 ml of tetradrofuran, and the mixture is stirred overnight at room temperature. Then 0.5 ml of ethanol is added to the reaction mixture, which is stirred for 1 hour and filtered. The crystals so obtained are washed with tetrahydrofuran and ether, affording white crystals of the title compound with a melting point above 230° C. and Rf=0.3 in thin-layer silica gel plates in the system methylene chloride/methanol (10:1).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH3:21])[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=2)[CH3:21])[N:11]=1
Reactant: CN(c1ccc(O)cc1)c1cc2ccccc2c(O)n1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccccc3c(O)n2)cc1
Yield: 69.8 %

Procedure:
A mixture of ethyl 2-bromopropionate (1.36 g), 4-[N-(1-hydroxyisoquinolin-3-yl)-N-methylamino]phenol (2.00 g), anhydrous potassium carbonate (1.04 g) and methyl ethyl ketone (20 ml) was heated under reflux for a period of 3 hours. The mixture was cooled, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give an oil, which was purified by column chromatography over silica gel (eluant dichloromethane to yield ethyl 2-{4-[N-(1-hydroxyisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.92 g) as a brown solid mp 96° C.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(OCC)(=O)C>CN(C)C=O>[C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH:23]=[CH2:24])[CH:15]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ncc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Temperature: 80 °C
Yield: 97.7 %

Procedure:
N-(1-Adamantylmethyl)-2,5-dichloroisonicotinamide (2.32 g) and tributyl(vinyl)stannane (2.61 g) were stirred together in dry N,N-dimethylformamide (50 mL) at room temperature under nitrogen. The latter was treated with a few crystals of 2,6-ditert-butyl-4-methylphenol and dichloro[bis(triphenylphosphine)]palladium(II) (0.24 g). The reaction mixture was warmed to 80° C. for 4 hours and subsequently cooled to room temperature. The mixture was poured into ethyl acetate (50 mL) and washed with water (2×25 mL) then brine (30 mL). The organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate:dichloromethane (1:20) to afford the sub-titled compound (2.21 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:9]1([C:15](O)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:38])=O.CN(C)C=O>ClCCl>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH2:7][N:8]([C:9]1([C:15]([Cl:38])=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)CCN(C1(C(=O)O)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C1(C(=O)Cl)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of (15.1 mmol) of the product from Step E in 73 mL of dichloromethane is treated with 1.4 mL (17 mmol, 1.1 equivalents) of oxalyl chloride and 0.02 mL (0.3 mmol, 0.02 equivalents) of dimethylformamide at ambient temperature, causing some bubbling, and is stirred overnight. The resulting solution of the title compound is used in step G without isolation.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:37]2[CH2:36][CH2:35][N:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([OH:27])[CH:29]=3)[CH2:39][CH2:38]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(O)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 72 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.