Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:15](=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH3:21])=[CH:10][CH:11]=2)[CH2:6]1)(=O)C>Cl>[ClH:30].[ClH:1].[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][N:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][NH:5][CH2:6]2)=[CH:11][CH:10]=1)=[O:31]
Reactant: CC(=O)N1CCc2ccc(C(=O)CCCCN(C)CCc3ccccc3Cl)cc2C1
Agent: Cl
Product: CN(CCCCC(=O)c1ccc2c(c1)CNCC2)CCc1ccccc1Cl
Yield: 170 %

Procedure:
A solution of (1-(2-acetyl-1,2,3,4-tetrahydro-7-isoquinolinyl)-5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-pentanone (5.0 g) obtained in Example 214 in concentrated hydrochloric acid (150 ml) was stirred at 130° C. for 2 hours, and the solvent of the reaction mixture was evaporated under reduced pressure to give the crude product of the title compound as a pale yellow solid (4.2 g). Further recrystallization from ethanol-diethyl ether afforded the title compound as colorless crystals having a melting point of 95° C. (dec).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])[N:10]=[C:6]2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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]>[CH2:15]([NH:14][C:12]([NH:11][C:9]1[N:10]=[C:6]2[CH:5]=[C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:3]=[C:2]([C:28]3[CH:29]=[N:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[N:7]2[N:8]=1)=[O:13])[CH3:16]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ccc(OC)nc3)n2n1

Procedure:
To a mixture of 1-(5-chloro-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-ethyl-urea (0.2 g, 0.63 mmol) obtained in step 1, 6-Methoxy-pyridine-3-boronic acid (0.12 g, 0.78 mmol), and sodium carbonate (0.71 mL of a 2 M aqueous solution) in dioxane (6 mL) was added the catalyst Pd(dppf)Cl2 (30 mg, 5 mol %) and the resulting mixture was heated to reflux for 36 hours. The solvent was removed under reduced pressure. Purification using silica gel chromatography (2-10% MeOH/CHCl3) gave the title compound as a solid LCMS (APC+) 390.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=O)[CH2:7][CH2:6]2.Cl.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][CH:20]=1)([CH3:18])[CH3:17].Cl>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8]1[NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]([CH3:18])[CH3:17])=[CH:24][C:23]=3[C:7]=1[CH2:6]2
Reactant: CC(C)c1ccc(NN)cc1
Reactant: COc1c(C)cc2c(c1C)CCC2=O
Agent: Cl
Solvent: CCO
Product: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2ccc(C(C)C)cc12
Temperature: 25 °C

Procedure:
A mixture of 5-methoxy-4,6-dimethyl-1-indanone (3.1 g, 16 mmol) and p-isopropylphenylhydrazine hydrochloride (3.05 g, 16 mmol), was heated to reflux in ethanol (20 cm3) containing concentrated hydrochloric acid (2 cm3). The reaction mixture was then heated at reflux for 4 hours and then allowed to cool to room temperature. The crystalline precipitate which formed, was filtered off, washed with 10% aqueous ethanol, and dried in a vacuum oven, to give the title compound as a pale green crystalline solid. Yield 3.04 g (62%). M.p. 130° C. (from ethanol). 1H NMR (CDCl3) δ: 1.33 (6H, d,), 2.34 (3H, s,), 2.35 (3H, s,), 3.02 (1H, septet,), 3.6 (1H, br,), 3.76 (2H, s,), 7.08 (1H, s,), 7.30 (1H, d,), 7.45 (1H, s,), 8.12 (1H, s,).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6](C)=[CH:5][C:4]=1[S:10]([C:13]1[CH:14]=[C:15]([CH2:22][OH:23])[C:16]2[O:20][CH:19]=[CH:18][C:17]=2[CH:21]=1)(=[O:12])=[O:11].C1(S(C2C=C(C(OC)=O)C3OC=CC=3C=2)(=O)=O)C=CC=CC=1>>[C:4]1([S:10]([C:13]2[CH:14]=[C:15]([CH2:22][OH:23])[C:16]3[O:20][CH:19]=[CH:18][C:17]=3[CH:21]=2)(=[O:12])=[O:11])[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(C)cc1S(=O)(=O)c1cc(CO)c2occc2c1
Agent: COC(=O)c1cc(S(=O)(=O)c2ccccc2)cc2ccoc12
Product: O=S(=O)(c1ccccc1)c1cc(CO)c2occc2c1

Procedure:
The title compound was prepared according to the procedure of Intermediate 68 starting from methyl 5-(phenylsulfonyl)-1-benzofuran-7-carboxylate (80 mg, 0.25 mmol; obtained in Step 2). The crude material was used directly in the subsequent reaction. MS (ESI+) for C15H12O4S m/z 289 (M+H)+.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[S:12].[OH-].[K+].I[CH3:16]>CC(C)=O>[CH3:16][S:12][C:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:1]=1
Reactant: CI
Reactant: S=C1CCCc2ccccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CSC1=Nc2ccccc2CCC1
Reaction time: 0.08 h

Procedure:
A solution of Example 182B (2.3 g, 12.97 mmol) in acetone (51.9 mL) was heated to 60° C. in and oil bath. Then potassium hydroxide (36.4 g, 649 mmol) was added followed by the dropwise addition of iodomethane (0.811 mL, 12.97 mmol). The resulting yellow slurry was stirred for 5 minutes and then the solids were collected by filtration. The solids were washed with acetone and the filtrate was concentrated to obtain the crude title compound which was used was used without purification for the next reaction.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25][C:24]=2[C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].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.O>[CH:3]1[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][C:2]=1[C:32]1[C:26]2[S:25][C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:28]=3[C:27]=2[CH:29]=[CH:30][CH:31]=1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Reactant: Brc1ccc2c3ccccc3c3ccccc3c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)sc1c(-c3ccc4c5ccccc5c5ccccc5c4c3)cccc12
Yield: 85.1 %

Procedure:
4.4 g (14.6 mmol) of 2-bromotriphenylene, 4.0 g (17.5 mmol) of 4-dibenzothiopheneboronic acid, 0.51 g (0.44 mmol) of tetrakistriphenylphosphinepalladium, and 4.0 g (43.4 mmol) of potassium carbonate were charged in a 250 mL round bottom flask with solvent 90 mL of toluene and 10 mL of water. The reaction mixture was purged with nitrogen for 30 min and then was heated up to reflux for overnight under nitrogen with stirring. The reaction mixture was cooled and the organic extracts were purified by column chromatography and recrystallization with toluene. 5.1 g (86%) of white solid was obtained as the product which was confirmed by proton NMR.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([C:10](=[O:25])[CH:11]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][O:8][CH2:7][O:6][CH2:5]1>CO>[CH3:3][C:4]1([CH:10]([OH:25])[CH:11]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:5][O:6][CH2:7][O:8][CH2:9]1
Reactant: CC1(C(=O)C(Cc2ccc(Cl)cc2)n2cncn2)COCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C(O)C(Cc2ccc(Cl)cc2)n2cncn2)COCOC1
Temperature: 20 °C
Reaction time: 12 h
Yield: 49.5 %

Procedure:
11.5 g (0.3 mole) of sodium borohydride are added, a little at a time, to a solution of 90 g (0.269 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propan-1-one in 250 ml of methanol, at from 0° to +5° C. The mixture is stirred for 12 hours at 20° C. and is then evaporated down. The residue is stirred for 1 hour with 200 ml of 20% strength potassium hydroxide solution and the mixture is then extracted with 500 ml of methylene chloride. The organic phase is washed with three times 50 ml of water, dried over sodium sulfate and evaporated down. The residue crystallizes at +5° C. after addition of 20 ml of ether. 45 g (49.6%) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propan-1-ol are isolated as white crystals of melting point 152°-154° C.
Reaction SMILES: [CH2:1]([CH:8]1[O:22][C:12]2=[CH:13][C:14]3[C:18]([CH:19]=[C:11]2[C:10](=O)[C:9]1=[O:24])=[N:17][C:16]([CH3:21])([CH3:20])[CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CN(C=O)C.O.NN>[CH2:1]([CH:8]1[O:22][C:12]2=[CH:13][C:14]3[C:18](=[CH:19][C:11]2=[CH:10][C:9]1=[O:24])[NH:17][C:16]([CH3:21])([CH3:20])[CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C=c2cc3c(cc2=N1)C(=O)C(=O)C(Cc1ccccc1)O3
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C=c2cc3c(cc2N1)=CC(=O)C(Cc1ccccc1)O3
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
To a solution of 6-Benzyl-2,2-dimethyl-2H-pyrano[2,3-f]indole-7,8-dione (500 mg, 1.57 mmol) in DMF (5 mL), hydrazine monohydrate (2.5 mL) was added, and the resulting mixture was stirred at 100° C. for 1.5 hour. Water was added thereto, and the resulting solution was extracted with ethyl acetate. The resulting organic phase was washed with saturated aqueous ammonium chloride solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column (hexane/ethyl acetate=3/1) to obtain the aimed product (yield: 65%).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:28])[C:5]([N:7]([CH3:27])[C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([O:23]C)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][C:31]=1[CH3:38]>C(O)C>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH:37][C:21]([C:19]2[N:20]=[C:9]3[C:8]4([N:7]([CH3:27])[C:5](=[O:6])[C:4]([N:2]([CH3:1])[CH3:3])=[O:28])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]4)[CH2:11][N:10]3[C:17](=[O:26])[C:18]=2[OH:25])=[O:23])=[CH:32][C:31]=1[CH3:38]
Reactant: Cc1cc(CN)ccc1F
Reactant: COC(=O)c1nc2n(c(=O)c1O)CC1CCC2(N(C)C(=O)C(=O)N(C)C)CC1
Solvent: CCO
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC2CCC3(N(C)C(=O)C(=O)N(C)C)CC2)ccc1F
Temperature: 90 °C
Yield: 65.4 %

Procedure:
To a mixture of methyl 10-(((dimethylamino)(oxo)acetyl)(methyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (3 g, 7.65 mmol) in ethanol (80 mL) was added (4-fluoro-3-methylphenyl)methanamine (2.90 mL, 22.94 mmol) and the mixture was heated at 90° C. for 18 h. The reaction mixture was cooled, concentrated, diluted with ethyl acetate and washed twice with 0.2N NaOH (2×100 mL). The organic layer was discarded and the aqueous layer acidified with conc. HCl and extracted with dichloromethane (2×150 mL), dried (Na2SO4), filtered and concentrated. The crude product was recrystallized from methanol to afford the title compound (2.5 g, 66% yield) as a crystalline white solid. 1H NMR (500 MHz, CDCl3) δ: 12.13 (1 H, s), 9.56 (1 H, brs), 7.20-7.23 (1 H, m), 7.15-7.20 (1 H, m), 6.88-6.93 (1 H, m), 4.83 (1 H, dd, J=15.56, 7.02 Hz), 4.55-4.62 (1 H, m), 4.39-4.45 (1 H, m), 3.60 (1 H, d, J=15.56 Hz), 3.33-3.47 (2 H, m), 3.01 (3 H, s), 2.99 (3H, s), 2.97 (3 H, s), 2.49 (1 H, brs), 2.23 (3 H, d, J=1.83 Hz), 1.97-2.09 (4 H, m), 1.74-1.84 (2 H, m). LCMS (M+H)=500.69. HPLC purity: >95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.Cl[C:38]1[N:43]=[CH:42][N:41]=[C:40]([CH:44]([C:50]#[N:51])[C:45]([N:47]([CH3:49])[CH3:48])=[O:46])[CH:39]=1.C(=O)(O)[O-].[Na+]>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(#N)C>[C:50]([CH:44]([C:40]1[CH:39]=[C:38]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)(=[O:28])=[O:29])[C:12]3=[N:13][CH:14]=2)[N:43]=[CH:42][N:41]=1)[C:45]([N:47]([CH3:49])[CH3:48])=[O:46])#[N:51]
Reactant: CN(C)C(=O)C(C#N)c1cc(Cl)ncn1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(C#N)C(=O)N(C)C)ncn3)cc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.0 g, 2.0 mmole), 2-(6-Chloro-pyrimidin-4-yl)-2-cyano-N,N-dimethyl-acetamide (prepared according to the method published in Tetrahedron Letters (2005) 46, 3587-3589) (670 mg, 3.0 mmole), sodium bicarbonate, (2M aq, 4.9 mmole), acetonitrile (13.2 mL), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (97 mg, 0.12 mmole) was heated in a microwave reactor at 120° C. for 45 min. The crude mixture was concentrated to dryness, suspended in water (50 mL), and stirred for 30 min. The resulting precipitate was filtered off, suspended in ethyl acetate (15 mL), and stirred for 15 h. The precipitate was filtered off, rinsed with ethyl acetate (3×5 mL), and air dried. Recrystallization from ethylacetate/methanol afforded 2-cyano-2-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-acetamide (762 mg, 68% yield) as a bright yellow solid. MS: m/z 567.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[N:5]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH:17]=[CH:18][CH:19]=2)[C:4](=[O:25])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12]([CH3:13])=[O:34])=[N:7][C:6]=2[N:5]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH:17]=[CH:18][CH:19]=2)[C:4](=[O:25])[CH:3]=1
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(SC)nc32)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
Steps 2 and 3. To a suspension of N-(3-(5-methyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5a; 5.15 g, 14.63 mmol) in DCM (100 mL) at 0° C. was added MCPBA (77 wt. %, 3.51 g, 15.65 mmol) in one portion. The resulting suspension was stirred at 0° C. for 1 h. The reaction mixture was diluted with DCM (100 mL) and treated with an ice cold solution of 1.0 M K2CO3. The aqueous layer was extracted with DCM (2×100 mL). The organic extracts were dried over Na2SO4, filtered and concentrated affording crude N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 1.09 g, 2.96 mmol, 20% yield) as a light yellow foam. The aqueous layer contained suspended material so it was filtered through a medium porosity sintered glass frit and washed with water and Et2O affording additional N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 4.59 g, 12.46 mmol, 85% yield) as a light yellow free-flowing solid after drying under vacuum. m/z (ESI, +ve ion) 369.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (1H, s), 9.33 (1H, s), 7.69-7.76 (1H, m), 7.66 (1H, d, J=1.8 Hz), 7.43-7.52 (1H, m), 6.97-7.07 (1H, m), 6.81 (1H, d, J=1.4 Hz), 6.44 (1H, dd, J=16.9, 10.1 Hz), 6.25 (1H, dd, J=16.9, 1.9 Hz), 5.69-5.81 (1H, m), 2.71 (3H, s), 2.59 (3H, d, J=1.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH2:8][CH3:9])[NH:4][C:3]=1[C:10]([O:12]CC)=[O:11].ClC1C=C(C(O)=O)NC=1C>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH2:8][CH3:9])[NH:4][C:3]=1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1[nH]c(CC)c(Cl)c1Cl
Agent: Cc1[nH]c(C(=O)O)cc1Cl
Product: CCc1[nH]c(C(=O)O)c(Cl)c1Cl

Procedure:
Title compound was synthesized from ethyl 3,4-dichloro-5-ethyl-1H-pyrrole-2-carboxylate (Intermediate 74) by an analogous method to Intermediate 8.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:10]([O:12]C)=[O:11])=[CH:6][CH:5]=1.O>CO>[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][CH:9]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 94.3 %

Procedure:
To a solution of 10 g of KOH in 80 ml of 50% methanol is added 30.2 g of methyl (p-chlorophenoxy)-[p-(p-chlorophenoxy)phenyl]acetate. The mixture is refluxed for 3 hours, cooled, poured into 100 ml of water. The solution is extracted with two 100-ml portions of ether. The aqueous layer is acidified with concentrated hydrochloric acid. The mixture is extracted with two 100-ml portions of ether and the extracts are washed with water, brine and dried (MgSO4). Evaporation of the solvent yields an oil which is triturated with petroleum ether to give 27.5 g of product as white crystals. Recrystallization from hexane-chloroform gives white plates, mp 141°-142° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[SH-:12].[Na+]>CN(C)C=O>[SH:12][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1cnc2ccccc2n1
Reactant: [SH-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Sc1cnc2ccccc2n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 157.3 %

Procedure:
2-Chloroquinoxaline (2 g) and sodium hydrosulphide (1.23 g) were stirred together in 25 ml of dimethylformamide and heated to 100° C. After 3 hours the reaction mixture was allowed to cool and then partitioned between 70 ml of water and 30 ml of ethyl acetate. The organic layer was separated and the aqueous layer extracted twice with 20 ml of ethyl acetate. The combined organic extracts were washed with sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to yield an orange solid (3.1 g). The product of this reaction was used in the next preparative step without further purification.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1.O[C:37]1[CH:41]=[N:40][S:39][N:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[S:39]1[N:40]=[CH:41][C:37]([O:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:30][CH2:31][O:32][CH2:33][CH:34]=4)=[C:25]([F:35])[CH:24]=3)[CH2:18]2)=[N:38]1
Reactant: Oc1cnsn1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCOCC2)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2cnsn2)CN1c1ccc(C2=CCOCC2)c(F)c1
Reaction time: 1.5 h
Yield: 72.9 %

Procedure:
Diisopropylazodicarboxylate (0.22 g, 1.1 mmol) was added dropwise at ambient temperature to a stirred solution of 5(R)-hydroxymethyl-3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one (WO97/09328; 0.275 g, 0.93 mmol), 3-hydroxy1,2,5-thiadiazole (Weinstock et al. Journal of Organic Chemistry 32, 2823 [1967]; 0.1 12 g, 1.1 mmol) and triphenylphosphine (0.288 g, 1.1 mmol) in dry THF (7 ml). The solution was kept for 1.5 hours. Solvent was evaporated and the residue was purified by flash column chromatography, eluting with EtOAc/isohexane (1:1) to give the title product (0.256 g , 73%) as a solid (mp 146-148 ° C.). MS: 378 (MH+); NMR: 2.4 (1H, bs); 3.78 (3H, t); 3.96 (1H, m); 4.2 (3H, m); 4.66 (2H, m); 5.1 (1H, m); 6.05 (1H, s); 7.27-7.5 (3H, m); 8.41 (1H, s).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:31])[CH2:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)[CH:9](C(OCC)=O)[C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:5]1[C:6](=[O:31])[CH2:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:19][CH:18]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCOC(=O)C1C(O)=C(C(=O)CC)C(=O)CC1c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(=O)C1=C(O)CC(c2ccc(OCc3ccccc3)cc2)CC1=O
Temperature: 70 °C

Procedure:
A mixture of 54 g (0.13 mol) of 2-propionyl-3-hydroxy-5-(4-benzyloxyphenyl)-4-(carboethoxy)cyclohex-2-en-1-one 30 g (0.37 mol)of 50 percent sodium hydroxide in 450 mL of 95 percent ethanol and 100 mL of water was stirred mechanically and heated at about 70° C. for 16 hours. The resulting clear yellow solution was cooled to about 60° C. and treated with 50 mL of concentrated HCl (some material was lost as the ensuing decarboxylation reaction erupted from the reaction vessel). The product precipitated from the solution and was isolated by filtration. Recrystallization from absolute ethanol gave the above named product as a beige crystalline solid in a yield of 24 g (54 percent of theoretical). The product melted at 114°-115° C.: 1H NMR (CDCl3) δ1.17 (t, 3H, --CH3), 2.60-3.48 (m, 7H, ring protons and --CH2CH3), 5.05 (s, 2H, ArCH2O--), 6.83-7.55 (m, 9H, ArH's), 18.1 (s, 1H, enol, H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[N:17]2[C:12]([CH3:20])([CH2:13][CH2:14][O:15][C:16]2([CH3:19])[CH3:18])[CH2:11]1.[CH:21](=[O:23])[CH3:22].[Cl-].[Na+]>O1CCCC1.O>[O:9]=[C:10]1[N:17]2[C:12]([CH3:20])([CH2:13][CH2:14][O:15][C:16]2([CH3:19])[CH3:18])[CH:11]1[CH:21]([OH:23])[CH3:22]
Reactant: CC=O
Reactant: CC12CCOC(C)(C)N1C(=O)C2
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C1C(=O)N2C(C)(C)OCCC12C
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
To a solution of 1.1 equivalents of freshly prepared lithium diisopropylamide in anhydrous tetrahydrofuran under a nitrogen atmosphere at -78° is added a solution of 8-oxo-2,2,6-trimethyl- 3-oxa-1-azabicyclo[4.2.0]octane in anhydrous tetrahydrofuran which has been cooled to -78° C. After two minutes, the resulting lithium enolate is treated with excess acetaldehyde. The solution is stirred for 30 minutes at -78° and then poured into water. The aqueous phase is saturated with sodium chloride and extracted with ethyl acetate. The combined ethyl acetate solutions are dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give the crude product. Purification by chromatography on silica gel using ethylacetate/benzene gives 8-oxo-2,2,6-trimethyl-7-(1-hydroxyethyl)-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C:28]1([CH2:27][CH2:26][CH2:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH2:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][NH:9]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1ccccc1CCCCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(CCCCc2ccccc2OCCC2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
10 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 1.13 g of 1-t-butoxycarbonyl-2-{2-[2-(4-phenylbutyl)phenoxy]ethyl}piperidine [prepared as described in step (b) above] in 10 ml of dioxane, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was washed with hexane and dried in vacuo, to give 0.94 g (yield 97%) of the title compound as a colorless oil.