Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][C:15]3[NH:14][C:13](=[O:17])[CH:12]=[CH:11][C:10]=3[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][C:15]2[NH:14][C:13](=[O:17])[CH:12]=[CH:11][C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: O=C1CC(c2ccccc2)Cc2[nH]c(=O)ccc21
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2[nH]c(=O)ccc21
Yield: 79.7 %

Procedure:
A mixture of 7-phenyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.19 g), aminoguanidine hydrochloride (0.092 g), concentrated hydrochloric acid (0.04 ml), water (0.04 ml) and ethanol (20 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 5-guanidinoimino-7-phenyl-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (Compound 99) (0.21 g) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.CS(C)=O>O>[OH:6][CH:3]1[CH2:4][CH2:5][N:1]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:2]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: OC1CCNC1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(O)C2)cc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 56.3 %

Procedure:
To a seal tube was added pyrrolidin-3-ol (1 gm, 11.48 mmol), ethyl 4-fluorobenzoate (2.90 gm, 17.22 mmol) and DMSO (20 ml). The reaction was stirred at 110° C. for 20 hrs. After this time, the reaction was diluted with water (50 ml). The resulting solution was extracted with EtOAc (2×50 ml). The combined organics were washed with saturated NaHCO3 (50 ml), water (50 ml) and saturated aqueous NaCl (50 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 50-100% EtOAc/Hex) to give the product ethyl 4-(3-hydroxypyrrolidin-1-yl)benzoate (1.52 g, 6.46 mmol, 56.3% yield) as white solid. Anal. Calcd. for C13H12NO3 m/z 235.3, found: 236.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.97-7.87 (m, 2H), 6.61-6.44 (m, 2H), 4.77-4.57 (m, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.63-3.51 (m, 2H), 3.49-3.40 (m, 1H), 3.34 (d, J=10.8 Hz, 1H), 2.27-2.03 (m, 2H), 1.73 (d, J=4.4 Hz, 1H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3C(OC(C)(C)C)=O)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)N1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCCN2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[1-(tert-Butoxycarbonyl)piperidine-2-carbonyl]-piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (27) (1.35 g; 2.29 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 4 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product as a solid foam.
Reaction SMILES: C([NH:4][C:5]1[C:6]([CH3:13])=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[CH3:11])(=O)C.S(=O)(=O)(O)O>C(O)C>[NH2:4][C:5]1[C:6]([CH3:13])=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: CC(=O)Nc1c(C)ccc(O)c1C
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1ccc(O)c(C)c1N
Yield: 69.1 %

Procedure:
A mixture of 10 g of 3-acetamido-2,4-dimethylphenol (55.9 mmol), 250 ml of concentrated sulfuric acid and 200 ml of ethanol was refluxed for 30 minutes and, then, concentrated under reduced pressure. The residue was dissolved in water and the solution was made alkaline with ammonia water and extracted with ether. The ether layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate (dehydration) and concentrated under reduced pressure. The residue was recrystallized from ethanolhexane to give 5.3 g (69%) of the title compound as colorless plates, m.p. 177°-179° C.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][CH:4]([C:9]1[C:10]([CH3:28])=[N:11][C:12]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][CH:4]([C:9]1[C:10]([CH3:28])=[N:11][C:12]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(CC(C)(C)C)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc(N3CCCCC3)nc(C)c2C(CC(C)(C)C)C(=O)O)cc1
Yield: 30 %

Procedure:
This compound was prepared according to general method D from methyl 4,4-dimethyl-2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate (0.024 g; 0.059 mmol), sodium hydroxide 10N (0.100 mL; 1.00 mmol) in methanol (1 mL) at 60° C. for 18 h. Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane, followed by a purification by preparative HPLC (HPLC method 1) furnished 0.007 g (29%) of the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C@@H:7]1[C@@H:11]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:10][N:9]([CH2:21][C:22](=[O:38])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]3=[O:36])=[CH:26][C:25]=2[F:37])[CH2:8]1)C.[OH-].[Na+]>C1COCC1>[Cl:20][C:17]1[S:16][C:15]([C:13]([NH:12][C@H:11]2[CH2:10][N:9]([CH2:21][C:22](=[O:38])[NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]4=[O:36])=[CH:26][C:25]=3[F:37])[CH2:8][C@@H:7]2[O:6][CH2:5][C:4]([OH:39])=[O:3])=[O:14])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CO[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CO[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.7 %

Procedure:
A solution of 359 mg ((3S,4S)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidin-3-yloxy)-acetic acid ethyl ester (example 96.2) in 10 ml THF was treated with 1.24 ml 1N NaOH and stirred for 5 hrs at r.t. The reaction mixture was concentrated. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 7:3) to give 279 mg ((3S,4S)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidin-3-yloxy)-acetic acid as white solid. MS 549.3 ([M+H]+)
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH:5]1[CH2:10][CH2:9][C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)=O.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:42]3[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:41]=3[NH:40][C:39]2=[O:48])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CCOCC.O.CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:7][CH2:6][CH:5]([N:32]3[CH2:33][CH2:34][CH:35]([N:38]4[C:42]5[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:41]=5[NH:40][C:39]4=[O:48])[CH2:36][CH2:37]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)cc1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Reaction time: 64 h

Procedure:
A mixture of 11 g of 4,4-bis(p-fluorophenyl)cyclohexyl tosylate, 6 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone, 3.5 g of potassium carbonate, 4.1 g of potassium iodide and 80 ml of dimethylformamide is stirred at 70°-80° C for 64 hours. The reaction mixture is poured into water, ether is added to the separated semi-solid, and the whole is stirred for 30 minutes. The substance insoluble in water and ether is collected by filtration, washed with ether and dried. The obtained crystals are dissolved in a mixture of chloroform and methanol (9:1), and the solution is concentrated to some degree and cooled. The precipitated crystals are collected by filtration and purified in the same manner to give 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone as white crystals, melting at 279°-284° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([NH:17][CH2:18][CH2:19][OH:20])([CH3:16])([CH3:15])[CH3:14]>C(O)C>[CH2:1]([O:8][CH2:9][CH:10]([OH:11])[CH2:12][N:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:18][CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CO2)cc1
Reactant: CC(C)(C)NCCO
Solvent: CCO
Product: CC(C)(C)N(CCO)CC(O)COCc1ccccc1
Reaction time: 8 h
Yield: 83.5 %

Procedure:
A solution of 2-[(benzyloxy)methyl]oxirane (350 mg) and 2-(tert-butylamino)ethanol (500 mg) in ethanol (20 mL) was heated to reflux temperature and left at this temperature overnight. The solution was concentrated at reduced pressure. The residue was purified by filtration through a short pad of silica eluting with 20% methanol in dichloromethane. This gave the title compound as a colourless oil (501 mg)
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[CH:23][CH:22]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1>CO.C(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([CH:29]2[CH2:34][CH2:33][N:32]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([N:5]4[C@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]4=[O:9])=[CH:18][CH:17]=3)=[O:16])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:26]=1
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: O
Solvent: CO
Product: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a mixture of (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (499 mg) described in Preparation Example 18, (4-chlorophenyl)piperidin-4-ylmethanone hydrochloride (520 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM)(829 mg) were added chloroform (3 mL), methanol (3 mL) and N-methylmorpholine (220 μL) and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform:methanol) to give the title compound (728 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.C[O:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:28]3[CH2:34][CH:33]4[N:35]([CH3:36])[CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[C:17]3[C:22]([O:23][C:24]=2[CH:25]=1)=[C:21]([O:26][CH3:27])[CH:20]=[CH:19][CH:18]=3)=[O:11].[OH-].[Na+].COC(C1C=CC2N(C3CC4N(C)C(CC4)C3)C3C(OC=2C=1)=CC=CC=3)=O>O1CCOCC1>[CH3:27][O:26][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[O:23][C:24]1[CH:25]=[C:12]([C:10]([OH:11])=[O:9])[CH:13]=[CH:14][C:15]=1[N:16]2[CH:28]1[CH2:34][CH:33]2[N:35]([CH3:36])[CH:30]([CH2:31][CH2:32]2)[CH2:29]1
Reactant: COC(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CC2CCC(C1)N2C
Agent: COC(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COc1cccc2c1Oc1cc(C(=O)O)ccc1N2C1CC2CCC(C1)N2C

Procedure:
To a solution of the TFA salt of 6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid methyl ester, 2e (270 mg, 0.7 mmol) in dioxane (15 mL) was added sodium hydroxide (31 mg, 0.77 mmol) for 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid methyl ester, 2a, the title compound 6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid, 3e was obtained as a mixture of endo and exo isomers. MS m/z (MH+) 381.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][OH:15])[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:24].C([O-])(O)=O.[Na+]>>[OH:15][CH2:14][CH2:13][N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[I:24])[C:7]1=[O:12]
Reactant: I
Reactant: Nc1cccc2c(=O)n(CCO)ccc12
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1c2cccc(I)c2ccn1CCO
Reaction time: 1 h

Procedure:
5-Amino-2-(2-hydroxyethyl)isoquinolin-1(2H)-one (1.62 g, 0.00793 mol) was added to a solution of sodium nitrite (2 g, 0.03 mol) in dimethyl sulfoxide (40 mL, 0.5 mol) at 35° C. Aqueous hydrogen iodide (4 mL, 0.03 mol) in dimethyl sulfoxide (40 mL, 0.5 mol) was added, and the reaction mixture was stirred for 1 hour. The cooled reaction mixture was neutralized with sat. aq. NaHCO3 and extracted with methylene chloride (3×50 mL). The combined methylene chloride extracts were washed with brine, dried over sodium sulfate and reduced in vacuo. The mixture was purified by column chromatography using an ethyl acetate:hexanes (0-100) gradient. The combined pure fractions were reduced in vacuo to yield the title compound as an off white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][NH2:10].[CH3:15][S:16][C:17]1[C:22]([N:23]=[C:24]=[O:25])=[C:21]([S:26][CH3:27])[CH:20]=[C:19]([CH3:28])[N:18]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:15][S:16][C:17]1[C:22]([NH:23][C:24]([NH:10][CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:25])=[C:21]([S:26][CH3:27])[CH:20]=[C:19]([CH3:28])[N:18]=1
Reactant: CCCCC(CN)c1ccccc1C
Reactant: CSc1cc(C)nc(SC)c1N=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(CNC(=O)Nc1c(SC)cc(C)nc1SC)c1ccccc1C
Temperature: 25 °C
Yield: 32.9 %

Procedure:
A solution of 2-(2-methylphenyl)hexylamine (153 mg, 0.8 mmol) and 2,4-bis(methylthio)-6-methylpyridin-3-yl isocyanate (180 mg, 0.8 mmol) in 3 ml dimethylformamide was heated at 80° C. under nitrogen overnight. The reaction mixture was cooled to room temperature and diluted with 60 ml ethyl acetate. The resulting solution was washed sequentially with 3×50 ml water and 50 ml brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed on silica gel (200 g), eluting with 7:3 hexane/ethyl acetate to yield the title compound as a white solid (110 mg, 33% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[C:22]([S:24][CH3:25])[N:21]=[C:20]([CH3:26])[N:19]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:68]([O:70]CC)=[CH2:69])CCC>O1CCOCC1.O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].[Cu]I>[F:15][C:13]1[CH:14]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([C:68](=[O:70])[CH3:69])=[N:3][C:4]=2[C:18]2[CH:23]=[C:22]([S:24][CH3:25])[N:21]=[C:20]([CH3:26])[N:19]=2)[CH:10]=[N:11][C:12]=1[O:16][CH3:17]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ncc(Nc2ncc(Cl)nc2-c2cc(SC)nc(C)n2)cc1F
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(Nc2ncc(C(C)=O)nc2-c2cc(SC)nc(C)n2)cc1F
Temperature: 100 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
A mixture of 5-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amine (151 mg, 0.384 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (36.6 mg, 0.077 mmol, Aldrich, St. Louis, Mo.), palladium diacetate (8.63 mg, 0.038 mmol, Aldrich, St. Louis, Mo.), copper(I) iodide (15 mg, 0.077 mmol, Aldrich, St. Louis, Mo.), cesium fluoride (117 mg, 0.769 mmol, Alfa Aesar) and tributyl(1-ethoxyvinyl)tin (0.195 mL, 0.577 mmol, Aldrich, St. Louis, Mo.) in dioxane (3 mL) was stirred at 100° C. for 18 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography, eluting with 10% EtOAc/CH2Cl2 to give 1-(5-(5-fluoro-6-methoxypyridin-3-ylamino)-6-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-yl)ethanone (102 mg, 0.255 mmol, 66.3% yield). 1H NMR (300 MHz, CDCl3) δ 2.66 (s, 3H) 2.71 (s, 3H) 2.81 (s, 3H) 4.05 (s, 3H) 8.04-8.33 (m, 3H) 8.92 (s, 1H) 12.99 (s, 1H). m/z (ESI, +ve ion) 401.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:14][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:2]1[N:3]=[C:4]([NH:14][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1)[CH:17]=[CH2:18]
Reactant: CCCc1csc2c(NC)nc(Cl)nc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC)c2scc(CCC)c2n1
Yield: 67.2 %

Procedure:
50 mg (0.21 mmol) of 2-chloro-4-methylamino-7-propylthieno[3,2-d]pyrimidine and 189 mg (3.31 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 37 mg (yield: 68.5%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:11][C:5]([CH:6](O)[CH2:7][CH2:8][CH3:9])=[CH:4][CH:3]=1.[OH2:12]>>[CH2:7]([CH:6]1[C:2]([OH:11])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:12])[CH2:8][CH3:9]
Reactant: O
Reactant: CCCC(O)c1ccc(C)o1
Product: CCCC1C(=O)C=CC1(C)O
Yield: 81 %

Procedure:
Into a four necked flask equipped with an agitator and a thermometer, 5-methyl-α-n-propyl-furfuryl alcohol (40 parts) and water (1200 parts) were charged, and the resultant mixture was stirred at a temperature of 95° to 100° C. in a nitrogen stream, during which the pH was maintained at 4.9 to 5.3. After confirming the complete consumption of the starting compound by gas chromatography, the reaction mixture was cooled and extracted with methyl isobutyl ketone. The extract was concentrated to give 2-n-propyl-3-hydroxy-3-methyl-4-cyclopentenone in a yield of 81 %.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([CH2:8][CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:23]([C:28]([OH:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3C(=O)O)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1ccc(OCc2cccc(-c3ccccc3C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
3′-[4-(2-tert-Butoxycarbonylethyl)phenoxymethyl]biphenyl-2-carboxylic acid (0.15 g, 0.35 mmol) was dissolved in trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2-ethyl acetate) to give the title compound (21 mg, yield 16%) as a colorless powder. MS (APCI−): 375 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:33])[NH2:32])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:44]([O:46][CH2:47][CH3:48])=[O:45]>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([NH:32][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:33])=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CCC(N)=O)cc2)cc1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)CCc1ccc(Oc2ccc(C(=Cc3cc(OC)cc(OC)c3)C(=O)OC)cc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2-{4-[4-(2-Carbamoyl-ethyl)-phenoxy]-phenyl }-3-(3,5-dimethoxyphenyl)-acrylic acid methyl ester (7) was obtained as a byproduct in the synthesis of 3-(3,5-dimethoxy-phenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylic acid methyl ester, performed essentially as shown in PCT/US99/09982 (WO 99/58127). 7 (460 mg, 1.0 mmol) was taken up in dry THF (6 mL) and cooled to −78° C. To this solution, lithium diisopropyl amide (LDA) (2M, 0.55 mL, 1.1 mmol) was added and stirred for 10 min. Ethyl chloroformate (0.11 mL, 1.2 mmol) was added and stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution and ethyl acetate (50 mL) was added. The organic layer was washed with brine (2×20 mL), dried on anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel chromatography and eluted with hexane-ethyl acetate (7:3). Yield: 264 mg, 49.8%.