Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(N[C@H]2CC[C@H](C)CC2)CCC1.NC1SC=NC=1.C([O:49][C:50](=[O:54])C(S)C)C>>[CH:24]1([N:16]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:50]([OH:54])=[O:49])=[CH:9][N:10]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCC2)[C@H]2CC[C@H](C)CC2)s1
Reactant: CCOC(=O)C(C)S
Agent: C[C@H]1CC[C@H](NC2CCC2)CC1
Agent: Nc1cncs1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCC2)CC1

Procedure:
{2-[3-Cyclobutyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester prepared as described in general procedure (A) using cyclobutyl-(trans-4-methyl-cyclohexyl)-amine and 5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.Cl[C:10]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH3:12].ClC(=C(C(OCC)=O)C(OCC)=O)CC.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:7]([N:6]1[C:2]([NH:1][C:10](=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH3:12])=[CH:3][CH:4]=[N:5]1)[CH3:8]
Reactant: CCn1nccc1N
Reactant: CC=C(Cl)C(C(=O)OCC)C(=O)OCC
Agent: CCOC(=O)C(C(=O)OCC)=C(Cl)CC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)=C(CC)Nc1ccnn1CC
Temperature: 90 °C

Procedure:
5-Amino-1-ethylpyrazole (5.85 g, 0.0526 moles, 1.06 equivalents) was added in one portion to 31.35 g of a solution at room temperature, wherein the solution is of diethyl (1-chloro-1-propen-1-yl)propanedioate and/or diethyl (1-chloropropylidene)propanedioate (about 11.65 g, 0.0496 moles, 1.0 equivalent) in toluene (about 19.70 g). Triethylamine (14 ml, 10.05 g, 0.0993 moles, 2.0 equivalents) was added slowly to the reaction mixture ensuring Tint<30° C. by use of an ice bath. The reaction mixture was then heated at 90° C. for approximately 15.5 hours and then was allowed to cool to room temperature. The reaction mixture was filtered, the filter cake washed with toluene (23 ml), and then the filter cake was pulled dry. Toluene (12 ml) was added to the filtrate, and the solution was concentrated in vacuo to about 55 ml volume. Toluene (12 ml) was added to the solution which was then concentrated down to about 55 ml, and this toluene (12 ml) addition and evaporation was repeated. The toluene solution (about 55 ml) washed with 2M aqueous sodium hydroxide solution (55 ml), and the two layers were separated. The organic layer was concentrated to dryness to yield diethyl {1-[(1-ethyl-1H-pyrazol-5-yl)amino]propylidene}propanedioate as a brown liquid (11.11 g, about 72% theory yield). HPLC (5 min generic solvent gradient): TRET about 3.05. Mass Spectrum: Found: MH+ 310.1, (M-H)− 308.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13](=O)[C:14]([NH2:16])=O)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].B.C1COCC1.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(C(=O)C(N)=O)c2c1
Agent: B
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cccc(CCN)c2c1
Yield: 80 %

Procedure:
480 mg of the compound obtained in Step B dissolved in THF (20 ml) are introduced into a reactor, followed by 2 eq. of AlCl3 and finally, slowly, 6 eq. of BH3.THF solution, and the reaction mixture is stirred for 2.5 hours. Water (12 ml) is then added, followed by 25 ml of 1N sodium hydroxide solution together with 800 mg of solid sodium hydroxide, and three extractions with methyl tert-butyl ether (20 ml) are carried out. The solvents are then dried over Na2SO4 and then evaporated off to yield the title product in the form of a yellow oil in a yield of 80% and with a chemical purity of 95%.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([O:24][CH3:25])=[O:23])=[CH:12][CH:11]=2)=[C:4]([CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1.[Cl:30][CH2:31][C:32](O)=[O:33].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:26]([C:4]1[N:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][Cl:30])[NH:7][C:6](=[O:8])[C:5]=1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24][CH3:25])=[O:23])=[CH:14][CH:15]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1nc(N)[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: O=C(O)CCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCc1nc(NC(=O)CCl)[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 8 h

Procedure:
A solution of 0.4 g of 2-amino-6-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]pyrimidin-4-one in, 10 ml of anhydrous DMF is added in succession with 0.1 g of chloroacetic acid, 0.21 g of DCC and 0.17 g of HOBT. After 8 h under magnetic stirring, the resulting solid is filtered off and the solvent is evaporated under reduced pressure. The residue is taken up with H2O and extracted with AcOEt. The organic phase is dried over Na2 SO4 and evaporated under reduced pressure to obtain 0.47 g of a yellowish spongy solid which can be reacted without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][OH:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][OH:28])[N:8]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CO)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 49.8 %

Procedure:
A mixture of 4′-{[4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1 g), cesium carbonate (2.1 g), 2-(bromomethyl)pyridine hydrobromide (0.81 g) and N,N-dimethylformamide (10 mL) was stirred at 50° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.62 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Br:14])=[O:23]
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Reactant: O=C=Nc1ccccc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Br)c1
Reaction time: 4 h
Yield: 72.6 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-bromophenyl isocyanate (0.30 ml, 2.40 mmol) in THF (2 ml) was added Et3N (33 ml, 0.24 mmol) at room temperature. After 4 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-bromophenyl)ureido]phenylacetate (770 mg, 73%) as a pale brown powder. 1H-NMR (CDCl3) δ3.55 (s, 2H), 3.70 (s, 3H), 6.97 (dd, J=7.3, 1.5 Hz, 1H), 7.22 (dd, J=8.5, 2.2 Hz, 1H), 7.29-7.33 (m, 2H), 7.48 (d, J=1.0, 2.2 Hz, 1H), 7.54 (dd, J=8.0, 1.2 Hz, 1H), 8.01 (m, 2H); MS (ESI) m/z 443 (M++1), 445 (M++3), 447 (M++5).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH:7]1[CH2:8][CH2:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCC(OS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (2.4 mL, 31 mmol) was slowly added to a dichloromethane solution (75 mL) of ethyl 4-hydroxycyclohexanecarboxylate (4.63 mL, 28.7 mmol) and triethylamine (8.2 mL, 59 mmol) at 0° C. The reaction mixture was stirred for 30 minutes, concentrated in vacuo and diluted in diethyl ether (100 mL). The solution was washed with 10% hydrochloric acid (25 mL), water (25 mL), and saturated sodium bicarbonate (15 mL). The organics were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 1.23 (t, J=7.1 Hz, 3H), 1.54-1.82 (m, 4H), 1.87-1.97 (m, 2H), 2.00-2.08 (m, 2H), 2.34-2.41 (m, 1H), 3.00 (s, 3H), 4.13 (q, J=7.1 Hz, 2H), 4.88-4.92 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.Cl[C:27]([O:29][CH3:30])=[O:28].C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[C:7]([C:27]([O:29][CH3:30])=[O:28])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: COC(=O)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.50 g, 1.612 mmol, see Example 1) was dissolved in THF (15 mL) and cooled to −78° C. s-BuLi (2.54 mL, 3.56 mmol) was then added dropwise, and the solution was stirred at −78° C. for 30 minutes. Methyl chloroformate (0.38 mL, 4.98 mmol) was then added as a THF (2 mL) solution, and the reaction was stirred for an additional 30 minutes. The reaction was then quenched with saturated NH4Cl and allowed to warm to room temperature. The reaction was then extracted with DCM (3×50 mL), dried, and filtered to give a crude residue. The crude residue was purified by column chromatography with 5:1 hexane:DCM to give methyl 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.55 g, 91% yield).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:8]([CH:10]([CH:12]=[CH2:13])[OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(OCC)(=O)C>O1CCOCC1.O=[Mn]=O>[CH2:1]([C:5]1[NH:9][C:8]([C:10](=[O:11])[CH:12]=[CH2:13])=[C:7]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(O)c1nc(CCCC)[nH]c1SCc1ccc(OC)cc1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CC(=O)c1[nH]c(CCCC)nc1SCc1ccc(OC)cc1
Yield: 90.5 %

Procedure:
3 g of the product of Stage 3 were dissolved at 30° C. in 60 ml of dioxane and the medium was allowed to return to ambient temperature. 1.56 g (2 equivalents) of MnO2 were added about every 30 minutes for about 2 hours, that being 10 equivalents in total. The mixture was poured into 500 ml of ethyl acetate and filtration was carried out. The filtrate was evaporated to dryness to obtain 2.7 g of a yellow solid which was chromatographed on silica with AcOEt/flugene (1-2) to obtain 2.1 g of the expected product (vivid yellow solid).
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.CCOC(C)=O>[CH3:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([C:1]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:5]
Reactant: CNc1ccccc1
Reactant: O=C(O)C1(C(=O)O)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)C1(C(=O)O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a solution of cyclopropane-1,1-dicarboxylic acid (1.5 g, 11.53 mmol) in THF (24 mL) TEA (1.6 mL, 11.53 mmol) was added dropwise and under stirring thionyl chloride (0.83 mL, 11.53 mmol) and the mixture stirred 30 min at room temperature. A solution of N-methylaniline (1.3 mL, 11.53 mmol) in THF (14 mL) was added dropwise at 0° C. and the mixture was stirred for 2 h. The mixture was diluted with EtOAc, extracted with 2N NaOH, acidified to pH˜2 by addition of 2N HCl and extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure affording 246 (1.24 g, 5.66 mmol, 49%) as a white solid. MS (m/z): (M+1) 220.0 (100%).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O.Cl>C(O)(=O)C>[CH3:11][N:12]1[CH:13]=[CH:14][CH:15]([C:3]2[C:2]([OH:10])=[CH:9][C:7]([CH3:8])=[CH:6][C:4]=2[OH:5])[CH2:16][CH2:17]1
Reactant: Cc1cc(O)cc(O)c1
Reactant: CN1CCCCC1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(O)c(C2C=CN(C)CC2)c(O)c1
Yield: 30.1 %

Procedure:
Orcinol hydrate (15 g) and N-methylpiperidone (11.0 g) were dissolved in 30 ml acetic acid and treated with HCl gas as described in Example VI giving 6.42 g of product, m.p. 241°-243°.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]2[CH2:8][CH:9]=[C:10]([CH:12]=O)[CH:11]=[C:5]2[O:4][CH2:3]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=4[CH:11]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: O=CC1=CCC2NC(=O)COC2=C1
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(N2CCN(Cc3ccc4c(c3)OCC(=O)N4)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
A mixture of 3-oxo-dihydro-2H-benzo[1,4]oxazine-7-carbaldehyde (0.5 g, 2.8 mmol), 1-(4-methyl-phenyl)-piperazine (0.5 g, 2.8 mmol), acetic acid (0.17 g, 2.8 mmol) and sodium triacetoxyborohydride (1.2 g, 5.9 mmol) in 20 mL of 1,2-dichloroethane is stirred at room temperature for 3 hours. The reaction is quenched with 50 mL of water, and the layers are separated. The aqueous phase is extracted with ethyl acetate (3×50 mL). The organic phases are combined and dried over sodium sulfate. Evaporation of the solvent gives a solid which is recrystallized twice from acetonitrile to give 0.31 g (33% yield) of 7-[4-(4-methyl-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazine-3-one; mp 208-210° C.
Reaction SMILES: [CH3:1][S:2][C:3]([S:30][CH3:31])=[CH:4][C:5]([C:7]1[N:23](C2CCCCO2)[C:10]2=[CH:11][C:12]3[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=3[CH:17]=[C:9]2[N:8]=1)=[O:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH3:31][S:30][C:3]([S:2][CH3:1])=[CH:4][C:5]([C:7]1[NH:23][C:10]2=[CH:11][C:12]3[C:13]([CH3:21])([CH3:22])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=3[CH:17]=[C:9]2[N:8]=1)=[O:6]
Reactant: CCN1C(=O)C(C)(C)c2cc3c(cc21)nc(C(=O)C=C(SC)SC)n3C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(C(=O)C=C(SC)SC)nc3cc21
Temperature: 25 °C
Yield: 38.6 %

Procedure:
Crude 2-(3,3-bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-1-(tetrahydro-pyran-2-yl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (2.25 g, 4.9 mmol) and p-toluenesulfonic acid monohydrate (0.5 g, 2.6 mmol) was dissolved in methanol (25 mL) and water (3 mL) and stirred at reflux for 3 h. After cooling to room temperature, water (50 mL) was added and the mixture extracted with etyhl acetate (3×50 mL). The combined organic layers were washed with water and concentrated in vacuo. The crude product was recrystallized from methanol to yield 2-(3,3-bis-methylsulfanyl-acryloyl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (0.71 g, 39%) as yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C@H:34]([OH:39])[C:35]([F:38])([F:37])[F:36].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:32][CH2:33][C@H:34]([OH:39])[C:35]([F:38])([F:37])[F:36])=[O:30])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: NC[C@H](O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)C(F)(F)F)[nH]2)c1
Reaction time: 2 h
Yield: 64.8 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (408 mg, 0.94 mmol) synthesized in Example (18a), (2S)-3-amino-1,1,1-trifluoro-2-propanol (177 mg, 1.37 mmol) and 4-dimethylaminopyridine (224 mg, 1.87 mmol) were dissolved in dichloromethane (20 mL), and WSCI.HCl (193 mg, 1.01 mmol) was added at room temperature, followed by stirring for 2 hours under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (200 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-70%) to afford the desired product (339 mg, yield 67%) as a white amorphous substance.
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)CC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[F:35].[CH2:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH2:37][CH3:38]>C1(C)C=CC=CC=1.C(O)C>[CH2:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH2:37][CH3:38].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:48]([NH:47][C:45](=[O:46])[C:42]2[CH:43]=[CH:44][C:39]([CH2:36][CH2:37][CH3:38])=[CH:40][CH:41]=2)=[S:49])=[CH:30][C:29]=1[F:35]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CCCc1ccc(C(=O)Cl)cc1
Agent: CCCc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
4-Propyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-propyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-propyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (71 mg, yield 86%).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(C1C=CC(C)=CC=1)(=O)=O.[I-:33].[Na+].O>CC(C)=O>[CH2:26]([O:25][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH2:14][CH2:13][CH2:12][I:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCCCC(COc2ccc(F)cc2)OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Fc1ccc(OCC(CCCI)OCc2ccccc2)cc1
Yield: 79.7 %

Procedure:
A solution of 4-benzyloxy-5-(4-fluorophenoxy)-1-pentanol tosylate (3.78 g., 8.24 mmoles) and sodium iodide (3.71 g., 25 mmoles) in acetone (70 ml.) is stirred at room temperature overnight (ca. 17 hours) and then heated on the steam bath for 15 minutes. The mixture is poured into cold water and extracted with ether three times. The combined extracts are washed with aqueous sodium thiosulfate and dried over anhydrous magnesium sulfate. The solvent is removed on a rotary evaporator to leave an oil residue which is further purified by chromatography on a silica gel (70 g.) column. Elution with chloroform gives the pure title compound (2.72 g., 6.57 mmoles, 79%). ir (neat) 3.28, 3.40, 6.20, 6.62, 6.87, 8.00, 8.23, 9.10, 12.07, 13.16, 13.58, 14.37μ; pmr (CCl4)δ1.4-2.2 (4H, m), 3.08 )2H, t, J=6Hz), 3.5-4.1 (3H, m), 4.47 (1H, d, J=12 Hz), 4.69 (1H, d, J=12Hz), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: N[C:2]1C=C(C)NC(=O)N=1.FC1C=CC(B(O)O)=CC=1.NC1C=CN(C2C=CC(F)=CC=2)C(=O)N=1.[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[C:41](=[O:52])[N:40]2[CH:53]=1>>[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[C:43]([CH3:2])[N:42]([C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[C:41](=[O:52])[N:40]2[CH:53]=1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Reactant: Cc1cc(N)nc(=O)[nH]1
Agent: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Agent: OB(O)c1ccc(F)cc1
Product: Cc1cc2nc(CCl)cn2c(=O)n1-c1ccc(F)cc1

Procedure:
2-Chloromethyl-6-(4-fluoro-phenyl)-7-methyl-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from 4-amino-6-methyl-1H-pyrimidin-2-one and 4-fluorophenylboronic acid using the methods as described above for the preparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]CC.[Na+].CCCCCC>C1COCC1>[OH:17]/[C:11](=[CH:9]\[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10])/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cncc(C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(O)=C/C(=O)c1cncc(C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-2 (0.5 g, 3.70 mmol) and diethyl oxalate (1.010 ml, 7.40 mmol) in THF (15 ml) was added sodium ethoxide (3.45 ml, 21% wt. in ethanol, 9.25 mmol). The resulting mixture was heated at 60° C. for 1 h followed by stirring at rt overnight. The reaction mixture was poured into cold hexane and the desire product 1-3 was collected as a light yellow solid: ESI+ MS [M+H]+ C12H14NO4=236.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:24]([C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31])#[N:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:31])#[N:25]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: N#Cc1ccccc1C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1C#N
Yield: 86.3 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2-cyanocinnamic acid (2.1 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.2 g, 86%) as crystals.