Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].P(Br)(Br)[Br:22].C(Cl)Cl>>[Br:22][CH:2]([C:4]1[O:5][C:6](=[O:20])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 51 %

Procedure:
The title compound was made in a similar way as that of the intermediate C6, using 3-(1-hydroxyethyl)-4-phenyl-1H-isochromen-1-one (Intermediate B1, 2.6 g, 9.76 mmol), 1M PBr3 in DCM (17.5 ml, 17.5 mmol) (30 ml) at RT. The crude was purified with Biotage Silica SNAP 100 g with a gradient of hexane and AcOEt to give the title compound (1.64 g, 51%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:50]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:50][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(CO)c2)NC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(CCl)c2)NC(=O)OC(C)(C)C)cc1

Procedure:
(S)-tert-Butyl 3-(3-(hydroxymethyl)phenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (1.0 g, 2.42 mmole) was dissolved in CH2Cl2 (5 ml). Triphenylphosphine (666 mg, 2.54 mmole) was added followed by N-chlorosuccinimide (355 mg, 2.66 mmole). After the vigorous reaction subsided, TLC showed ˜10% of unreacted starting material remained. Added 300 mg more N-chlorosuccinimide. TLC showed that the reaction was complete. The reaction mixture was purified without work-up by flash chromatography. Yield=1.0 g. MS (m/z) 433 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br.[Br:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=O>>[BrH:15].[N:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:16]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Product: COC(=O)c1ccc(-c2nc(-c3ccncc3)cs2)cc1
Yield: 66 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 4-bromoacetylpyridine hydrobromide to obtain methyl 4-[4-(4-pyridyl)-2-thiazolyl]benzoate hydrobromide. The product was recrystallized from ethanol. Yield: 66%. Pale yellow prisms. Melting point: 238 to 240° C.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:20]=[C:21]([CH2:28][OH:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=1[OH:25].C(OCC)(=O)C>C(Cl)Cl>[OH:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]2[O:4][C:3]([C:1]#[C:2][C:19]3[CH:20]=[C:21]([CH2:28][OH:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=3[OH:25])([CH3:17])[CH2:8][CH2:7][C:6]=2[C:9]=1[CH3:16]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: COc1cc(CO)cc(I)c1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(CO)cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)c1O

Procedure:
This compound was obtained by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 3-iodo-4-hydroxy-5-methoxybenzenemethanol [P. Claus et al. Monatsh. Chem. 103, 1178 (1972)] under the conditions described in Example 1. The product was isolated by chromatography over silica gel using 30% (V/V) of ethyl acetate in methylene chloride. Crystallization from ether/hexane yielded colorless crystals with m.p. 160°-163°.
Reaction SMILES: Br.[C:2]([S:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=[NH:4])[NH2:3].[C:16]([O-])(=O)[CH3:17].[NH4+].C([N:23]=[C:24]=[O:25])C.O>CN(C=O)C>[CH2:16]([N:13]([CH2:10][CH3:11])[C:24]([NH2:23])=[O:25])[CH3:17].[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][S:5][C:2](=[NH:3])[NH2:4])=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: CCN=C=O
Reactant: CC(=O)[O-]
Agent: Br
Agent: N=C(N)SCc1ccc([N+](=O)[O-])cc1
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-nitrobenzyl carbamimidothioate hydrobromide (2.5 g, 8.55 mmol) in DMF (10 mL) was added aqueous buffer solution of ammonium acetate (pH ˜7, 4.0 mL) followed by addition of ethyl isocyanate (10 mL. 85.57 mmol) at rt and the mixture stirred at rt for 48 h. After completion of reaction (by TLC), water (10 mL) was added and a white precipitate formed. The reaction mixture was filtered and solid was washed with water to obtain the desired product as white solid (1.40 g, 41%). MS: 354.18 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1.[N:21]([CH2:24][CH3:25])=[C:22]=[O:23]>CN(C)C=O>[CH2:24]([NH:21][C:22]([N:16]1[CH2:17][CH2:18][CH:13]([C:8]2[O:9][C:10]3[C:5]([C:6](=[O:20])[C:7]=2[CH3:19])=[CH:4][CH:3]=[C:2]([OH:1])[C:11]=3[CH3:12])[CH2:14][CH2:15]1)=[O:23])[CH3:25]
Reactant: Cc1c(C2CCNCC2)oc2c(C)c(O)ccc2c1=O
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)N1CCC(c2oc3c(C)c(O)ccc3c(=O)c2C)CC1
Reaction time: 48 h
Yield: 60.4 %

Procedure:
To a solution of 7-hydroxy-3,8-dimethyl-2-(piperidin-4-yl)-4H-chromen-4-one (68 mg, 0.25 mmol) obtained in Example 7-2 in dimethylformamide (2 mL), isocyanatoethane (19 μL, 0.25 mmol) was added dropwise under cooling with ice, and then the mixture was brought back to room temperature and stirred for 2 days. The reaction solution was concentrated, and then the obtained residue was purified by reverse-phase HPLC to obtain 52 mg of the title compound (yield: 59%).
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([N:18]=[CH:19]N(C)C)=[S:17])[CH:10]=1)(=[O:8])=[O:7])C.[CH2:23](Br)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].Cl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:24]([C:23]1[S:17][C:16]([NH:15][C:11]2[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=2)=[N:18][CH:19]=1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CN(C)C=NC(=S)Nc1cccc(S(=O)(=O)N=CN(C)C)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1cccc(Nc2ncc(C(=O)c3ccccc3)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
A mixture of 44 mg (0.13 mmol) N-Dimethylaminomethylene-3-(3-dimethylaminomethylene-thioureido)-benzenesulfonamide and 26 mg (0.13 mmol) phenacyl bromide in 0.8 ml DMF was stirred for 16 h at room temperature. 0.12 ml HCl (37%) was added and the mixture was stirred for 69 h at 100° C. After addition of 0.12 ml N,N-Diisopropylethylamine the mixture was subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 6 mg (13%) of the title compound.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)CCc1cccc(C(=O)O)c1
Reactant: NCc1ccccc1
Product: CC(C)CCc1cccc(C(=O)NCc2ccccc2)c1
Yield: 74.9 %

Procedure:
Using preparation method 1, 96B (288 mg, 1.5 mmol) was reacted with benzylamine (240 μL, 236 mg, 2.2 mmol). Purification by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100% afforded white crystals (316 mg, 74%). NMR 1H (ppm, CDCl3): 7.62 (s, 1H), 7.56-7.53 (m, 1H), 7.36-7.27 (m, 7H), 6.35 (br. s, 1H), 4.64 (d, J3=5.7 Hz, 2H), 2.66-2.60 (m, 2H), 1.64-1.46 (m, 3H), 0.92 (d, J3=6.3 Hz, 6H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[NH2:9][C:10]1[C:15]([Br:16])=[CH:14][C:13]([C:17](=[O:24])/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:12][C:11]=1[Br:25]>CS(C)=O>[NH2:9][C:10]1[C:11]([Br:25])=[CH:12][C:13]([C:17]([C@@H:18]2[CH2:4][C@H:19]2[C:20]([O:22][CH3:23])=[O:21])=[O:24])=[CH:14][C:15]=1[Br:16]
Reactant: C[S+](C)(C)=O
Reactant: COC(=O)/C=C/C(=O)c1cc(Br)c(N)c(Br)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@H]1C(=O)c1cc(Br)c(N)c(Br)c1

Procedure:
0.45 g (0.01781 mol) of 95% sodium hydride was added in small amounts to a solution of 3.9 g (0.02074 mol) of trimethyl-oxosulfonium iodide in 50 mL anhydrous dimethylsulfoxide at ambient temperature, with stirring. The mixture was stirred for another 30 minutes at ambient temperature and then a solution of 5.8 g (0.01598 mol) of methyl trans-4-(4-amino-3,5-dibromophenyl)-4-oxobutenoate in 50 mL of dimethylsulfoxide was added dropwise without external heating, whereupon the temperature of the mixture rose to 35° C., and stirring was continued for another hour at ambient temperature. The mixture was stirred into in 500 mL of saturated aqueous saline solution, then extracted exhaustively with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and evaporated down in vacuo. The residue yielded 2.6 g (43% of theoretical) of a colorless oil after purification by column chromatography on silica gel (30 to 60 μm) using EE/cyclohexane (1/1 v/v) as eluant. IR (KBr): 3475, 3363 (NH2); 1728, 1662 (C═O) cm−1; MS: M+=375/377/379 (Br2).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7](=[O:13])[C:8]([O:10]CC)=[O:9])=[CH:4][S:3]1.[OH-].[Na+]>>[O:1]=[C:2]1[NH:6][C:5]([C:7](=[O:13])[C:8]([OH:10])=[O:9])=[CH:4][S:3]1
Reactant: CCOC(=O)C(=O)c1csc(=O)[nH]1
Agent: CCOC(=O)C(=O)c1csc(O)n1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(=O)c1csc(=O)[nH]1
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylate, (1.45 g.) and 1 N sodium hydroxide aqueous solution (21 ml.) was allowed to stand for 30 minutes at room temperature. After the reaction, the reaction mixture was washed with diethyl ether and then adjusted to pH 1 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and diethyl ether and dried to give powder of 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylic acid, (0.30 g.). On the other hand, the filtration was extracted with ethyl acetate, and the ethyl acetate was distilled off from the extract to give the same object compound (0.40 g.).
Reaction SMILES: [OH-].[Na+].[I-:3].[Na+].[OH:5][C:6]1[C:7]([C:16]([OH:18])=[O:17])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CO>[OH:5][C:6]1[C:7]([C:16]([OH:18])=[O:17])=[CH:8][C:9]2[C:14]([C:15]=1[I:3])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: [I-]
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cc2ccccc2c(I)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A mixture of NaOH (2.12 g) in methanol (100 mL) was stirred until the solution was homogeneous. Sodium iodide (3.98 g) and 3-hydroxy-2-naphthoic acid (5.00 g) were added and allowed to stir for 30 min. The resulting suspension was cooled to 0° C. and a 5.25% (w/v) aqueous solution of sodium hypochlorite was added dropwise and stirring continued for 1 h. Saturated sodium thiosulfate (25 mL) was added and after 5 min the solution was acidified to pH 2 by addition of 6N HCl resulting in the formation of a yellow precipitate which was filtered and washed with water (50 mL). The precipitate was transferred to a round-bottomed flask, dissolved in methanol (70 mL) and toluene (100 mL), concentrated, redissolved in methanol (70 mL), concentrated, redissolved again in methanol (70 mL) and toluene (100 mL) and concentrated to afford the product as a yellow solid (6.26 g). MS m/z 313 (M−1). 1H NMR (DMSO-d6): δ12.41 (broad, 1 H), 8.63 (s, 1 H), 8.05-7.97 (m, 2 H), 7.70 (m, 1 H), 7.42 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[CH:7]/[C:8]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)([CH3:10])[CH3:9])=[O:5])[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)([CH3:10])[CH3:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)/C=C/C(C)(C)n1ccnc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(C)(C)n1ccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A mixture of 0.59 g of the 2-propenyl compound (prepared as described in Reference Example 9), 0.30 g of 5% palladium on carbon and 6 ml of ethanol was stirred at room temperature for 1.5 hours under an atmosphere of hydrogen, and the catalyst was filtered off. After evaporation under reduced pressure, the residue was purified by column chromatography on silica gel using a mixture of chloroform and ethanol (99:1) as eluent to give 0.57 g of the title compound having the following physical characteristics:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Br:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: Brc1cccc(Br)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CNc2cccc(Br)n2)cc1
Yield: 91.3 %

Procedure:
A solution of 2,6-dibromopyridine 6-1 (37.3 g, 157 mmol), 4-methoxybenzylamine (21.6 g, 157 mmol), and diisopropylethylamine (22.4 g, 173 mmol) in 1,4-dioxane (150 mL) was heated at reflux for 24 h. The reaction mixture was cooled, concentrated in vacuo, and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (125 mL). The organic layer was washed with water (100 mL) followed by brine (100 mL) and dried (Na2SO4). The organic layer was filtered, concentrated in vacuo, and purified by flash chromatography (silica, 10% to 40% EtOAc/hexanes) affording 42 g of amine 6-2 as a white solid in 91% yield.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N:22]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1)C.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[C:42]#[CH:43].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[C:42]#[C:43][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N:22]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][CH:24]([CH3:25])[CH3:26])[CH:15]=2)[C:4]([OH:3])=[O:33])=[CH:12][CH:11]=1
Reactant: C#Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(Cc1ccc(I)cc1)c1ccc(OC)c(N(CC(C)C)C(=O)C(C)(C)C)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(C(Cc2ccc(C#Cc3c(Cl)cccc3Cl)cc2)C(=O)O)cc1N(CC(C)C)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(4-iodophenyl)-2-{3-[(2,2-dimethylpropionyl) isobutylamino]-4-methoxyphenyl}propionic acid ethyl ester (0.15 g, 0.27 mmol) was dissolved in triethylamine (2 mL), the solution was further added with 1,3-dichloro-2-ethynylbenzene (0.15 g, 0.53 mmol), copper iodide (I) (5 mg, 0.026 mmol) and tetrakis(triphenylphosphine) palladium (15 mg, 0.013 mmol), and the mixture was stirred at room temperature for 15 hours. The solution was treated with a citric acid solution. The solution was then extracted with ethyl acetate, washed with a saturated brine, the extract was dried over anhydrous magnesium sulfate, evaporated under reduced pressure so as to remove the solvent, and the resultant residue was purified through silica gel column chromatography (hexane:ethyl acetate (v/v)=3:1) to thereby obtain 3-[4-(2,6-dichlorophenylethynyl)phenyl]-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl} propionic acid ethyl ester (yield: 0.11 g, yield ratio: 68%).
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21]>>[C:1]1([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][N:9]([C:20](=[O:21])[C:19]3[CH:18]=[C:17]([O:16][CH3:15])[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCC1(c2ccccc2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepared by the method of example 3.1 using 2-(3-phenyl-pyrrolidin-3-yl)-ethanol (10.47 mmol) and 3,4,5-trimethoxy-benzoyl chloride (10.49 mmol). Chromatographed on silica gel (200 g ) eluting with ethyl acetate and then 3% methanol in dichloromethane to give the title compound:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:26]=O)[CH:9]=1.CO.[CH3:30][NH2:31].[BH4-].[Na+].[ClH:34].C(=O)([O-])O.[Na+]>CO>[ClH:34].[CH3:30][NH:31][CH2:26][C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:23])=[O:24])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=1
Reactant: Cc1ccccc1-c1cc(C=O)cn1S(=O)(=O)c1cccc(S(C)(=O)=O)c1
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2C)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
5-(2-Methylphenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (250 mg) was dissolved in methanol (25 mL), 40% methylamine methanol solution (482 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (71 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (30 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3), and dissolved in methanol (5 mL). To the solution was added a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 156 mg, 55%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl[CH2:13][C:14]#[N:15].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH:6]([C:5]1[C:4]([CH3:11])=[CH:3][C:2]([O:1][CH2:13][C:14]#[N:15])=[CH:9][C:8]=1[CH3:10])=[O:7]
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cc(OCC#N)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-hydroxy-2,6-dimethyl-benzaldehyde (150 mg), chloroacetonitrile (0.1 mL), and Cs2CO3 (390 mg) in acetone (10 mL) was stirred at room temperature for 16 h. The mixture was concentrated, diluted with water, and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography (SiO2, 3:1 hexane/EtOAc) gave (4-formyl-3,5-dimethyl-phenoxy)-acetonitrile.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:17]([NH2:20])[CH:18]=[CH2:19].C(=O)([O-])O.[Na+]>>[CH2:17]([NH:20][C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]([CH3:16])=[CH2:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:18]=[CH2:19]
Reactant: C=CCN
Reactant: C=C(C)CNc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC(=C)C)c2scc(C)c2n1
Yield: 32.8 %

Procedure:
305 mg (1.2 mmol) of 2-chloro-7-methyl-4-(2-methyl-2-propenylamino)thieno[3,2-d]pyrimidine and 1.14 g (19.2 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 108 mg (yield: 32.7%) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]3[CH:26]=[N:25][N:24]([CH3:27])[C:22]3=2)[N:17]([S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:16]=1)[CH3:14].[I:38]I.CC(O)=O.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[CH2:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]3[CH:26]=[N:25][N:24]([CH3:27])[C:22]3=2)[N:17]([S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=2)(=[O:30])=[O:29])[C:16]=1[I:38])[CH3:14]
Reactant: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc3cnn(C)c3c12
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCc1c(I)n(S(=O)(=O)c2ccc(C)cc2)c2ncc3cnn(C)c3c12
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
Diisopropylamine (0.260 mL, 1.83 mmol) in THF (5 mL) was cooled to about −70° C. then the n-BuLi (1.6 M in hexanes, 1.04 mL, 1.67 mmol) was added drop-wise. The mixture was stirred at about −70° C. for about 15 min then allowed to warm to about 20° C. The resulting solution was added drop-wise to the 8-ethyl-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.295 g, 0.832 mmol) in THF (5 mL) at about −60 to −70° C. then the mixture was stirred for about 1 h. Iodine (0.239 g, 0.942 mmol) in THF (2 mL) was added drop-wise to the mixture and then it was stirred at about −70° C. for about 1 h. The reaction was treated with AcOH (0.143 mL, 2.50 mmol) then about 1 mL of saturated aqueous NH4Cl was added then the solution was warmed to rt. The mixture was diluted with EtOAc (50 mL) and water (20 mL) then the layers were separated. The organic layer was washed with saturated aqueous NaCl (20 mL) then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified on a 10 g silica gel column with 94:6 DCM/EtOAc as an eluent to give 8-Ethyl-7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.155 g, 39%): LC/MS (Table 2, Method a) Rt=2.78 min; MS m/z 481 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH2:8][CH2:9]Br)[CH:3]=1.C(OCC)(=O)[CH2:12][C:13]([O:15]CC)=[O:14]>>[C:13]([CH2:12][CH2:9][CH2:8][CH2:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)([OH:15])=[O:14]
Reactant: Cc1cc(CCCBr)no1
Reactant: CCOC(=O)CC(=O)OCC
Product: Cc1cc(CCCCC(=O)O)no1
Yield: 56 %

Procedure:
3-(4-Carboxybutyl)-5-methylisoxazole was prepared from 5-methyl-3-(3-bromopropyl)isoxazole and diethyl malonate according to the procedure of part (c) above, and was obtained in 56% yield as a colorless solid, m.p. 58°-60° C. when recrystallized from carbon tetrachloride.