Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][O:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][N:33](C(OC(C)(C)C)=O)[CH2:34][C@@H:21]23)[CH:26]=1>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:17][C:18]1[CH:19]=[C:20]2[C:24]3=[C:25]([CH2:27][O:28][CH2:29][CH2:30][N:23]3[C@H:22]3[CH2:31][CH2:32][NH:33][CH2:34][C@@H:21]23)[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Product: FC(F)(F)c1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C(F)(F)F)c1

Procedure:
Using 2,4-bis(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 129. LRMS (ES)+: 472.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[N+:22]([C-:25]([CH:28]=O)[CH:26]=O)([O-:24])=[O:23].[Na+].O>CC(O)=O>[N+:22]([C:25]1[CH:26]=[N:1][C:2]2[N:6]([N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)[C:3]=2[C:20]#[N:21])[CH:28]=1)([O-:24])=[O:23]
Reactant: O=C[C-](C=O)[N+](=O)[O-]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc([N+](=O)[O-])cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (83 mg, 0.3 mmol) in HOAc (2 mL) was added sodium 2-nitro-1,3-dioxopropan-2-ide (47 mg, 0.3 mmol). After stirring at RT for 1 hr, water (2 mL) was added. The mixture was partitioned between EA (25 mL) and brine (25 mL). The combined organic layers were washed with brine (25 mL×2), dried over Na2SO4 and concentrated to afford 90 mg of 6-nitro-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (84%) as a yellow solid. MS (ESI) m/e [M+1]+ 358.2.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH:15]([CH3:17])[N:14]([CH3:18])[CH:13]([CH3:19])[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[CH3:18][N:14]1[CH:15]([CH3:17])[CH2:16][NH:11][CH2:12][CH:13]1[CH3:19]
Reactant: CC1CN(C(=O)OCc2ccccc2)CC(C)N1C
Agent: [Pd]
Solvent: CCO
Product: CC1CNCC(C)N1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under an inert atmosphere of nitrogen, 3,4,5-trimethyl-piperazine-1-carboxylic acid benzyl ester (1 eq, 1.87 mmol, 0.49 g) is dissolved in EtOH (20 ml) and palladium on carbon (0.1 eq, 0.187 mmol, 0.2 g) is added. The reaction is stirred at room temperature under an atmosphere of hydrogen for 4 hrs. The reaction mixture is filtered through Celite® and the solvent evaporated under vacuo to afford the title compound.
Reaction SMILES: [ClH:1].CO[C:4](=[NH:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH3:14]>CO>[ClH:1].[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH2:13])=[NH:14])=[CH:6][CH:7]=1
Reactant: COC(=N)c1ccc(OC)cc1
Reactant: N
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=N)N)cc1
Temperature: 0 °C

Procedure:
35.9 g of 4-methoxybenzimidic acid methylester hydrochloride was dissolved in 300 ml of methanol. After saturation with ammonia gas under cooling in ice-water and stirring, the solution was stirred at room temperature for 15 hours. Then, methanol was evaporated in vacuo. Ethyl acetate was added to the residue. The precipitated crystals were filtered off and dried. Whereby 30.9 g of the desired substance was obtained as white crystals. Melting point is 220° to 221° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[C:22]([F:25])([F:24])[F:23])=[C:11]([F:28])[CH:10]=2)[S:3]1.Cl[CH2:30][CH2:31][N:32]([CH3:34])[CH3:33]>>[CH3:33][N:32]([CH3:34])[CH2:31][CH2:30][N:6]1[C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[C:22]([F:25])([F:23])[F:24])=[C:11]([F:28])[CH:10]=2)[S:3][C:2]1=[O:1]
Reactant: CN(C)CCCl
Reactant: N#Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2F)c(C(F)(F)F)c1
Product: CN(C)CCN1C(=O)SC(=Cc2ccc(Oc3ccc(C#N)cc3C(F)(F)F)c(F)c2)C1=O

Procedure:
The title compound was prepared using 4-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-fluoro-phenoxy]-3-trifluoromethyl-benzonitrile and (2-Chloro-ethyl)-dimethyl-amine as described in Example 1. 1H NMR (400 Hz, CDCl3) δ7.95 (s, 1H), 7.76 (s, 1H), 7.69 (dd, 1H), 7.27 (m, 3H), 6.84 (d, 1H), 3.91 (t, 2H), 2.76 (bt, 2H), 2.40 (s, 6H); LC/MS (m/z) [M+1]+ 480.1 (calculated for C22H18F4N3O3S, 480.45).
Reaction SMILES: C(C1C(F)=CC(O)=C(C=1)C(NCC1C=CC=C([N+]([O-])=O)C=1)=O)#N.C([O:26][C:27](=[O:52])[CH2:28][O:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([C:37]#[N:38])=[CH:32][C:31]=1[C:39](=[O:51])[NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([N+:48]([O-:50])=[O:49])[CH:43]=1)C.CO>O1CCOCC1.ClCCl>[C:37]([C:33]1[C:34]([F:36])=[CH:35][C:30]([O:29][CH2:28][C:27]([OH:52])=[O:26])=[C:31]([C:39](=[O:51])[NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([N+:48]([O-:50])=[O:49])[CH:43]=2)[CH:32]=1)#[N:38]
Reactant: CCOC(=O)COc1cc(F)c(C#N)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Agent: N#Cc1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)c(O)cc1F
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)c(OCC(=O)O)cc1F

Procedure:
[4-Cyano-5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid was prepared in an analogous manner to that set forth in Example 45 (Steps 8-9) except that in Step 8, 5-cyano-4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide was used in place of N-(4-bromo-2-fluorobenzyl)-4-fluoro-2-hydroxy-5-methyl-benzamide. In Step 9, special care was taken in the hydrolysis of [4-cyano-5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester. The hydrolysis was performed in dioxane instead of ethanol and quenched after 15 minutes to prevent hydrolysis of the cyano functionality: mp 179-180° C.; Rf 0.22 (20 6 methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 9.12 (t, J=6.0 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H), 8.19 (s, 1H), 8.10 (dd, J1=8.4 Hz, J2=2.6 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.45 (d, J=11.4 Hz, 1H), 4.99 (s, 2H), 4.61 (d, J=6.0 Hz, 2H); ESI-LC/MS m/z calcd for C17H12FN3O6: 373.1; Found 472.0 (M−1)−. Anal. calcd for C17H12FN3O6: C, 54.70; N, 11.26; H, 3.24. Found C, 54.43; N, 11.07; H, 3.32.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:22](=[O:23])[C:21]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:19]([O:18][CH3:17])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Product: COc1cc(OC)cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
The method of example 3.1 was used with 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (1 mmol) and 3,5-dimethoxy-benzoyl chloride (1 mmol) to prepare the title compound. Chromatography on silica gel eluting sequentially with ethyl acetate and then 6% methanol in dichloromethane gave the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]1=[O:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])[C:24]1=[O:31])=[O:29]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: COc1ccccc1N1CCC(C(=O)O)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCC(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)C1=O
Yield: 67.8 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 1-(2-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.102; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in dichloromethane (2 mL) and DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.121 g (68%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2-methoxyphenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [Na].[SH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:7]([O:6][C:4]([CH2:3][S:2][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:8]
Reactant: CCOC(=O)CCCCl
Reactant: CCOC(=O)CS
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCCSCC(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
Sodium metal (4.3 g, 0.18 mol) was added cautiously in small portions to ethanol (150 mL). After the sodium completely dissolved, the mixture was cooled to 0° C. and ethyl 2-sulfanylacetate (21.9 g, 0.18 mol), was added. Ethyl 4-chlorobutanoate (27.4 g, 0.18 mol) was then added slowly and the resulting mixture stirred overnight at rt. The solid was filtered off, and then the filtrate concentrated under reduced pressure. The oil obtained was partitioned between water and ethyl acetate. The organic layer was collected, dried over anhydrous Na2SO4 and concentrated under vacuum to give the desired ethyl 4-((ethoxycarbonyl)methylthio)butanoate (40.2 g, 95%) as colorless oil. The crude material was used without further purification in the follow step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:19][CH2:20][CH2:21][Cl:22]>C1COCC1>[Cl:22][CH2:21][CH2:20][CH2:19][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: ClCCCBr
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(CCCCl)(C(=O)O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
Under a nitrogen atmosphere, to a mixture of 2-(4-chlorophenyl)propanoic acid (13.3 g) in THF (140 mL) was added n-butyllithium (1.6M hexane solution, 90.3 mL) at −60° C. to —70° C., and the mixture was allowed to warm to −20° C. 1-Bromo-3-chloropropane (11.4 g) was added to the reaction mixture at −20° C. to 10° C., and the mixture was stirred at room temperature for 12 hr. The reaction mixture was extracted with 1N aqueous sodium hydroxide solution (2×100 mL), and the extract was acidified with 3N hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (3×100 mL), the extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15.7 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:14]([O:16][CH2:17]Cl)[CH3:15]>CN(C=O)C>[CH2:14]([O:16][CH2:17][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:15]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCOc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
A mixture of 10 g of 3-(trifluoromethyl)phenol and 15 ml of DMF was added dropwise to a mixture of 2.71 g of sodium hydride (60%, oil-based) and 45 ml of DMF under ice-cooling, and the mixture was stirred for 30 minutes. Subsequently, a mixture of 7.0 g of chloromethyl ethyl ether and 5 ml of DMF was added dropwise thereto, and the mixture was stirred for 1 hour. The reaction mixture was added to ice water. This mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure, to obtain 13 g of 1-ethoxymethoxy-3-(trifluoromethyl)benzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Br:11])[N+:3]=1[O-].O>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)[n+]([O-])c(Br)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Br)nc(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
2,6-dibromo-4-nitro pyridine 1-oxide (14.5 g, 48.6 mmol) was taken up in 130 mL of acetic acid and iron powder (11 g, 196.9 mmol) was added in portionwise and the mixture was stirred at room temperature for 45 minutes. 500 mL of water was added and the product was extracted with EtOAc (500 mL). The organic layer was washed with 300 mL of water then with 300 mL of a sat K2CO3 sol and then with 300 mL of brine. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give 11.1 g of the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:28])[CH2:12][N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][C:19]4=[O:27])[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].NCC(O)=O>O1CCOCC1.[Cu]I>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:28])[CH2:12][N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)[C:19]4=[O:27])[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(CN1CCC2(CC1)C(=O)Nc1ccccc12)N1CCN(C2CCC2)CC1
Reactant: Brc1ccccn1
Agent: [Cu]I
Agent: NCC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C(CN1CCC2(CC1)C(=O)N(c1ccccn1)c1ccccc12)N1CCN(C2CCC2)CC1
Temperature: 110 °C

Procedure:
A mixture of 1′-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]spiro[indole-3,4′-piperidin]-2(1H)-one (0.052 mmol), 2-bromopyridine (0.078 mmol), CuI (2 mg, 0.01 mmol), K3PO4 (28 mg, 0.13 mmol), glycine (1 mg, 0.012 mmol) in 1,4-dioxane (3 ml) is degassed by Argon then heated in a sealed tube at 110° C. for 24 h. Solid is filtered and the filtrate is concentrated and purified by PTLC to give the title compound as a light yellow solid. LC-MS (M+1): 459.3.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[C:10]([N:13]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]1=[O:19])(=[O:12])[NH2:11]>C(#N)C.[Cl-].[Zn+2].[Cl-]>[C:14]([OH:19])(=[O:2])/[CH:15]=[CH:16]\[C:17](=[O:18])[NH:13][C:10](=[O:12])[NH2:11].[C:14]([OH:19])(=[O:2])/[CH:15]=[CH:16]\[C:17](=[O:18])[NH:13][C:10](=[O:12])[NH2:11].[C:14]([OH:19])(=[O:2])/[CH:15]=[CH:16]\[C:17](=[O:18])[NH:13][C:10](=[O:12])[NH2:11].[CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2]
Reactant: NC(=O)N1C(=O)C=CC1=O
Agent: CCC(CO)(CO)CO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: NC(=O)NC(=O)/C=C\C(=O)O
Reaction time: 5 h
Yield: 361.5 %

Procedure:
A mixture of 9.86 g of trimethylolpropane (0.074 moles), 31.3 g of N-carbamylmaleimide (0.224 moles) and 0.85 g of zinc chloride (0.00625 moles) in 215 mL of acetonitrile was heated to reflux. After 5 hours, the acetonitrile was evaporated to afford 40.7 g of trimethylolpropane trimaleurate as a white solid. M.P.: 70°-76° C.; 1H NMR (DMSO-d6): δ 10.5 (s, 3 H), 7.2-7.7 (m, 6 H), 6.3-6.6 (m, 6 H), 4.1 (s, 6 H), 1.35 (q, 2 H), 1.85 (t, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH2:34][CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH3:41]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH2:34][CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CN1CCCC1CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCCC1CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of 2-(2-aminoethyl)-1-methylpyrrolidine (5.6 g, 0.0435 mole) in tetrahydrofuran (6 ml) was added and the reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The solvents were removed under reduced pressure. The resulting solid was triturated in water (200 ml), collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, and water was added. Upon cooling, a solid precipitated. The solid was collected by filtration and air dried to give 4.46 g (64%) of solid. A 0.5-g sample was dried under high vacuum to give 0.40 g of title compound, mp 170°-172° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:33]O>>[CH3:33][O:17][C:16]([C:14]1[N:15]=[C:11]([NH:10][C:8](=[O:9])[CH:7]([C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[S:12][CH:13]=1)=[O:18]
Reactant: O=C(O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Reactant: CO
Agent: Cl
Product: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Yield: 39 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxylic acid (100 mg, 0.23 mmol) in methanol (10 mL) was treated with concentrated hydrochloric acid (1 mL) and then heated under reflux for 16 h. At this time, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and then washed with water (5 mL). The aqueous layer was further extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (40 mg, 39%) as a white foam: EI-HRMS m/e calcd for C25H26N2O4S (M+) 450.1613, found 450.1615.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[C:8]1([C@@H:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C=CCCC1
Reactant: OB(O)c1ccccc1
Solvent: O
Product: O=C1CCC[C@@H](c2ccccc2)C1
Yield: 80 %

Procedure:
Cyclohexenone (30 mg, 0.312 mmol), a rhodium complex of Rh(acac) (C2H4)2 (5.2 mg, 0.02 mmol), 50 mg of the polymer having the (R)-BINAP group (17) obtained in Preparation Example 1 and a phenylboronic acid (244 mg, 2.0 mmol) were reacted in 4 mL of water at 100° C. for 13 hours. The reaction mixture was filtered out to recover the polymer having the (R)-BINAP group. Meanwhile, the filtrate was extracted with ether and washed with saturated sodium hydrogen carbonate aqueous solution and saturated saline. It was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by preparative chromatography (hexyane:ethyl acetate=3:1) to obtain 43.5 mg of (R)-3-phenylcyclohexanone with optical purity of 97% ee in 80% yield.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([CH2:15][O:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:25])=[O:2])[C:5]=3[C:6]([OH:8])=[O:7])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: COC(=O)c1cccc(OCc2ccc3c(c2)OCO3)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(OCc2ccc3c(c2)OCO3)c1C(=O)O

Procedure:
A solution of 3-(benzo[1,3]dioxol-5-ylmethoxy)-phthalic acid dimethyl ester (1.6 g crude, 4.8 mmol) in reagent alcohol (100 mL) and 3 N sodium hydroxide (35 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (80 mL) and washed with methylene chloride (3×70 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×60 mL) and the combined organic layers was washed with water (2×70 mL), dried and concentrated to give 3-(benzo[1,3]dioxol-5-ylmethoxy)-phthalic acid as an off-white solid (1.2 g, 80% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:10][C:3]1[CH:4]=[C:5]([CH2:6][N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[CH:8]=[CH:9][C:2]=1[OH:1]
Reactant: CN1CCNCC1
Reactant: Cc1cc(C=O)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1cc(CN2CCN(C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A mixture of 4-hydroxy-3-methylbenzaldehyde (3.27 g, 24 mmol) and 1-methylpiperazine (2.7 g, 27.0 mmol) in dichloroethane (100 mL) was stirred at rt for 30 min. Sodium triacetoxyborohydride (6.2 g, 29 mmol) was added in portions and the reaction mixture was stirred at rt over night. A further portion of 1-methylpiperazine was added and stirring was continued for 24 h. Aqueous NaHCO3 (sat.) was added, the phases were separated and the aqueous phase was saturated with sodium chloride and extracted with DCM twice. The combined organic solutions were dried (MgSO4) and evaporated and the residue was purified by column chromatography on SiO2 using 0-20% MeOH in EtOAc:MeOH 95:5 as eluent. There was obtained 3.50 g (66%) of 9A as a solid. 1H NMR (500 MHz, CDCl3): δ 2.21 (2, 3H), 2.29 (s, 3H), 2.32-2.72 (bm, 8H), 3.42 (s, 2H), 6.55 (d, 1H), 6.90 (d, 1H), 7.02 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]([CH:19]([CH3:21])[CH3:20])[C:14](OCC)=[O:15]>>[CH:19]([CH:13]1[S:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[N:11][C:14]1=[O:15])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: Cc1ccccc1NC(N)=S
Product: Cc1ccccc1NC1=NC(=O)C(C(C)C)S1

Procedure:
Synthesis was performed from N-(2-methylphenyl)thiourea and ethyl 2-bromo-3-methylbutanoate according to Method C.